Sample records for human coronary endothelium

  1. Nitric oxide and coronary vascular endothelium adaptations in hypertension

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    Andrew S Levy


    Full Text Available Andrew S Levy*, Justin CS Chung*, Jeffrey T Kroetsch*, James WE RushDepartment of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada; *These authors contributed equally to this workAbstract: This review highlights a number of nitric oxide (NO-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca2+ control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been

  2. Decreased endothelium-dependent coronary vasomotion in healthy young smokers

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    Iwado, Yasuyoshi; Yoshinaga, Keiichiro; Furuyama, Hideto; Tsukamoto, Eriko; Tamaki, Nagara [Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita-Ku, Kita 15 Nishi 7, Sapporo, 060-8638 (Japan); Ito, Yoshinori; Noriyasu, Kazuyuki [Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo (Japan); Katoh, Chietsugu; Kuge, Yuji [Department of Tracer Kinetics, Hokkaido University Graduate School of Medicine, Sapporo (Japan)


    Chronic cigarette smoking alters coronary vascular endothelial response. To determine whether altered response also occurs in young individuals without manifest coronary disease we quantified coronary blood flow at rest, following adenosine vasodilator stress and during the cold pressor test in healthy young smokers. Myocardial blood flow (MBF) was quantified by oxygen-15 labelled water positron emission tomography in 30 healthy men aged from 20 to 35 years (18 smokers and 12 non-smokers, aged 27.4{+-}4.4 vs 26.3{+-}3.3). The smokers had been smoking cigarettes for 9.4{+-}4.9 pack-years. MBF was measured at rest, during intravenous adenosine triphosphate (ATP: 0.16 mg kg{sup -1} min{sup -1}) infusion (hyperaemic response), and during cold pressor test (CPT) (endothelial vasodilator response). Rest MBF and hyperaemic MBF did not differ significantly between the smokers and the non-smokers (rest: 0.86{+-}0.11 vs 0.92{+-}0.14 and ATP: 3.20{+-}1.12 vs 3.69{+-}0.76 ml g{sup -1} min{sup -1}; P=NS). Coronary flow reserve was similar between the two groups (smokers: 3.78{+-}1.83; non-smokers: 4.03{+-}0.68; P=NS). Although CPT induced a similar increase in rate-pressure product (RPP) in the smokers and the non-smokers (10,430{+-}1,820 vs 9,236{+-}1,356 beats min{sup -1} mmHg{sup -1}), CPT MBF corrected by RPP was significantly decreased in the smokers (0.65{+-}0.12 ml g{sup -1} min{sup -1}) compared with the non-smokers (0.87{+-}0.12 ml g{sup -1} min{sup -1}) (P<0.05). In addition, the ratio of CPT MBF to resting MBF was inversely correlated with pack-years (r=-0.57, P=0.014). Endothelium-dependent coronary artery vasodilator function is impaired in apparently healthy young smokers. (orig.)

  3. Known players, new interplay in atherogenesis: Chronic shear stress and carbamylated-LDL induce and modulate expression of atherogenic LR11 in human coronary artery endothelium. (United States)

    Bajari, Tarek M; Winnicki, Wolfgang; Gensberger, Eva-Theres; Scharrer, Susanna I; Regele, Heinz; Aumayr, Klaus; Kopecky, Chantal; Gmeiner, Bernhard M; Hermann, Marcela; Zeillinger, Robert; Sengölge, Gürkan


    In this study we examined whether low-density lipoprotein (LDL) receptor family members represent a link between blood flow characteristics and modified low-density lipoproteins involved in endothelial injury, a pivotal factor in atherogenesis. We demonstrated the expression of pro-atherogenic LDL receptor relative (LR11) for the first time in human coronary artery endothelial cells (HCAEC) in vitro and in vivo. Next, LR11 expression and regulation were explored in HCAEC cultured conventionally or on the inner surface of hollow fiber capillaries under exposure to shear stress for 10 days in the presence or absence of LDL. There was no LR11 expression under static conditions. When exposed to chronic low shear stress (2.5 dynes/cm²) transmembrane and soluble endothelial-LR11 were detected in high levels irrespective of the type of LDL added (carbamylated or native). In contrast, chronic high shear stress (25 dynes/cm²) inhibited the LR11-inducing effect of LDL such that transmembrane and soluble LR11 expression became non-detectable with native LDL. Carbamylated LDL significantly counteracted this atheroprotective effect of high shear stress as shown by lower, yet sustained expression of soluble and transmembrane LR11. Oxidised LDL showed similar effects compared to carbamylated LDL but caused significantly lower LR11 expression under chronic high shear stress. Medium from HCAEC under LR11-inducing conditions enhanced vascular smooth muscle cell migration, which was abrogated by the anti-LR11 antibody. Expression of LR11 depended entirely on p38MAPK phosphorylation. We conclude that coronary endothelial LR11 expression modulated by LDL and chronic shear stress contributes to atherogenesis. LR11 and p38MAPK are potential targets for prevention of atherosclerosis.

  4. Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle (United States)

    Yu, Xuan; Ma, Handong; Barman, Scott A.; Liu, Alexander T.; Sellers, Minga; Stallone, John N.; Prossnitz, Eric R.; White, Richard E.


    Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERα and ERβ, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BKCa) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BKCa channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BKCa channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens. PMID:21791623

  5. Endothelium-derived hyperpolarization and coronary vasodilation: diverse and integrated roles of epoxyeicosatrienoic acids, hydrogen peroxide and gap junctions (United States)

    Ellinsworth, David C.; Sandow, Shaun L.; Shukla, Nilima; Liu, Yanping; Jeremy, Jamie Y.; Gutterman, David D.


    Myocardial perfusion and coronary vascular resistance are regulated by signalling metabolites released from the local myocardium that act either directly on the vascular smooth muscle cells (VSMC) or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is endothelium-derived hyperpolarization (EDH) of the arteriolar smooth muscle, with epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H2O2) playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H2O2 are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H2O2 can also promote endothelial Ca2+-activated K+ channel activity secondary to the amplification of extracellular Ca2+ influx and Ca2+ mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions, or potentially lead to the release of a chemically-distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signalling involving EETs and H2O2 may be integrated; being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H2O2 regulate vessel tone, and also examines the hypothesis that myoendothelial microdomain signalling facilitates EDH activity in the human heart. PMID:26541094

  6. Genes Expressed in Human Tumor Endothelium (United States)

    St. Croix, Brad; Rago, Carlo; Velculescu, Victor; Traverso, Giovanni; Romans, Katharine E.; Montgomery, Elizabeth; Lal, Anita; Riggins, Gregory J.; Lengauer, Christoph; Vogelstein, Bert; Kinzler, Kenneth W.


    To gain a molecular understanding of tumor angiogenesis, we compared gene expression patterns of endothelial cells derived from blood vessels of normal and malignant colorectal tissues. Of over 170 transcripts predominantly expressed in the endothelium, 79 were differentially expressed, including 46 that were specifically elevated in tumor-associated endothelium. Several of these genes encode extracellular matrix proteins, but most are of unknown function. Most of these tumor endothelial markers were expressed in a wide range of tumor types, as well as in normal vessels associated with wound healing and corpus luteum formation. These studies demonstrate that tumor and normal endothelium are distinct at the molecular level, a finding that may have significant implications for the development of anti-angiogenic therapies.

  7. Polysaccharide coating of human corneal endothelium

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    Schroder, H D; Sperling, S


    Electron microscopy revealed the presence of a 600-1500 A thick layer of polysaccharide on the surface of human corneal endothelial cells. The surface layer was visualized by combined fixation and staining in a mixture of ruthenium red and osmium tetroxide. The coating material was stable...

  8. Cell pattern in adult human corneal endothelium.

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    Carlos H Wörner

    Full Text Available A review of the current data on the cell density of normal adult human endothelial cells was carried out in order to establish some common parameters appearing in the different considered populations. From the analysis of cell growth patterns, it is inferred that the cell aging rate is similar for each of the different considered populations. Also, the morphology, the cell distribution and the tendency to hexagonallity are studied. The results are consistent with the hypothesis that this phenomenon is analogous with cell behavior in other structures such as dry foams and grains in polycrystalline materials. Therefore, its driving force may be controlled by the surface tension and the mobility of the boundaries.

  9. Potentiation of phorbol ester-induced coronary vasoconstriction in dogs following endothelium disruption

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    Roberts, R.B.; Ku, D.D.


    In the present study, the effect of phorbol ester, 12-0-tetradecanoylphorbol 13-acetate (TPA), activation of protein kinase C on coronary vascular reactivity was studied in isolated dog coronary arteries. Addition of TPA (10-100 nM) produced a slow, time- and dose-dependent contraction reaching a maximum at approx 2-3 hrs and was essentially irreversible upon washing. Disruption of the endothelium(EC) greatly accelerated the development as well as increase the magnitude of TPA contraction (50-100%). Prior treatment of vessels with phentolamine (, cyproheptadine ( and ibuprofen ( did not alter the TPA contraction. Furthermore, in contrast to previously reported calcium-dependence of TPA contraction in other vessels, complete removal of extracellular calcium (Ca/sub 0/) or addition of nimodipine after TPA(30nM) resulted in only 32 +/- 4% and 25 +/- 3% reversal of TPA contraction, respectively. Addition of amiloride ( to 1mM), however, resulted in a dose-dependent reversal of TPA contraction. The results of the present study indicate that a similar activation of protein kinase C by TPA leads to potent coronary vasoconstriction, which is not completely dependent on Ca/sub 0/. More importantly, these results further support their hypothesis that EC also functions as an inhibitory barrier to prevent circulating vasoconstrictors from exerting their deleterious constrictory effects.

  10. The sulphydryl containing ACE inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis. (United States)

    Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia


    Pediatric and adult cancer patients, following the use of the antitumor drug Doxorubicin develop cardiotoxicity. Pharmacological protection of microvascular endothelium might produce a double benefit: (i) reduction of myocardial toxicity (the primary target of Doxorubicin action) and (ii) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells. This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor (ACEI) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium. We found that exposure of endothelial cells to Doxorubicin (0.1-1μM range) impaired cell survival by promoting their apoptosis. ERK1/2 related p53 activation, but not reactive oxygen species, was responsible for Doxorubicin induced caspase-3 cleavage. P53 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat. The previously described PI-3K/eNOS/endogenous fibroblast growth factor signaling was not involved in the protective effect, which, instead, could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat. Furthermore, considering the tumor environment, the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin. In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage, without affecting its antitumor efficacy. Thus, sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity.

  11. Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats. (United States)

    Borgo, M V; Claudio, E R G; Silva, F B; Romero, W G; Gouvea, S A; Moysés, M R; Santos, R L; Almeida, S A; Podratz, P L; Graceli, J B; Abreu, G R


    Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

  12. Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

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    Borgo, M.V.; Claudio, E.R.G.; Silva, F.B.; Romero, W.G.; Gouvea, S.A.; Moysés, M.R.; Santos, R.L.; Almeida, S.A. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal de Espírito Santo, Vitória, ES (Brazil); Podratz, P.L.; Graceli, J.B. [Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Abreu, G.R. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal de Espírito Santo, Vitória, ES (Brazil)


    Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

  13. Vascular Protective Effect of an Ethanol Extract of Camellia japonica Fruit: Endothelium-Dependent Relaxation of Coronary Artery and Reduction of Smooth Muscle Cell Migration

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    Sin-Hee Park


    Full Text Available Camellia japonica is a popular garden plant in Asia and widely used as cosmetic sources and traditional medicine. However, the possibility that C. japonica affects cardiovascular system remains unclear. The aim of the present study was to evaluate vascular effects of an extract of C. japonica. Vascular reactivity was assessed in organ baths using porcine coronary arteries and inhibition of proliferation and migration were assessed using human vascular smooth muscle cells (VSMCs. All four different parts, leaf, stem, flower, and fruits, caused concentration-dependent relaxations and C. japonica fruit (CJF extract showed the strongest vasorelaxation and its effect was endothelium dependent. Relaxations to CJF were markedly reduced by inhibitor of endothelial nitric oxide synthase (eNOS and inhibitor of PI3-kinase, but not affected by inhibitor of cyclooxygenase and endothelium-derived hyperpolarizing factor-mediated response. CJF induced activated a time- and concentration-dependent phosphorylation of eNOS in endothelial cells. Altogether, these studies have demonstrated that CJF is a potent endothelium-dependent vasodilator and this effect was involved in, at least in part, PI3K-eNOS-NO pathway. Moreover, CJF attenuated TNF-α induced proliferation and PDGF-BB induced migration of VSMCs. The present findings indicate that CJF could be a valuable candidate of herbal medicine for cardiovascular diseases associated with endothelial dysfunction and atherosclerosis.

  14. Impairment of Coronary Arteriolar Endothelium-Dependent Dilation after Multi-Walled Carbon Nanotube Inhalation: A Time-Course Study

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    Timothy R. Nurkiewicz


    Full Text Available Engineered nanomaterials have been developed for widespread applications due to many highly unique and desirable characteristics. The purpose of this study was to assess pulmonary inflammation and subepicardial arteriolar reactivity in response to multi-walled carbon nanotube (MWCNT inhalation and evaluate the time course of vascular alterations. Rats were exposed to MWCNT aerosols producing pulmonary deposition. Pulmonary inflammation via bronchoalveolar lavage and MWCNT translocation from the lungs to systemic organs was evident 24 h post-inhalation. Coronary arterioles were evaluated 24–168 h post-exposure to determine microvascular response to changes in transmural pressure, endothelium-dependent and -independent reactivity. Myogenic responsiveness, vascular smooth muscle reactivity to nitric oxide, and α-adrenergic responses all remained intact. However, a severe impact on endothelium-dependent dilation was observed within 24 h after MWCNT inhalation, a condition which improved, but did not fully return to control after 168 h. In conclusion, results indicate that MWCNT inhalation not only leads to pulmonary inflammation and cytotoxicity at low lung burdens, but also a low level of particle translocation to systemic organs. MWCNT inhalation also leads to impairments of endothelium-dependent dilation in the coronary microcirculation within 24 h, a condition which does not fully dissipate within 168 h. The innovations within the field of nanotechnology, while exciting and novel, can only reach their full potential if toxicity is first properly assessed.

  15. Transport of Gold Nanoparticles by Vascular Endothelium from Different Human Tissues (United States)

    Gromnicova, Radka; Kaya, Mehmet; Romero, Ignacio A.; Williams, Phil; Satchell, Simon; Sharrack, Basil; Male, David


    The selective entry of nanoparticles into target tissues is the key factor which determines their tissue distribution. Entry is primarily controlled by microvascular endothelial cells, which have tissue-specific properties. This study investigated the cellular properties involved in selective transport of gold nanoparticles (<5 nm) coated with PEG-amine/galactose in two different human vascular endothelia. Kidney endothelium (ciGENC) showed higher uptake of these nanoparticles than brain endothelium (hCMEC/D3), reflecting their biodistribution in vivo. Nanoparticle uptake and subcellular localisation was quantified by transmission electron microscopy. The rate of internalisation was approximately 4x higher in kidney endothelium than brain endothelium. Vesicular endocytosis was approximately 4x greater than cytosolic uptake in both cell types, and endocytosis was blocked by metabolic inhibition, whereas cytosolic uptake was energy-independent. The cellular basis for the different rates of internalisation was investigated. Morphologically, both endothelia had similar profiles of vesicles and cell volumes. However, the rate of endocytosis was higher in kidney endothelium. Moreover, the glycocalyces of the endothelia differed, as determined by lectin-binding, and partial removal of the glycocalyx reduced nanoparticle uptake by kidney endothelium, but not brain endothelium. This study identifies tissue-specific properties of vascular endothelium that affects their interaction with nanoparticles and rate of transport. PMID:27560685

  16. Endothelium-derived hyperpolarizing factor mediated relaxations in pig coronary arteries do not involve Gi/o proteins

    Institute of Scientific and Technical Information of China (English)

    Kwok Fu Jacobus NG; Susan Wai Sum LEUNG; Picky Ying Keung MAN; Paul M VANHOUTTE


    Aim: Endothelium-dependent relaxations to certain neurohumoral substances are mediated by pertussis toxin-sensitive Gi/o protein. Our experiments were designed to determine the role, if any, of pertussis toxin-sensitive G-proteins in relaxations attributed to endothelium-derived hyperpolarizing factor (EDHF). Methods: Pig coronary arterial rings with endothelia were suspended in organ chambers filled with Krebs-Ringer bicarbonate solution maintained at 37℃ and continuously aerated with 95%O2 and 5% CO2. Isometric tension was measured during contractions to prostaglandin F2, in the presence of indomethacin and Nω-nitro-L-arginine methyl ester (L-NAME). Results: Thrombin, the thrombin re-ceptor-activating peptide SFLLRN, bradykinin, substance P, and calcimycin pro-duced dose-dependent relaxations. These relaxations were not inhibited by prior incubation with pertussis toxin, but were abolished upon the addition of charyb-dotoxin plus apamin. Relaxations to the α2-adrenergic agonist UK14304 and those to serotonin were abolished in the presence of indomethacin and L-NAME. Conclusion: Unlike nitric oxide-mediated relaxations, EDHF-mediated relax-ations of pig coronary arteries do not involve pertussis toxin-sensitive pathways and are Gi/o protein independent.

  17. Cultivation of Human Microvascular Endothelial Cells on Topographical Substrates to Mimic the Human Corneal Endothelium

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    Jie Shi Chua


    Full Text Available Human corneal endothelial cells have a limited ability to replicate in vivo and in vitro. Allograft transplantation becomes necessary when an accident or trauma results in excessive cell loss. The reconstruction of the cornea endothelium using autologous cell sources is a promising alternative option for therapeutic or in vitro drug testing applications. The native corneal endothelium rests on the Descemet’s membrane, which has nanotopographies of fibers and pores. The use of synthetic topographies mimics the native environment, and it is hypothesized that this can direct the behavior and growth of human microvascular endothelial cells (HMVECs to resemble the corneal endothelium. In this study, HMVECs are cultivated on substrates with micron and nano-scaled pillar and well topographies. Closely packed HMVEC monolayers with polygonal cells and well-developed tight junctions were formed on the topographical substrates. Sodium/potassium (Na+/K+ adenine triphosphatase (ATPase expression was enhanced on the microwells substrate, which also promotes microvilli formation, while more hexagonal-like cells are found on the micropillars samples. The data obtained suggests that the use of optimized surface patterning, in particular, the microtopographies, can induce HMVECs to adopt a more corneal endothelium-like morphology with similar barrier and pump functions. The mechanism involved in cell contact guidance by the specific topographical features will be of interest for future studies.

  18. The human corneal endothelium in keratoconus: A specular microscopic study. (United States)

    Laing, R A; Sandstrom, M M; Berrospi, A R; Leibowitz, H M


    The corneal endothelium in 12 cases of keratoconus was examined with the clinical specular microscope. There appeared to be an increase in cellular pleomorphism with many cells considerably smaller than normal distributed throughout the endothelial cell population. There were also many large, elongated cells whose long axis showed a definite tendency to assume a similar directional orientation. The long axis of these cells seemed oriented toward the apex of the cone, and the cells appeared to have been stretched by the ectatic process. Many endothelial cells contained dark intracellular structures. Their significance is unknown. The single cornea in this series with a history of acute hydrops contained a localized area in which the endothelial cells were seven to ten times larger than normal. This suggests that rupture of the endothelium and Descemet's membrane, responsible for the acute edematous process, occurs at this site, and that the adjacent cells enlarged to fill the defect.

  19. Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats (United States)

    Delgado, Nathalie T. B.; Rouver, Wender do N.; Freitas-Lima, Leandro C.; de Paula, Tiago D.-C.; Duarte, Andressa; Silva, Josiane F.; Lemos, Virgínia S.; Santos, Alexandre M. C.; Mauad, Helder; Santos, Roger L.; Moysés, Margareth R.


    prevented the decreasing in plasmatic nitrite. We observed a reduction in total cholesterol and LDL in the Sham-PHE group. The treatment with PHE enhances the endothelium-dependent coronary relaxation and improves cardiovascular parameters, which suggests a therapeutic role of PHE. PMID:28101057

  20. Pathophysiology of vascular endothelium and circulating platelets : implications for coronary revascularisation and treatment

    NARCIS (Netherlands)

    Amoroso, G; van Veldhuisen, DJ; Tio, RA; Mariani, M


    Constant vasodilatation, inhibition of platelet and leukocyte adhesion, and local thrombolysis are the mechanisms through which an intact endothelial layer exerts its protective action on coronary circulation. A loss in these features is not only the first step in the development of atherosclerosis,

  1. Glucose-coated gold nanoparticles transfer across human brain endothelium and enter astrocytes in vitro.

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    Radka Gromnicova

    Full Text Available The blood-brain barrier prevents the entry of many therapeutic agents into the brain. Various nanocarriers have been developed to help agents to cross this barrier, but they all have limitations, with regard to tissue-selectivity and their ability to cross the endothelium. This study investigated the potential for 4 nm coated gold nanoparticles to act as selective carriers across human brain endothelium and subsequently to enter astrocytes. The transfer rate of glucose-coated gold nanoparticles across primary human brain endothelium was at least three times faster than across non-brain endothelia. Movement of these nanoparticles occurred across the apical and basal plasma membranes via the cytosol with relatively little vesicular or paracellular migration; antibiotics that interfere with vesicular transport did not block migration. The transfer rate was also dependent on the surface coating of the nanoparticle and incubation temperature. Using a novel 3-dimensional co-culture system, which includes primary human astrocytes and a brain endothelial cell line hCMEC/D3, we demonstrated that the glucose-coated nanoparticles traverse the endothelium, move through the extracellular matrix and localize in astrocytes. The movement of the nanoparticles through the matrix was >10 µm/hour and they appeared in the nuclei of the astrocytes in considerable numbers. These nanoparticles have the correct properties for efficient and selective carriers of therapeutic agents across the blood-brain barrier.

  2. Aronia melanocarpa juice, a rich source of polyphenols, induces endothelium-dependent relaxations in porcine coronary arteries via the redox-sensitive activation of endothelial nitric oxide synthase. (United States)

    Kim, Jong Hun; Auger, Cyril; Kurita, Ikuko; Anselm, Eric; Rivoarilala, Lalainasoa Odile; Lee, Hyong Joo; Lee, Ki Won; Schini-Kerth, Valérie B


    This study examined the ability of Aronia melanocarpa (chokeberry) juice, a rich source of polyphenols, to cause NO-mediated endothelium-dependent relaxations of isolated coronary arteries and, if so, to determine the underlying mechanism and the active polyphenols. A. melanocarpa juice caused potent endothelium-dependent relaxations in porcine coronary artery rings. Relaxations to A. melanocarpa juice were minimally affected by inhibition of the formation of vasoactive prostanoids and endothelium-derived hyperpolarizing factor-mediated responses, and markedly reduced by N(ω)-nitro-l-arginine (endothelial NO synthase (eNOS) inhibitor), membrane permeant analogs of superoxide dismutase and catalase, PP2 (Src kinase inhibitor), and wortmannin (PI3-kinase inhibitor). In cultured endothelial cells, A. melanocarpa juice increased the formation of NO as assessed by electron paramagnetic resonance spectroscopy using the spin trap iron(II)diethyldithiocarbamate, and reactive oxygen species using dihydroethidium. These responses were associated with the redox-sensitive phosphorylation of Src, Akt and eNOS. A. melanocarpa juice-derived fractions containing conjugated cyanidins and chlorogenic acids induced the phosphorylation of Akt and eNOS. The present findings indicate that A. melanocarpa juice is a potent stimulator of the endothelial formation of NO in coronary arteries; this effect involves the phosphorylation of eNOS via the redox-sensitive activation of the Src/PI3-kinase/Akt pathway mostly by conjugated cyanidins and chlorogenic acids.

  3. Pycnogenol, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans. (United States)

    Nishioka, Kenji; Hidaka, Takayuki; Nakamura, Shuji; Umemura, Takashi; Jitsuiki, Daisuke; Soga, Junko; Goto, Chikara; Chayama, Kazuaki; Yoshizumi, Masao; Higashi, Yukihito


    Pycnogenol, an extract of bark from the French maritime pine, Pinus pinaster Ait., consists of a concentrate of water-soluble polyphenols. Pycnogenol contains the bioflavonoids catechin and taxifolin as well as phenolcarbonic acids. Antioxidants, such as bioflavonoids, enhance endothelial nitric oxide (NO) synthase expression and subsequent NO release from endothelial cells. The purpose of this study was to determine Pycnogenol's effects on endothelium-dependent vasodilation in humans. This was a double-blind, randomized, placebo and active drug study. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, in healthy young men before and after 2 weeks of daily oral administration of Pycnogenol (180 mg/day) (n=8) or placebo (n=8). FBF was measured by using strain-gauge plethysmography. Neither the placebo nor Pycnogenol altered forearm or systemic hemodynamics. Pycnogenol, but not placebo, augmented FBF response to ACh, from 13.1 +/- 7.0 to 18.5 +/- 4.0 mL/min per 100 mL tissue (pPycnogenol groups. The administration of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, completely abolished Pycnogenol-induced augmentation of the FBF response to ACh. These findings suggest that Pycnogenol augments endothelium-dependent vasodilation by increasing in NO production. Pycnogenol would be useful for treating various diseases whose pathogeneses involve endothelial dysfunction.

  4. Endothelium specific matrilysin (MMP-7) expression in human cancers

    NARCIS (Netherlands)

    Sier, C.F.M.; Hawinkels, L.J.A.C.; Zijlmans, H.J.M.A.A.; Zuidwijk, K.; Jonge de; Muller, E.S.M.; Ferreira, V.; Hanemaaijer, R.; Mulder-Stapel, A.A.; Kenter, G.G.; Verspaget, H.W.; Gorter, A.


    Over-expression of matrilysin (MMP-7) is predominantly associated with epithelial (pre)malignant cells. In the present study MMP-7 expression is also found in endothelial cells in various human cancer types. Endothelial MMP-7 was associated with CD34 and/or CD105 expression. These immunohistochemica

  5. Mechanisms underlying the endothelium-dependent vasodilatory effect of an aqueous extract of Elaeis Guineensis Jacq. (Arecaceae) in porcine coronary artery rings. (United States)

    Ndiaye, Mamadou; Anselm, Eric; Séne, Madièye; Diatta, Williams; Dièye, Amadou Moctar; Faye, Babacar; Schini-Kerth, Valérie B


    This study was undertaken to investigate the vasodilatory effect of an aqueous extract of Elaeis guineensis Jacq (EGE) in the porcine coronary artery and elicit its possible mechanism(s) of action. Vascular effects of crude extract of dried and powdered leaves of Elaeis guineensis were evaluated on isolated coronary arteries on organ chambers. Determination of eNOS expression and the phosphorylation level of eNOS were determined by Western blot analysis. In the presence of indomethacin, EGE caused pronounced relaxations in endothelium-intact but not in endothelium-denuded coronary artery rings. Relaxations to EGE were significantly reduced by N(ω)-nitro-L-arginine (L-NA, a competitive inhibitor of NO synthase), slightly but not significantly by charybdotoxin plus apamin (two potent inhibitors of EDHF-mediated responses) and abolished by the combination of L-NA and charybdotoxin plus apamin. Relaxations to EGE were abolished by the membrane permeant, SOD mimetic, MnTMPyP, and significantly reduced by wortmannin, an inhibitor of PI3-kinase. Exposure of endothelial cells to EGE increased the phosphorylation level of eNOS at Ser1177 in a time and concentration-dependent manner. MnTMPyP abolished the EGE-induced phosphorylation of eNOS.In conclusion, the obtained data indicate that EGE induces pronounced endothelium-dependent relaxations of the porcine coronary artery, which involve predominantly NO. The stimulatory effect of EGE on eNOS involves the redox-sensitive phosphorylation of eNOS at Ser1177 most likely via the PI3-kinase pathway.

  6. Does vitamin C or its combination with vitamin E improve radial artery endothelium-dependent vasodilatation in patients awaiting coronary artery bypass surgery?


    Uzun, Alper; Yener, Umit; Cicek, Omer Faruk; Yalcinkaya, Adnan; Diken, Adem; Ozkan, Turgut; Ulas, Mahmut; Yener, Ozlem; Turkvatan, Aysel


    Background We evaluated the vasodilatory effects of two antioxidants, vitamins C (ascorbic acid) and E (α-tocopherol), on radial artery and endothelium-dependent responses in patients awaiting coronary artery bypass surgery. Methods The study was performed in three groups. The first group took 2 g of vitamin C orally (n = 31, vitamin C group), the second group took 2 g of vitamin C with 600 mg of vitamin E orally (n = 31, vitamins C + E group), and the third group took no medication (n = 31, ...

  7. Delay in liver bud development during early embryogenesis leads to violation of epicardium formation and its epithelial-to-mesenchymal transformation, but do not affect coronary endothelium formation

    Directory of Open Access Journals (Sweden)

    Pototskaya O. Yu.


    Full Text Available Despite intensive investigation of heart embryogenesis the origin of coronary endothelium is still under debate. Existence of close interrelation between proepicardium, liver bud, sinus venosus and early coronary vessels is obvious, but the nature of this interconnection is unclear as well as exact source of endothelial cells. Thus, the purpose of our research was to investigate the effect of inhibition of liver bud development on formation of coronary vessels. To inhibit the liver bud we injected aminoguanidine sulfate into the yolk sack of chick embryos on 14 stage of development by HH (first group - to prevent contact between proepicardium and liver, and on 16 stage (second group to allow contact between proepicardium and liver during a short period of time. In the first group it was observed the violation of epicardium formation and early death during first 3 days of incubation. At embryos it was revealed thinning of myocardium and atrio-ventricular cushions, abnormal looping – presumably due to the absence of epicardium. The death was caused by heart insufficiency. In the second group it was observed the beginning of epicardium formation, but the heart defects were the same as in the first group – presumably due to the absence of epicardium-derived cells. At embryos of this group, who survived till 26 stage of development (4.5 day of incubation, despite absence of cellular component in subepicardial space and almost completely absence of liver, we observed formation of coronary vessels. They were concentrated on the dorsal surface of atrio-vetricular channel and were presented by continuation of endothelium of the sinus venosus.

  8. Exercise training-induced adaptations in mediators of sustained endothelium-dependent coronary artery relaxation in a porcine model of ischemic heart disease (United States)

    Heaps, Cristine L.; Robles, Juan Carlos; Sarin, Vandana; Mattox, Mildred L.; Parker, Janet L.


    Objective Test the hypothesis that exercise training enhances sustained relaxation to persistent endothelium-dependent vasodilator exposure via increased nitric oxide contribution in small coronary arteries of control and ischemic hearts. Methods Yucatan swine were designated to a control group or a group in which an ameroid constrictor was placed around the proximal LCX. Subsequently, pigs from both groups were assigned to exercise (5 days/week; 16 weeks) or sedentary regimens. Coronary arteries (~100–350 μm) were isolated from control pigs and from both nonoccluded and collateral-dependent regions of chronically-occluded hearts. Results In arteries from control pigs, training significantly enhanced relaxation responses to increasing concentrations of bradykinin (10−10 to 10−7 M) and sustained relaxation to a single bradykinin concentration (30 nM), which were abolished by NOS inhibition. Training also significantly prolonged bradykinin-mediated relaxation in collateral-dependent arteries of occluded pigs, which was associated with more persistent increases in endothelial cellular Ca2+ levels, and reversed with NOS inhibition. Protein levels for eNOS and p-eNOS-(Ser1179), but not caveolin-1, Hsp90, or Akt, were significantly increased with occlusion, independent of training state. Conclusions Exercise training enhances sustained relaxation to endothelium-dependent agonist stimulation in small arteries of control and ischemic hearts by enhanced nitric oxide contribution and endothelial Ca2+ responses. PMID:24447072

  9. Coincident expression and distribution of melanotransferrin and transferrin receptor in human brain capillary endothelium. (United States)

    Rothenberger, S; Food, M R; Gabathuler, R; Kennard, M L; Yamada, T; Yasuhara, O; McGeer, P L; Jefferies, W A


    One method of iron transport across the blood brain barrier (BBB) involves the transferrin receptor (TR), which is localized to the specialized brain capillary endothelium. The melanotransferrin (MTf) molecule, also called p97, has been widely described as a melanoma specific molecule, however, its expression in brain tissues has not been addressed. MTf has a high level of sequence homology to transferrin (Tf) and lactoferrin, but is unusual because it predominantly occurs as a membrane bound, glycosylphosphatidylinositol (GPI) anchored molecule, but can also occur as a soluble form. We have recently demonstrated that GPI-anchored MTf provides a novel route for cellular iron uptake which is independent of Tf and its receptor. Here we consider whether MTf may have a role in the transport of iron across the BBB. The distributions of MTf, Tf and the TR were studied immunohistochemically in human brain tissues. The distributions of MTf and TR were remarkably similar, and quite different from that of Tf. In all brain tissues examined, MTf and the TR were highly localized to capillary endothelium, while Tf itself was mainly localized to glial cells. These data suggest that MTf may play a role in iron transport within the human brain.

  10. Construction of human liver cancer vascular endothelium cDNA expression library and screening of the endothelium-associated antigen genes

    Institute of Scientific and Technical Information of China (English)

    Xing Zhong; Yu-Liang Ran; Jin-Ning Lou; Dong Hu; Long Yu; Yu-Shan Zhang; Zhuan Zhou; Zhi-Hua Yang


    AIM: To gain tumor endothelium associated antigen genes from human liver cancer vascular endothelial cells (HLCVECs)cDNA expression library, so as to find some new possible targets for the diagnosis and therapy of liver tumor.METHODS: HLCVECs were isolated and purified from a fresh hepatocellular carcinoma tissue sample, and were cultured and proliferated in vitro. A cDNA expression library was constructed with the mRNA extracted from HLCVECs.Anti-sera were prepared from immunized BALB/c mice through subcutaneous injection with high dose of fixed HLCVECs, and were then tested for their specificity against HLCVECs and angiogenic effectsin vitro, such as inhibiting proliferation and inducing apoptosis of tumor endothelial cells, using immunocytochemistry, immunofiuorescence,cell cycle analysis and MTT assays, etc. The identified xenogeneic sera from immunized mice were employed to screen the library of HLCVECs by modified serological analyses of recombinant cDNA expression libraries (SEREX).The positive clones were sequenced and analyzed by bioinformatics.RESULTS: The primary cDNA library consisted of 2x106recombinants. Thirty-six positive clones were obtained from6×10s independent clones by immunoscreening. Bio-informatics analysis of cDNA sequences indicated that 36 positive clones represented 18 different genes. Among them, 3 were new genes previously unreported, 2 of which were hypothetical genes. The other L5 were already known ones. Series analysis of gene expression (SAGE) database showed that ERP70,GRP58, GAPDH, SSB, S100A6, BMP-6, DVS27, HSP70 and NAC alpha in these genes were associated with endothelium and angiogenesis, but their effects on HLCVECs were still unclear. GAPDH, S100A6, BMP-6 and hsp70 were identified by SEREX in other tumor cDNA expression libraries.CONCLUSION: By screening of HLCVECs cDNA expression library using sera from immunized mice with HLCVECs,the functional genes associated with tumor endothelium or angiogenesis were identified. The

  11. Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. (United States)

    Stanley, Christopher P; Hind, William H; Tufarelli, Cristina; O'Sullivan, Saoirse E


    The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown. Using wire myography, the vascular effects of CBD were assessed in human mesenteric arteries, and the mechanisms of action probed pharmacologically. CBD-induced intracellular signalling was characterized using human aortic endothelial cells (HAECs). CBD caused acute, non-recoverable vasorelaxation of human mesenteric arteries with an Rmax of ∼ 40%. This was inhibited by cannabinoid receptor 1 (CB1) receptor antagonists, desensitization of transient receptor potential channels using capsaicin, removal of the endothelium, and inhibition of potassium efflux. There was no role for cannabinoid receptor-2 (CB2) receptor, peroxisome proliferator activated receptor (PPAR)γ, the novel endothelial cannabinoid receptor (CBe), or cyclooxygenase. CBD-induced vasorelaxation was blunted in males, and in patients with type 2 diabetes or hypercholesterolemia. In HAECs, CBD significantly reduced phosphorylated JNK, NFκB, p70s6 K and STAT5, and significantly increased phosphorylated CREB, ERK1/2, and Akt levels. CBD also increased phosphorylated eNOS (ser1177), which was correlated with increased levels of ERK1/2 and Akt levels. CB1 receptor antagonism prevented the increase in eNOS phosphorylation. This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

  12. Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans. (United States)

    Spilk, Samson; Herr, Michael D; Sinoway, Lawrence I; Leuenberger, Urs A


    Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole + L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial Po2 ~37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole + L-NMMA reduced (P vasodilation and could be particularly relevant when other vasodilator systems are impaired.

  13. Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.

    Directory of Open Access Journals (Sweden)

    Branka Stancevic

    Full Text Available These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT. Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x, and a hypoxia-inducible dual-binding HIF-2α-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.

  14. Angiotensin II receptor mRNA expression and vasoconstriction in human coronary arteries

    DEFF Research Database (Denmark)

    Wackenfors, Angelica; Pantev, Emil; Emilson, Malin;


    Angiotensin II is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, heart failure and atherosclerosis. In the present study, angiotensin II receptor mRNA expression levels were quantified by real-time polymerase chain reaction and the vasocontractile responses...... to angiotensin II were characterised by in vitro pharmacology in endothelium-denuded human coronary arteries. Angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression levels were significantly down-regulated in arteries from patients with heart failure as compared to controls. The angiotensin II...

  15. Sevoflurane mitigates shedding of hyaluronan from the coronary endothelium, also during ischemia/reperfusion: an ex vivo animal study

    Directory of Open Access Journals (Sweden)

    Chen C


    Full Text Available Congcong Chen,1,3 Daniel Chappell,2,3 Thorsten Annecke,2,3 Peter Conzen,2 Matthias Jacob,2,3 Ulrich Welsch,4 Bernhard Zwissler,2 Bernhard F Becker3 1Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China; 2Clinic of Anesthesiology, Ludwig-Maximilians-University, Munich, Germany; 3Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany; 4Institute of Anatomy, Ludwig-Maximilians-University, Munich, Germany Abstract: Glycosaminoglycan hyaluronan (HA, a major constituent of the endothelial glycocalyx, helps to maintain vascular integrity. Preconditioning the heart with volatile anesthetic agents protects against ischemia/reperfusion injury. We investigated a possible protective effect of sevoflurane on the glycocalyx, especially on HA. The effect of pre-ischemic treatment with sevoflurane (15 minutes at 2% vol/vol gas on shedding of HA was evaluated in 28 isolated, beating guinea pig hearts, subjected to warm ischemia (20 minutes at 37°C followed by reperfusion (40 minutes, half with and half without preconditioning by sevoflurane. HA concentration was measured in the coronary effluent. Over the last 20 minutes of reperfusion hydroxyethyl starch (1 g% was continuously infused and the epicardial transudate collected over the last 5 minutes for measuring the colloid extravasation. Additional hearts were fixed by perfusion after the end of reperfusion for immunohistology and electron microscopy. Sevoflurane did not significantly affect post-ischemic oxidative stress, but strongly inhibited shedding of HA during the whole period, surprisingly even prior to ischemia. Immunohistology demonstrated that heparan sulfates and SDC1 of the glycocalyx were also preserved by sevoflurane. Electron microscopy revealed shedding of glycocalyx caused by ischemia and a mostly intact glycocalyx in hearts exposed to sevoflurane. Coronary vascular permeability of the

  16. LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans. (United States)

    Michel, C Charles; Nanjee, M Nazeem; Olszewski, Waldemar L; Miller, Norman E


    The mechanisms by which LDLs and HDLs cross the vascular endothelium from plasma into interstitial fluid are not understood, and have never been studied in humans in vivo. We determined whether the plasma-to-lymph clearance rates of LDL and HDL conform with those predicted by passive ultrafiltration through intercellular pores, or if it is necessary to invoke an active process such as receptor-mediated transcytosis. Plasma and afferent peripheral lymph were collected under steady-state conditions from 30 healthy men, and assayed for seven globular proteins of molecular radii 2.89-8.95 nm, complement C3, and apo AI, apo AII, and apo B. Plasma-to-lymph clearance rates of the seven proteins fitted the relation expected for molecules of their size when transported through two populations of pores of radius 4.95 and 20.1 nm. The same model parameters were then found to accurately predict the clearance rates of both HDL and LDL. The apparent clearance of complement C3, previously shown to be secreted by cultured endothelium, exceeded that predicted by the model. We conclude that the transport of HDL and LDL from plasma into interstitial fluid across the peripheral vascular endothelium in healthy humans can be explained by ultrafiltration without invoking an additional active process such as transcytosis.

  17. Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids.

    Directory of Open Access Journals (Sweden)

    Cyrill Géraud

    Full Text Available Liver sinusoidal endothelium is strategically positioned to control access of fluids, macromolecules and cells to the liver parenchyma and to serve clearance functions upstream of the hepatocytes. While clearance of macromolecular debris from the peripheral blood is performed by liver sinusoidal endothelial cells (LSECs using a delicate endocytic receptor system featuring stabilin-1 and -2, the mannose receptor and CD32b, vascular permeability and cell trafficking are controlled by transcellular pores, i.e. the fenestrae, and by intercellular junctional complexes. In contrast to blood vascular and lymphatic endothelial cells in other organs, the junctional complexes of LSECs have not yet been consistently characterized in molecular terms. In a comprehensive analysis, we here show that LSECs express the typical proteins found in endothelial adherens junctions (AJ, i.e. VE-cadherin as well as α-, β-, p120-catenin and plakoglobin. Tight junction (TJ transmembrane proteins typical of endothelial cells, i.e. claudin-5 and occludin, were not expressed by rat LSECs while heterogenous immunreactivity for claudin-5 was detected in human LSECs. In contrast, junctional molecules preferentially associating with TJ such as JAM-A, B and C and zonula occludens proteins ZO-1 and ZO-2 were readily detected in LSECs. Remarkably, among the JAMs JAM-C was considerably over-expressed in LSECs as compared to lung microvascular endothelial cells. In conclusion, we show here that LSECs form a special kind of mixed-type intercellular junctions characterized by co-occurrence of endothelial AJ proteins, and of ZO-1 and -2, and JAMs. The distinct molecular architecture of the intercellular junctional complexes of LSECs corroborates previous ultrastructural findings and provides the molecular basis for further analyses of the endothelial barrier function of liver sinusoids under pathologic conditions ranging from hepatic inflammation to formation of liver metastasis.

  18. Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium

    NARCIS (Netherlands)

    Jain, Abhishek; Meer, van der Andries D.; Papa, Anne-Laure; Barrile, Riccardo; Lai, Angela; Schlechter, Benjamin L.; Otieno, Monicah A.; Louden, Calvert S.; Hamilton, Geraldine A.; Michelson, Alan D.; Frelinger, Andrew L.; Ingber, Donald E.


    The vascular endothelium and shear stress are critical determinants of physiological hemostasis and platelet function in vivo, yet current diagnostic and monitoring devices do not fully incorporate endothelial function under flow in their assessment and, therefore, they can be unreliable and inaccur

  19. In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium. (United States)

    Grosicki, Marek; Wójcik, Tomasz; Chlopicki, Stefan; Kieć-Kononowicz, Katarzyna


    It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium.

  20. Glutaminolysis is Essential for Energy Production and Ion Transport in Human Corneal Endothelium

    Directory of Open Access Journals (Sweden)

    Wenlin Zhang


    Full Text Available Corneal endothelium (CE is among the most metabolically active tissues in the body. This elevated metabolic rate helps the CE maintain corneal transparency by its ion and fluid transport properties, which when disrupted, leads to visual impairment. Here we demonstrate that glutamine catabolism (glutaminolysis through TCA cycle generates a large fraction of the ATP needed to maintain CE function, and this glutaminolysis is severely disrupted in cells deficient in NH3:H+ cotransporter Solute Carrier Family 4 Member 11 (SLC4A11. Considering SLC4A11 mutations leads to corneal endothelial dystrophy and sensorineural deafness, our results indicate that SLC4A11-associated developmental and degenerative disorders result from altered glutamine catabolism. Overall, our results describe an important metabolic mechanism that provides CE cells with the energy required to maintain high level transport activity, reveal a direct link between glutamine metabolism and developmental and degenerative neuronal diseases, and suggest an approach for protecting the CE during ophthalmic surgeries.

  1. A chemically defined 2,3-trans procyanidin fraction from willow bark causes redox-sensitive endothelium-dependent relaxation in porcine coronary arteries. (United States)

    Kaufeld, Aurica M; Pertz, Heinz H; Kolodziej, Herbert


    Extracts of the bark of willow species (Salix spp.) are popular herbal remedies to relieve fever and inflammation. The effects are attributed to salicin and structurally related phenolic metabolites, while polyphenols including procyanidins are suggested to contribute to the overall effect of willow bark. This study aimed at investigating the relaxant response to a highly purified and chemically defined 2,3-trans procyanidin fraction in porcine coronary arteries. The procyanidin sample produced a concentration-dependent relaxation in U46619-precontracted tissues. Relaxation was predominantly mediated through the redox-sensitive activation of the endothelial phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, leading to the subsequent activation of endothelial nitric oxide synthase (eNOS) by phosphorylation, as evidenced by Western blotting using human umbilical vein endothelial cells (HUVECs). That the relaxant response to Salix procyanidins was reactive oxygen species (ROS)-dependent with O2(-) as the key species followed from densitometric analysis using 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA assay) and employment of various ROS inhibitors, respectively. The data also suggested the modification of intracellular Ca(2+) levels and KCa channel functions. In addition, our organ bath studies showed that Salix procyanidins reversed the abrogation of the relaxant response to bradykinin by oxidized low-density lipoproteins (oxLDL) in coronary arteries, suggesting a vasoprotective effect of willow bark against detrimental oxLDL in pathological conditions. Taken together, our findings suggest for the first time that 2,3-trans procyanidins may contribute not only to the beneficial effects of willow bark but also to health-promoting benefits of diverse natural products of plant origin.

  2. Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial

    Energy Technology Data Exchange (ETDEWEB)

    Harel, Francois [Montreal Heart Institute, Research Center, Montreal, QC (Canada); Universite de Montreal, Department of Nuclear Medicine, Montreal, Quebec (Canada); Langleben, David; Abikhzer, Gad [McGill University, Lady Davis Institute and Jewish General Hospital, Montreal, Quebec (Canada); Provencher, Steve; Guimond, Jean [Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec (Canada); Fournier, Alain; Letourneau, Myriam [INRS-Institut Armand-Frappier, Laval, Quebec (Canada); Finnerty, Vincent; Nguyen, Quang T.; Levac, Xavier [Montreal Heart Institute, Research Center, Montreal, QC (Canada); Mansour, Asmaa; Guertin, Marie-Claude [Montreal Health Innovation Coordination Center, Montreal, QC (Canada); Dupuis, Jocelyn [Montreal Heart Institute, Research Center, Montreal, QC (Canada); Universite de Montreal, Department of Medicine, Montreal, Quebec (Canada)


    The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi {sup 99m}Tc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∝50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using {sup 99m}Tc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and

  3. MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium (United States)

    Cerutti, Camilla; Edwards, Laura J.; de Vries, Helga E.; Sharrack, Basil; Male, David K.; Romero, Ignacio A.


    Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation. PMID:28358058

  4. Whole blood viscosity and erythrocyte deformability are related to endothelium-dependent vasodilation and coronary risk in the elderly. The prospective investigation of the vasculature in Uppsala seniors (PIVUS) study. (United States)

    Sandhagen, Bo; Lind, Lars


    It has previously been shown that a high hemoglobin value, a major determinant of whole blood viscosity (WBV), predicts cardiovascular events. One putative mechanism might be an impaired endothelial function. Erythrocyte deformability is another rheologic feature of the erythrocyte being of importance for the flow properties of the blood, especially in the capillaries. The present study evaluates the relationships between blood viscosity, erythrocyte deformability assessed as erythrocyte fluidity (EF), coronary risk and endothelial vasodilatory function. In the population-based PIVUS study (1016 subjects aged 70); endothelium-dependent vasodilation (EDV) was evaluated by the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). WBV, plasma viscosity (PV) and EF were measured in a random sample of 573 subjects. WBV and PV were positively and EF negatively related to Framingham risk score. EDV was inversely related to both whole blood and plasma viscosity. FMD was not related to any rheologic variable. In multiple regression analyses WBV and EF were significantly related to EDV independently of gender, hypertension, smoking, hypercholesterolemia, obesity and diabetes. Acetylcholine-induced vasodilation in the forearm, but not FMD, was negatively related to whole blood viscosity and positively related to EF independently of traditional risk factors in elderly subjects, indicating a pathophysiological link between impaired hemorheology and coronary risk.

  5. Expression and localization of claudins-3 and -12 in transformed human brain endothelium

    Directory of Open Access Journals (Sweden)

    Schrade Anja


    Full Text Available Abstract Background The aim of this study was to characterize the hCMEC/D3 cell line, an in vitro model of the human Blood Brain Barrier (BBB for the expression of brain endothelial specific claudins-3 and -12. Findings hCMEC/D3 cells express claudins-3 and -12. Claudin-3 is distinctly localized to the TJ whereas claudin -12 is observed in the perinuclear region and completely absent from TJs. We show that the expression of both proteins is lost in cell passage numbers where the BBB properties are no longer fully conserved. Expression and localization of claudin-3 is not modulated by simvastatin shown to improve barrier function in vitro and also recommended for routine hCMEC/D3 culture. Conclusions These results support conservation of claudin-3 and -12 expression in the hCMEC/D3 cell line and make claudin-3 a potential marker for BBB characteristics in vitro.

  6. LPS from Porphyromonas gingivalis increases the sensitivity of contractile response mediated by endothelin-B (ET(B)) receptors in cultured endothelium-intact rat coronary arteries

    DEFF Research Database (Denmark)

    Ghorbani, Bahareh; Holmstrup, Palle; Edvinsson, Lars;


    The purpose of our study was to examine if lipopolysaccharide (LPS) from Porphyromonas gingivalis (P.g.) modifies the vasomotor responses to Endothelin-1 (ET-1) and Sarafotoxin 6c (S6c) in rat coronary arteries. The arteries were studied directly or following organ culture for 24h in absence and ...

  7. Proteomic identification of dysferlin-interacting protein complexes in human vascular endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Cleo; Utokaparch, Soraya; Sharma, Arpeeta; Yu, Carol; Abraham, Thomas; Borchers, Christoph [UBC James Hogg Research Centre, Institute for Heart and Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia (Canada); University of Victoria - Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia (Canada); Bernatchez, Pascal, E-mail: [UBC James Hogg Research Centre, Institute for Heart and Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia (Canada); University of Victoria - Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia (Canada)


    Highlights: Black-Right-Pointing-Pointer Bi-directional (inward and outward) movement of GFP-dysferlin in COS-7 cells. Black-Right-Pointing-Pointer Dysferlin interacts with key signaling proteins for transcytosis in EC. Black-Right-Pointing-Pointer Dysferlin mediates trafficking of vesicles carrying protein cargos in EC. -- Abstract: Dysferlin is a membrane-anchored protein known to facilitate membrane repair in skeletal muscles following mechanical injury. Mutations of dysferlin gene impair sarcolemma integrity, a hallmark of certain forms of muscular dystrophy in patients. Dysferlin contains seven calcium-dependent C2 binding domains, which are required to promote fusion of intracellular membrane vesicles. Emerging evidence reveal the unexpected expression of dysferlin in non-muscle, non-mechanically active tissues, such as endothelial cells, which cast doubts over the belief that ferlin proteins act exclusively as membrane repair proteins. We and others have shown that deficient trafficking of membrane bound proteins in dysferlin-deficient cells, suggesting that dysferlin might mediate trafficking of client proteins. Herein, we describe the intracellular trafficking and movement of GFP-dysferlin positive vesicles in unfixed reconstituted cells using live microscopy. By performing GST pull-down assays followed by mass spectrometry, we identified dysferlin binding protein complexes in human vascular endothelial cells. Together, our data further support the claims that dysferlin not only mediates membrane repair but also trafficking of client proteins, ultimately, help bridging dysferlinopathies to aberrant membrane signaling.

  8. Amiodarona causa vasodilatação dependente do endotélio em artérias coronárias caninas Amiodarone causes endothelium-dependent vasodilation in canine coronary arteries

    Directory of Open Access Journals (Sweden)

    Alfredo José Rodrigues


    Full Text Available OBJETIVO: Avaliar os efeitos vasodilatadores da amiodarona em artérias coronárias caninas empregando soluções de amiodarona dissolvida em polisorbato 80 ou em água. MÉTODOS: Anéis de artéria coronária, com e sem o endotélio íntegro, foram imersos em solução de krebs e conectadas a um transdutor para aferição de força isométrica promovida por contração vascular. As artérias foram expostas a concentrações crescentes de polisorbato 80, amiodarona dissolvida em água, amiodarona dissolvida em polisorbato 80 e uma apresentação comercial da amiodarona (Cordarone®. Os experimentos foram conduzidos na presença e na ausência dos seguintes bloqueadores enzimáticos: apenas indometacina, Nômega-nitro-L-arginina associada à indometacina e apenas Nômega-nitro-L-arginina. RESULTADOS: O polisorbato 80 causou pequeno relaxamento não dependente do endotélio. O Cordarone®, a amiodarona dissolvida em água e em polisorbato 80 promoveram relaxamento dependente do endotélio, que foi de maior magnitude para a amiodarona dissolvida em polisorbato e para o Cordarone®. Apenas a associação de indometacina com a Nômega-nitro-L-arginina foi capaz de abolir o relaxamento dependente do endotélio provocado pela amiodarona dissolvida em polisorbato 80. CONCLUSÃO: Os resultados obtidos indicam que a vasodilatação promovida pela amiodarona em artérias coronárias caninas é causada principalmente pela estimulação da liberação de óxido nítrico e fatores endoteliais relaxantes dependentes das ciclo-oxigenases.OBJECTIVE: To assess the vasodilating effects of amiodarone on canine coronary arteries by using solutions of amiodarone dissolved in polysorbate 80 or water. METHODS: Rings of coronary arteries, with or without intact endothelium, were immersed in Krebs solution and connected to a transducer for measuring the isometric force promoted by a vascular contraction. The arteries were exposed to increasing concentrations of

  9. A Laser-Assisted Anastomotic Technique : Feasibility on Human Diseased Coronary Arteries

    NARCIS (Netherlands)

    Stecher, David; Bronkers, Glenn; Vink, Aryan; Homoet-van der Kraak, Petra H|info:eu-repo/dai/nl/313984166; Helthuis, Jasper; Pasterkamp, Gerard|info:eu-repo/dai/nl/138488304; Buijsrogge, Marc P|info:eu-repo/dai/nl/24420098X


    OBJECTIVE: Atherosclerotic disease might hamper the efficacy of the Excimer laser-assisted Trinity Clip anastomotic connector in coronary arteries. Therefore, its efficacy was evaluated on human diseased coronary arteries (study 1). In addition, the acute laser effects onto the coronary wall were as

  10. Heparin inhibits human coronary artery smooth muscle cell migration. (United States)

    Kohno, M; Yokokawa, K; Yasunari, K; Minami, M; Kano, H; Mandal, A K; Yoshikawa, J


    Heparin, an anticoagulant, has been shown to reduce neointimal proliferation and restenosis following vascular injury in experimental studies, but the clinical trials of heparin in coronary balloon angioplasty have been negative. The current study, therefore, examined the effect of heparin on basal or stimulated migration by serum and platelet-derived growth factor (PDGF)-BB in cultured human coronary artery smooth muscle cells (SMCs) by Boyden's chamber method. In addition, the reversibility of the heparin effect on human coronary artery SMC migration was examined. Fetal calf serum (FCS) and PDGF-BB stimulated SMC migration in a concentration-dependent manner. Heparin in moderate to high concentration (10 to 100 U/mL) exhibited concentration-related inhibition of FCS- and PDGF-BB-stimulated SMC migration; however, a low concentration (1 U/mL) of heparin had no inhibitory effects. Heparin also had weak inhibitory effects on nonstimulated SMC migration. The SMCs that were exposed to a high concentration (100 U/mL) of heparin for 6 hours were capable of migrating after a short lag period of removal of heparin from the culture medium. These SMCs also showed recovery of responses to FCS and PDGF-BB by migrating significantly greater than the nonstimulated level. Furthermore, heparin-containing medium did not contain detached cells. These results indicate that heparin inhibits human coronary artery SMC migration, especially when stimulated by FCS or PDGF-BB, and that this inhibitory effect of heparin is reversible and not simply a function of killing cells.

  11. Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells. (United States)

    Kohno, M; Yokokawa, K; Yasunari, K; Kano, H; Minami, M; Ueda, M; Yoshikawa, J


    The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.

  12. Chronic exposure to the ultraviolet radiation levels from arc welding does not result in obvious damage to the human corneal endothelium. (United States)

    Oblak, Emil; Doughty, Michael J


    Occupational exposure of the cornea to ultraviolet radiation (UVR, e.g. in welding) is a well-known cause of 'arc eye' (photo-keratoconjunctivitis), but has also been considered to be a risk for the development of alterations in the size (polymegethism) and shape (pleomorphism) of the deeper-lying human corneal endothelial cells. Human data are however limited and so a further study was undertaken, with a control group. Non-contact specular micrographs of the central region of the corneal endothelium were obtained from 40 white males aged between 32 and 63 years; 20 were arc welders with an average of 25 +/- 7 years job experience, while the others were office workers (n = 20). All the welders reported occupational exposure to UVR (i.e. welders 'flashes') and up to 3 times per year. None of the subjects had a history of contact lens wear, major eye disease or surgery. The endothelial image was scanned, projected onto an overlay and cell border marking carried out in a masked fashion. The overlay was independently analysed, by a customised semi-automated method, providing cell-border-adjusted data on cell areas and cell shape (sides) on 124 to 260 cells per image. The endothelial cell density (ECD) values were also calculated from individual cell area values. All corneas appeared to be healthy, and showed no fluorescein staining indicating damage to the surface epithelium. Central corneal thickness values were normal at 0.531 +/- 0.031 (mean +/- SD) and 0.527 +/- 0.036 mm in the welders and non-welders respectively. All endothelia appeared healthy, with no evidence of cell oedema. The group-mean endothelial cell area was 393 +/- 35 and 392 +/- 21 microm2, ECD values were 2855 +/- 224 cells mm(-2) and 2852 +/- 210 cells mm(-2), while the percentages of 6-sided cells were 60 +/- 5.2 and 59 +/- 4.1% respectively. Cell area distributions were statistically identical (p > or = 0.8), and cell area-side relationships were marginally, but not statistically different. This

  13. Transvenous coronary angiography in humans with synchrotron radiation

    Energy Technology Data Exchange (ETDEWEB)

    Thomlinson, W.


    The transvenous coronary angiography project at the National Synchrotron Light Source (NSLS) is presently undergoing a significant upgrade to the hardware and software in the synchrotron medical facility. When completed, the project will have reached a level of maturity in the imaging technology which will allow the research team to begin to concentrate on medical research programs. This paper will review the status of the project and imaging technology and will discuss the current upgrades and future advanced technology initiatives. The advantages of using the radiation from a synchrotron, over that from a standard x-ray source, were the motivation for the project. A total of 23 human imaging sessions have been carried out with in the project. The primary goals have been to establish the imaging parameters and protocol necessary to obtain clinically useful images.

  14. Familial hypercholesterolaemic downsized pig with human-like coronary atherosclerosis: a model for preclinical studies

    DEFF Research Database (Denmark)

    Thim, Troels; Hagensen, Mette; Drouet, L.


    site-specifically by inflicting coronary artery balloon injury. Both spontaneously developed and balloon accelerated coronary plaques mirrored pertinent human plaque features, including a large necrotic core covered by a thin and inflamed fibrous cap as seen in the most common type of thrombosis...

  15. Infection of human endothelium in vitro by cytomegalovirus causes enhanced expression of purinergic receptors : A potential virus escape mechanism?

    NARCIS (Netherlands)

    Zandberg, Mariet; van Son, Willem J.; Harmsen, Martin C.; Bakker, Winston W.


    Background. Human cytomegalovirus (CMV) uses different strategies to escape from human host defense reactions. Previously we have observed that infection of endothelial cells with CMV in vitro leads to enhanced activity of endothelial ectonucleotidases. These ectoenzymes are responsible for hydrolys

  16. Infection of human endothelium in vitro by cytomegalovirus causes enhanced expression of purinergic receptors : A potential virus escape mechanism?

    NARCIS (Netherlands)

    Zandberg, Mariet; van Son, Willem J.; Harmsen, Martin C.; Bakker, Winston W.


    Background. Human cytomegalovirus (CMV) uses different strategies to escape from human host defense reactions. Previously we have observed that infection of endothelial cells with CMV in vitro leads to enhanced activity of endothelial ectonucleotidases. These ectoenzymes are responsible for

  17. Arecoline increases basic fibroblast growth factor but reduces expression of IL-1, IL-6, G-CSF and GM-CSF in human umbilical vein endothelium. (United States)

    Ullah, Mafaz; Cox, Stephen; Kelly, Elizabeth; Moore, Malcolm A S; Zoellner, Hans


    Areca nut chewing is associated with oral submucous fibrosis (OSF). Raised vascular basic fibroblast growth factor may induce fibrosis. Arecoline is a muscarinic alkaloid in areca nut, which we earlier reported causes injury and necrosis of human endothelium. Human umbilical vein endothelial cells were exposed to arecoline with or without tumor necrosis factor-α, and separately to acetylcholine, muscarine, or nicotine. Protein levels of basic fibroblast growth factor, as well as the inflammatory cytokines: granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor, and Interleukins-6, 1-α and 1-β, were determined by enzyme-linked immunosorbent assay. mRNA levels were established by real-time reverse transcription polymerase chain reaction. Basic fibroblast growth factor was released into the culture medium at arecoline levels causing necrosis (P arecoline on levels of the inflammatory cytokines (P arecoline reduced this stimulated expression (P Arecoline had no effect on mRNA for basic fibroblast growth factor, although there was reduced mRNA for the separate inflammatory cytokines studied. The effect of acetylcholine, muscarine, and nicotine was minimal and dissimilar to that of arecoline. Data raise the possibility that arecoline-induced, vascular basic fibroblast growth factor contributes to OSF, by combining increased growth factor expression with endothelial necrosis, and thus driving fibroblast proliferation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


    Directory of Open Access Journals (Sweden)

    R. Manoranjitham


    Full Text Available Background: The coronary sinus is a dilated venous channel opening into the right atrium of the heart. The coronary venous system has gained importance in recent years for electrophysiological procedures like arrhythmia ablation, biventricular pacing and implantation of cardiac pacemakers. The present study aims to study the formation and tributaries of coronary sinus and also the morphology of thebesian valve. Materials and Methods: 30 formalin fixed cadaveric hearts available in the department of Anatomy, Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur, Tamil nadu, was used for the study. The formation and tributaries of coronary sinus were noted. The length of coronary sinus in millimeters was measured from the union of great cardiac vein and left marginal vein upto the opening of the coronary sinus in the right atrium with vernier calipers. The width of the coronary ostium in the right atrium was measured in millimeters with vernier calipers. Results: In 93.33% specimens the coronary sinus was formed by the union of great cardiac vein and left marginal vein. In 3.33% specimens it was formed by the union of great cardiac vein and posterior vein of left ventricle, and in 3.33% specimens it was formed by the union of great cardiac vein and oblique vein of left atrium. The left marginal vein was absent in 2 specimens and small cardiac vein was absent in 1 specimen. The mean length of coronary sinus was 54.98 + 12.2mm. The mean width of coronary sinus ostium was 9.35 + 3.24mm. The Thebesian valve was present in 93.33% specimens and it was semilunar in shape. Conclusion: The knowledge of coronary sinus anatomy will be helpful during electrophysiological procedures.

  19. Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery

    DEFF Research Database (Denmark)

    Chan, Kayi Y; Baun, Michael; de Vries, René;


    We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries....

  20. Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery

    DEFF Research Database (Denmark)

    Chan, Kayi Y; Baun, Michael; de Vries, René;


    We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries.......We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries....

  1. Gene expression profiles of human dendritic cells interacting with Aspergillus fumigatus in a bilayer model of the alveolar epithelium/endothelium interface.

    Directory of Open Access Journals (Sweden)

    Charles Oliver Morton

    Full Text Available The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549 and endothelium (human pulmonary artery epithelial cells, HPAEC on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC, monocyte-derived DC (moDC and myeloid DC (mDC, were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.

  2. Gene expression profiles of human dendritic cells interacting with Aspergillus fumigatus in a bilayer model of the alveolar epithelium/endothelium interface. (United States)

    Morton, Charles Oliver; Fliesser, Mirjam; Dittrich, Marcus; Mueller, Tobias; Bauer, Ruth; Kneitz, Susanne; Hope, William; Rogers, Thomas Richard; Einsele, Hermann; Loeffler, Juergen


    The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.

  3. Effects of acrylic resin monomers on porcine coronary artery reactivity. (United States)

    Abebe, Worku; West, Daniel; Rueggeberg, Frederick A; Pashley, David; Mozaffari, Mahmood S


    The purpose of the present investigation was to assess the reactivity of porcine coronary arteries under in vitro conditions following their exposure to methyl methacrylate (MMA) and hydroxyethyl methacrylate (HEMA) monomers. Confirming previous studies using rat aortas, both MMA and HEMA induced acute/direct relaxation of coronary ring preparations, which was partly dependent on the endothelium. With prolonged tissue exposure, both monomers caused time- and concentration-dependent inhibition of receptor-mediated contraction of the vascular smooth muscle caused by prostaglandin F2∝ (PGF2∝), with HEMA causing more inhibition than MMA. Hydroxyethyl methacrylate, but not MMA, also produced impairment of non-receptor-mediated contraction of the coronary smooth muscle induced by KCl. On the other hand, neither HEMA nor MMA altered relaxation of the smooth muscle produced by the direct-acting pharmacological agent, sodium nitroprusside (SNP). While exposure to HEMA impaired endothelium-dependent vasorelaxation caused by bradykinin (BK), MMA markedly enhanced this endothelial-mediated response of the arteries. The enhanced endothelial response produced by MMA was linked to nitric oxide (NO) release. In conclusion, with prolonged tissue exposure, MMA causes less pronounced effects/adverse consequences on coronary smooth muscle function relative to the effect of HEMA, while enhancing vasorelaxation associated with release of NO from the endothelium. Accordingly, MMA-containing resin materials appear to be safer for human applications than materials containing HEMA.

  4. Human urotensin II in internal mammary and radial arteries of patients undergoing coronary surgery

    DEFF Research Database (Denmark)

    Chen, Zhi-Wu; Yang, Qin; Huang, Yu


    patients undergoing coronary bypass surgery were studied in organ baths. Urotensin receptor expression was determined by RT-PCR. RESULTS: hU-II contracted IMA with pD(2) of 8.57+/-0.41 and 45.4+/-9.1% E(max) of contraction to 100 mM KCl, whereas caused less contractile responses in RA (pD(2):8.30+/-0.79, E......(max):20.4+/-4.8%, ppD(2):8.39+/-0.43, E(max):56.1+/-4.0%) and RA (pD(2):9.03+/-0.46, E(max):65.2+/-7.1%). The relaxation was abolished by endothelium denudation...

  5. Angiographic Features and Cardiovascular Risk Factors in Human Immunodeficiency Virus-Infected Patients With First-Time Acute Coronary Syndrome

    DEFF Research Database (Denmark)

    Knudsen, Andreas; Mathiasen, Anders B; Worck, R.H.


    A matched cohort study was conducted comparing patients with first-time acute coronary syndromes infected with human immunodeficiency virus (HIV) to non-HIV-infected patients with and without diabetes matched for smoking, gender, and type of acute coronary syndrome who underwent first-time coronary...


    Directory of Open Access Journals (Sweden)



    Full Text Available CONTEXT: With ever increasing incidence of coronary heart disease, a thorough study of the coronary arteries is the need of time. AIM: The aim of the present study is to evaluate the coronary dominance pattern which will help the cardiac physicians and surgeons for better diagnosis and management of coronary arte ry disease. MATERIALS AND METHODS: The study undertaken in the Department of Anatomy, Assam Medical College included 75 perinatal and 15 adult cadaveric human hearts which were preserved in 10% formaldehyde solution after simple dissecting procedure and the dominance was noted. RESULTS: In the present study, out of total of 90 cases the right coronary dominance was found to be present in 58 cases (64.44%.This included 34(60.71% males and 24(70.59% females. Total cases of left coronary dominance were fo und to be 22(24.45%. Among these, 15(26.79% were males and 7(20.59% were females. Finally 10(11.11% co - dominant cases were found, of which 7 cases (12.50% were males and 3 cases (8.82% were females. CONCLUSION : Thus the study revealed that most of th e cases were having right coronary predominance. KEYWORDS : Coronary arteries, Dominance .

  7. Role of nitric oxide in coronary vasomotion during handgrip exercise. (United States)

    Nishikawa, Y; Kanki, H; Ogawa, S


    Endothelium-dependent modulation of coronary vasomotion during increased sympathetic tone remains unclear in normal and atherosclerotic human coronory arteries. We evaluated the role of endothelium-derived nitric oxide in vasomotion during isometric exercise in normal subjects (n = 7) and in patients with coronary artery disease (CAD) (n = 10). Coronary blood flow and epicardial coronary artery diameter to the handgrip test were measured before and after intracoronary administration of 100 micromol/min of N(G)-monomethyl L-arginine (L-NMMA). Heart rate and aortic blood pressure increased during handgrip test. Handgrip test caused a significant dilation in the diameter of the epicardial coronary artery in normal subjects (9.9% +/- 3.9%, mean +/- SD) and in the diameter of smooth segments of patients with CAD (5% +/- 3.7%, p < 0.05 vs normal subjects). In contrast, the diameter of irregular segments in patients with CAD decreased during handgrip test (-9.8 +/- 3.9%). After L-NMMA, the epicardial coronary artery significantly increased during handgrip test compared with before L-NMMA in normal subjects. L-NMMA did not have any effect on handgrip test induced vasodilation in the smooth segments and vasoconstriction in the irregular segments in the patients with CAD. Handgrip test-induced increases in coronary blood flow did not change after L-NMMA in both groups. Nitric oxide does not play a major role in HNG-induced vasodilation in epicardial and microcirculatory vessels in normal human coronary circulation. Although the decreased release in nitric oxide may modulate the abnormal response of the epicardial coronary artery to handgrip test, this does not explain the paradoxic constrictive response from the depressed but still dilatory response in the patients with CAD.

  8. Interaction of human malignant melanoma (ST-ML-12) tumor spheroids with endothelial cell monolayers. Damage to endothelium by oxygen-derived free radicals. (United States)

    Offner, F. A.; Wirtz, H. C.; Schiefer, J.; Bigalke, I.; Klosterhalfen, B.; Bittinger, F.; Mittermayer, C.; Kirkpatrick, C. J.


    Clinical and experimental observations suggest that tumor-induced endothelial cell injury may be one of several initial events in the establishment of tumor metastases. To test this hypothesis, the authors have analyzed the interaction of malignant melanoma (ST-ML-12) multicenter tumor spheroids with endothelial cell monolayers in a three-dimensional coculture system. After 1.5 hours of interaction, the authors observed a toxic effect on endothelial cells in the perispheroid region. The latter was demonstrated by testing membrane integrity with the fluorescent probes acridine orange/ethidium bromide and resulted in sensitivity to shear stress of the damaged cells. The endothelium then underwent a regenerative cycle to replace the denuded halo. Addition of the oxygen radical-scavenging enzyme superoxide dismutase to the culture medium prevented this endothelial cell damage in a dose-dependent manner for up to 12 hours. By contrast, catalase, deferoxamine mesylate, allopurinol, and the proteinase inhibitors soybean trypsin inhibitor and aprotinin were not protective under the same conditions. The endothelial damage was dependent on the attachment of the spheroids. Medium conditioned by ST-ML-12-spheroids proved to be ineffective. A similar, but less prominent, deleterious effect was seen when human peritoneal mesothelial cells were used in place of the human umbilical vein endothelial cells. Spheroids of the uroepithelial cell line HU-609 were used as control. No toxicity was observed in these cocultures. Melanin biosynthesis is associated with the production of oxygen-derived free radicals. The results suggest a possible implication of these free radicals in metastasis formation of malignant melanoma. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1519667

  9. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. (United States)

    Nummer, Daniel; Suri-Payer, Elisabeth; Schmitz-Winnenthal, Hubertus; Bonertz, Andreas; Galindo, Luis; Antolovich, Dalibor; Koch, Moritz; Büchler, Markus; Weitz, Jürgen; Schirrmacher, Volker; Beckhove, Philipp


    Regulatory T (Treg) cells have been detected in human carcinomas and may play a role in preventing the rejection of malignant cells. We quantified Treg cells and the expression of the addressins and the respective ligands that attract them in blood and in human pancreatic tumors and adjacent nonmalignant tissues from 47 patients. The capacity of Treg cells to adhere to and transmigrate through autologous endothelial cells was tested in vitro using spheroid adhesion assays and in vivo using a xenotransplant NOD/SCID model and in the presence and absence of antibodies to addressins. All statistical tests were two-sided. More Treg cells infiltrated pancreatic carcinomas than adjacent nonmalignant pancreatic tissues (120 cells per mm2 versus 80 cells per mm2, difference = 40 cells per mm2, 95% confidence interval [CI] = 21.2 cells per mm2 to 52.1 cells per mm2; P<.001). In contrast to conventional CD4+ T cells, more blood-derived Treg cells adhered to (1.0% versus 5.2%, difference = 4.2%, 95% CI = 2.7% to 5.6%; P<.001) and transmigrated through (3332 cells versus 4976 cells, difference = 1644 cells, 95% CI = 708 cells to 2580 cells; P = .008) autologous tumor-derived endothelial cells in vitro and in vivo (458 cells versus 605 cells, difference = 147 cells, 95% CI = 50.8 to 237.2 cells; P = .04). Tumor-derived endothelial cells expressed higher levels of addressins--including mucosal adressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD62-E, and CD166--than endothelial cells from normal tissue. Experiments using antibodies to addressins showed that transmigration was mediated by interactions of addressins, including MAdCAM-1, VCAM-1, CD62-E, and CD166 with their respective ligands, beta7 integrin, CD62L, and CD166, which were expressed specifically on Treg cells. Tumor-induced expression of addressins on the surface of endothelial cells allows a selective transmigration of Treg cells from peripheral blood to tumor tissues.

  10. Insulin-increased L-arginine transport requires A(2A adenosine receptors activation in human umbilical vein endothelium.

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    Enrique Guzmán-Gutiérrez

    Full Text Available Adenosine causes vasodilation of human placenta vasculature by increasing the transport of arginine via cationic amino acid transporters 1 (hCAT-1. This process involves the activation of A(2A adenosine receptors (A(2AAR in human umbilical vein endothelial cells (HUVECs. Insulin increases hCAT-1 activity and expression in HUVECs, and A(2AAR stimulation increases insulin sensitivity in subjects with insulin resistance. However, whether A(2AAR plays a role in insulin-mediated increase in L-arginine transport in HUVECs is unknown. To determine this, we first assayed the kinetics of saturable L-arginine transport (1 minute, 37°C in the absence or presence of nitrobenzylthioinosine (NBTI, 10 µmol/L, adenosine transport inhibitor and/or adenosine receptors agonist/antagonists. We also determined hCAT-1 protein and mRNA expression levels (Western blots and quantitative PCR, and SLC7A1 (for hCAT-1 reporter promoter activity. Insulin and NBTI increased the extracellular adenosine concentration, the maximal velocity for L-arginine transport without altering the apparent K(m for L-arginine transport, hCAT-1 protein and mRNA expression levels, and SLC7A1 transcriptional activity. An A2AAR antagonist ZM-241385 blocked these effects. ZM241385 inhibited SLC7A1 reporter transcriptional activity to the same extent in cells transfected with pGL3-hCAT-1(-1606 or pGL3-hCAT-1(-650 constructs in the presence of NBTI + insulin. However, SLC7A1 reporter activity was increased by NBTI only in cells transfected with pGL3-hCAT-1(-1606, and the ZM-241385 sensitive fraction of the NBTI response was similar in the absence or in the presence of insulin. Thus, insulin modulation of hCAT-1 expression and activity requires functional A(2AAR in HUVECs, a mechanism that may be applicable to diseases associated with fetal insulin resistance, such as gestational diabetes.

  11. A myocardial infarction-associated SNP at 6p24 interferes with MEF2 binding and associates with PHACTR1 expression levels in human coronary arteries (United States)

    Won, Hong-Hee; Lo, Ken Sin; Do, Ron; Henderson, Christopher A.; Lavoie-St-Amour, Claire; Langlois, Simon; Rivas, Daniel; Lehoux, Stephanie; Kathiresan, Sekar; Tardif, Jean-Claude; Musunuru, Kiran; Lettre, Guillaume


    Objective Coronary artery disease (CAD), including myocardial infarction (MI), is the main cause of death in the world. Genome-wide association studies (GWAS) have identified dozens of single nucleotide polymorphisms (SNPs) associated with CAD/MI. One of the most robust CAD/MI genetic associations is with intronic SNPs in the gene PHACTR1 on chromosome 6p24. How these PHACTR1 SNPs influence CAD/MI risk, and whether PHACTR1 itself is the causal gene at the locus, is currently unknown. Approach and results Using genetic fine-mapping and DNA re-sequencing experiments, we prioritized an intronic SNP (rs9349379) in PHACTR1 as causal variant.We showed that this variant is an expression quantitative trait locus (eQTL) for PHACTR1 expression in human coronary arteries. Experiments in endothelial cell extracts confirmed that alleles at rs9349379 are differentially bound by the transcription factors MEF2. We engineered a deletion of this MEF2 binding site using CRISPR/Cas9 genome-editing methodology. Heterozygous endothelial cells carrying this deletion express 35% less PHACTR1. Finally, we found no evidence that PHACTR1 expression levels are induced when stimulating human endothelial cells with VEGF, TNFα or shear stress. Conclusions Our results establish a link between intronic SNPs in PHACTR1, MEF2 binding and transcriptional functions at the locus, PHACTR1 expression levels in coronary arteries and CAD/MI risk. Because PHACTR1 SNPs are not associated with the traditional risk factors for CAD/MI (e.g. blood lipids or pressure, diabetes), our results suggest that PHACTR1 may influence CAD/MI risk through as yet unknown mechanisms in the vascular endothelium. PMID:25838425

  12. 低氧对人肺腺癌A549细胞迁移和黏附的影响%Effect of hypoxia on migration, invasion and adhesion to endothelium of human pulmonary adenocarcinoma A549 cells

    Institute of Scientific and Technical Information of China (English)

    Weigan Shen; Jun Zhu; Zhiyong Yu; Qingyu Xue


    Objective:To evaluate the effect of hypoxia on migration,invasion and adhesion to endothelium of human pulmonary adenocarcinoma A549 cells.Methods:Wound-healing and Transwell invasion assays were performed to study the effect of hypoxia on migration and invasion of A549 cells,and A549 cells were added to a monolayer of human umbilical vein endothelial cells (HUVECs) to test the ability to adhere to endothelium.Immunofluorescence assay and luciferase reporter gene assay were also used to evaluate the effect of hypoxia on distribution of E-cadherin,β-catenin,and actin,and hypoxia-inducible factor-1 (HIF-1)-dependent transcription,respectively.Results:Hypoxia facilitated A549 cell migration,invasion,and A549 cell-endothelial cells adhesion,and modulated the distribution of E-cadherin and β-catenin,and actin cytoskeleton rearrangement,and up-regulated HIF-1-dependent reporter gene expression in A549 cells.Conclusion:Promotion of A549 cell migration,invasion,and adhesion on endothelium by hypoxia might be modulated through its up-regulating HIF-l-dependent gene expression,which then induced the redistribution of E-cadherin and β-catenin,and the actin cytoskeletal reorganization.

  13. Mass transport of low density lipoprotein in reconstructed hemodynamic environments of human carotid arteries: the role of volume and solute flux through the endothelium. (United States)

    Kim, Sungho; Giddens, Don P


    The accumulation of low density lipoprotein (LDL) in the arterial intima is a critical step in the initiation and progression of atheromatous lesions. In this study we examine subject-specific LDL transport into the intima of carotid bifurcations in three human subjects using a three-pore model for LDL mass transfer. Subject-specific carotid artery computational models were derived using magnetic resonance imaging (MRI) to obtain the geometry and phase-contract MRI (PC-MRI) to acquire pulsatile inflow and outflow boundary conditions for each subject. The subjects were selected to represent a wide range of anatomical configurations and different stages of atherosclerotic development from mild to moderate intimal thickening. A fluid-solid interaction (FSI) model was implemented in the computational fluid dynamics (CFD) approach in order to consider the effects of a compliant vessel on wall shear stress (WSS). The WSS-dependent response of the endothelium to LDL mass transfer was modeled by multiple pathways to include the contributions of leaky junctions, normal junctions, and transcytosis to LDL solute and plasma volume flux from the lumen into the intima. Time averaged WSS (TAWSS) over the cardiac cycle was computed to represent the spatial WSS distribution, and wall thickness (WTH) was determined from black blood MRI (BBMRI) so as to visualize intimal thickening patterns in the bifurcations. The regions which are exposed to low TAWSS correspond to elevated WTH and higher mass and volume flux via the leaky junctions. In all subjects, the maximum LDL solute flux was observed to be immediately downstream of the stenosis, supporting observations that existing atherosclerotic lesions tend to progress in the downstream direction of the stenosis.

  14. Inflammatory response and the endothelium. (United States)

    Meroni, P L; Borghi, M O; Raschi, E; Ventura, D; Sarzi Puttini, P C; Atzeni, F; Lonati, L; Parati, G; Tincani, A; Mari, D; Tedesco, F


    Antiphospholipid-mediated endothelium perturbation plays a role in antiphospholipid syndrome (APS)-associated vasculopathy. Antiphospholipid antibodies activate endothelium both in vitro and in vivo experimental models by inducing a pro-inflammatory/-coagulant phenotype; the antibodies recognize beta2 glycoprotein I (beta2GPI) on human endothelial cells (EC) from different parts of the vasculature. In spite of such large in vitro evidence, few studies have addressed the issue whether or not a comparable endothelial perturbation might be detectable in vivo. We investigated several indirect ex vivo parameters of endothelial dysfunction: plasma levels of soluble adhesion molecules (sADM), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays. The study included: patients with primary antiphospholipid syndrome (n=32), with the syndrome secondary to non-active systemic lupus erythematosus (SLE, n=10), six patients with persistent antiphospholipid positivity at medium/high titre without any clinical manifestation of the syndrome. Fifty-two age and sex matched healthy subjects have been enrolled as controls. In addition, circulating endothelial cells identified by flow cytometry and the brachial artery flow-mediated vasodilation (FMV) were evaluated in 26 patients (20 primary and 6 lupus syndromes) and 30 healthy controls. Plasma levels of soluble adhesion molecules did not differ from controls, while a significant increase in von Willebrand factor titres (P<0.05) was found. No significant difference was found regarding the number of circulating endothelial cells and flow-mediated vasodilation. As a whole, these findings do suggest that antiphospholipid antibodies per se are not able to support a full-blown endothelial perturbation in vivo. As shown in antiphospholipid syndrome experimental animal models, a two-hit hypothesis is suggested.

  15. Effects of valsartan on angiotensin II-induced migration of human coronary artery smooth muscle cells. (United States)

    Kohno, M; Ohmori, K; Nozaki, S; Mizushige, K; Yasunari, K; Kano, H; Minami, M; Yoshikawa, J


    The migration as well as proliferation of coronary artery medial smooth muscle cells (SMC) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerosis. In the current study, we examined the effects of the angiotensin type 1 receptor antagonist valsartan on angiotensin II (Ang II)-induced migration of cultured human coronary artery SMC using Boyden's chamber methods. Ang II significantly stimulated human coronary artery SMC migration in a concentration-dependent manner between 10(-6) and 10(-8) mol/l when cells of passage 4 to 6 were used. However, the migration response to Ang II was moderately decreased in cells of passage 10 to 12, and was markedly decreased in cells of passage 15 to 17, compared to that of passage 4 to 6. Ang II-induced migration was blocked by the Ang II type 1 (AT1) receptor antagonist valsartan in a concentration-dependent manner. By contrast, the Ang II type 2 (AT2) receptor antagonist PD 123319 did not affect Ang II-induced migration. Ang II modestly increased the cell number of human coronary artery SMC after a 24-h incubation. This increase in cell numbers was also clearly blocked by valsartan, but not by PD 123319. These results indicate that Ang II stimulates migration as well as proliferation via AT1 receptors in human coronary artery SMC when cells of passage 4 to 6 are used. Valsartan may prevent the progression of coronary atherosclerosis through an inhibition of Ang II-induced migration and proliferation in these cells, although in vivo evidence is lacking.

  16. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.


    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical

  17. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.


    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical tri


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    Vijayamma Kunnath Narayanan


    Full Text Available BACKGROUND The coronary arteries are the biggest vasa vasora in the body since the heart is considered to be a modified blood vessel. The increased myocardial oxygen demand of the heart is met wholly by two coronary arteries. Hence, patients with coronary artery disease are prone to develop myocardial ischemia. The study is aimed at the structural changes of this vessels in the population of middle Kerala of various age groups from birth to seventy years. MATERIALS AND METHODS The specimen for histological study were fixed in 10% formalin and subjected to tissue processing. The sections were taken at the thickness of 5 microns and stained by using Haematoxylin- Eosin method and Verhoeff’s method for elastic fibers. The thickness of arterial wall were measured using ocular micrometer. RESULTS Structural changes of the three layered vessel walls were observed. Intimal proliferation, splitting, fragmentation and reduplication of internal elastic lamina were the important histological observation in the arterial wall as age advances. It was observed that there was a sixty fold increase in the thickness of intima from foetal to sixth decade of life. Tunica media exhibit a six fold increase in thickness probably due to muscular hypertrophy. The tunica adventitia have a threefold increase in thickness which least compared with other tunics. CONCLUSION These changes may favour atherosclerosis resulting in myocardial ischemia. Ischemic heart disease is the major cause of death and disability among the age group of third to sixth decade of life.

  19. Isolation and Culture of Human Microvascular endothelium for comparison of the morphological and molecular characteristics of Microvascular endothelial cells under normal gravity against simulated micro gravity

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    Tholcopiyan L


    Full Text Available BACKGROUND: Vascular endothelial cells play a major role in wound healing and also in growth of the tumors. Angiogenesis can be a target for treating diseases that are due to either poor vascularisation or decreased blood supply as in stroke, ulcers, heart disease, etc or abnormal and increased vasculature like in tumours. Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help in the treatment of such diseases (1. Ex vivo generation of blood vessels may offer an excellent alternative to the synthetic valves that are being currently used in cardiology. Micro gravity also referred to, as weightlessness is not essentially zero gravity but rather minimal gravity. According to cell type, micro gravity causes variety of changes in proliferation and differentiation of cells while also affecting the migration of cells and cellular functions (2, 3. Siamwala et al from AUKBC have already studied the effects of microgravity on the microvascular endothelial cells from bovine lung and macrovascular endothelial cells from the bovine pulmonary artery. It was observed that the proliferation and migration of macrovascular endothelial cells were increased in microgravity (4, 5. Nitric oxide production was also studied and observed that microgravity treatment did not change nitric oxide production by microvascular endothelial cells (4OBJECTIVE: Isolation and Comparison of culture characteristics of Human microvascular endothelium cultured conventionally and in novel nanomaterial scaffold and further study the morphological and molecular characteristics of microvascular endothelial cells under normal gravity against simulated micro gravityMATERIALS AND METHODS: The human Omentum samples were obtained using surgical procedures after informed consent. The microvascular endothelial cells were isolated following the protocol described by Scott et al (6.The isolated cells were seeded in two groups; Group I

  20. Geometry-based pressure drop prediction in mildly diseased human coronary arteries

    NARCIS (Netherlands)

    J.T.C. Schrauwen (Jelle); J.J. Wentzel (Jolanda); A.F.W. van der Steen (Ton); F.J.H. Gijsen (Frank)


    textabstractPressure drop (△. p) estimations in human coronary arteries have several important applications, including determination of appropriate boundary conditions for CFD and estimation of fractional flow reserve (FFR). In this study a △. p prediction was made based on geometrical features deri

  1. Simulation of stent deployment in a realistic human coronary artery

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    van der Steen Anton FW


    Full Text Available Abstract Background The process of restenosis after a stenting procedure is related to local biomechanical environment. Arterial wall stresses caused by the interaction of the stent with the vascular wall and possibly stress induced stent strut fracture are two important parameters. The knowledge of these parameters after stent deployment in a patient derived 3D reconstruction of a diseased coronary artery might give insights in the understanding of the process of restenosis. Methods 3D reconstruction of a mildly stenosed coronary artery was carried out based on a combination of biplane angiography and intravascular ultrasound. Finite element method computations were performed to simulate the deployment of a stent inside the reconstructed coronary artery model at inflation pressure of 1.0 MPa. Strut thickness of the stent was varied to investigate stresses in the stent and the vessel wall. Results Deformed configurations, pressure-lumen area relationship and stress distribution in the arterial wall and stent struts were studied. The simulations show how the stent pushes the arterial wall towards the outside allowing the expansion of the occluded artery. Higher stresses in the arterial wall are present behind the stent struts and in regions where the arterial wall was thin. Values of 200 MPa for the peak stresses in the stent strut were detected near the connecting parts between the stent struts, and they were only just below the fatigue stress. Decreasing strut thickness might reduce arterial damage without increasing stresses in the struts significantly. Conclusion The method presented in this paper can be used to predict stresses in the stent struts and the vessel wall, and thus evaluate whether a specific stent design is optimal for a specific patient.

  2. Effect of the endothelin family of peptides on human coronary artery smooth-muscle cell migration. (United States)

    Kohno, M; Yokokawa, K; Yasunari, K; Kano, H; Minami, M; Yoshikawa, J


    The migration of coronary artery medial smooth-muscle cells (SMCs) is one of the key events in the process of intimal thickening in coronary atherosclerotic lesions. The objectives of the present study were to determine whether any of the three isoforms of endothelin (ET), ET-1, ET-2, and ET-3, or an intermediate form of ET, big ET-1, induces migration of human coronary artery SMCs, and to investigate the possible interaction of ET peptides and well-known migration-stimulatory factors, platelet-derived growth factor (PDGF)-BB and angiotensin II (Ang II), on SMC migration by the Boyden's chamber method. None of the ET peptides alone induced SMC migration between 10(-9) and 10(-7) mol/L. In contrast, ET-1 and ET-2 significantly induced SMC migration in the presence of low concentrations of PDGF-BB (0.5 ng/mL) or Ang II (10(-9) mol/L), although ET-3 was less active (ET-1 = ET-2 > ET-3). In contrast, big ET-1 was without significant activity on PDGF-BB-or Ang II-induced SMC migration. The potentiation of SMC migration by ET peptides was clearly inhibited by the ETA receptor antagonist BG-123 in a concentration-dependent manner. These results suggest that the ET family of peptides, especially ET-1 and ET-2, can induce human coronary artery SMC migration in combination with PDGF-BB or Ang II, probably via ETA receptors. Taken together with the finding that the concentrations of ET, PDGF-BB and Ang II are locally increased at sites of endothelial injury, this indicates that ET may be an initial stimulus for human coronary artery medial SMC recruitment during coronary atherosclerosis, possibly in combination with PDGF-BB or Ang II.

  3. 5-HT1D receptor agonists and human coronary artery reactivity in vitro: crossover comparisons of 5-HT and sumatriptan with rizatriptan and L-741,519. (United States)

    Longmore, J; Boulanger, C M; Desta, B; Hill, R G; Schofield, W N; Taylor, A A


    1. Rizatriptan (MK-462, (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine)) and its structurally related analogue L-741,519 (N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-receptor agonists. Rizatriptan has shown efficacy as an anti-migraine agent in clinical trials. Since angiographic studies in patients have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction, we compared the effects of rizatriptan and L-741,519 with those of 5-HT and sumatriptan on endothelium-denuded segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients undergoing cardiac transplantation (n = 16 viable arteries from 13 males, 3 females, aged 38-68 years) and arterial segments (5-6 mm in length) were mounted in organ baths for isometric tension recording. Each segment was first exposed to 45mM KCl and then to 5-HT (1 nM-100 microM). Concentration-effect curves to rizatriptan and sumatriptan (Study 1, n = 6 or 7 arteries) or sumatriptan and L-741,519 (Study 2, n = 8 arteries) were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. 3. One artery showed severe atheroma and was not included in the analysis. ANOVA showed that 5-HT responsiveness varied significantly between arteries from different patients; but not between arterial segments from the same patient. Desensitization was seen consistently across all agonists but did not significantly affect inter-agonist comparisons. 4. There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of Emax values being 5-HT > sumatriptan > L-741,519 > rizatriptan. In terms of EC50 values, L-741,519 was significantly more potent than sumatriptan. 5. The present study (using a 'cross-over' experimental protocol) confirms our previous observation that rizatriptan is less

  4. MMP-1 serum levels predict coronary atherosclerosis in humans

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    Reiser Maximilian


    Full Text Available Background Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease. Methods 260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. Results In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85; p Conclusion MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.

  5. Angiographic Features and Cardiovascular Risk Factors in Human Immunodeficiency Virus-Infected Patients With First-Time Acute Coronary Syndrome

    DEFF Research Database (Denmark)

    Knudsen, Andreas; Mathiasen, Anders B; Worck, R.H.;


    A matched cohort study was conducted comparing patients with first-time acute coronary syndromes infected with human immunodeficiency virus (HIV) to non-HIV-infected patients with and without diabetes matched for smoking, gender, and type of acute coronary syndrome who underwent first-time coronary...... angiography. A total of 48 HIV-infected patients were identified from a national database. Coronary angiography showed that the HIV-infected patients had significantly fewer lesions with classification B2/C than the 2 control groups (p...

  6. Bidirectional Regulatory Effects of Dexmedetomidine on Porcine Coronary Tone In Vitro (United States)

    Zhou, Shu-Zhi; Li, Zhi-Ming; Liu, Xue-Ru; Zhou, Jun; Tan, Xiao-Qiu; Yang, Yan; Wei, Ji-Cheng


    Background Studies in vivo have shown that dexmedetomidine (DEX) could protect the myocardium and modulate the coronary blood flow. This study aimed to investigate the direct and concentration-dependent effects of DEX on the tone of porcine coronary artery in vitro and the underlying mechanisms. Material/Methods Distal branches of the porcine anterior descending coronary arteries were dissected and cut into 3–5 mm rings. The tones of coronary rings in response to cumulative DEX were measured using the PowerLab system. Coronary rings were divided into three groups: 1) endothelium-intact coronary rings without drug pretreatment (control); 2) endothelium-intact coronary rings pretreated with either yohimbine, tetraethylamine (TEA) or NG-nitro-L-arginine methyl ester (L-NAME); and 3) endothelium-denuded coronary rings pretreated with either yohimbine or TEA. Results DEX induced coronary ring relaxation at lower concentrations (10−9 to 10−7 M) followed by constriction at higher concentrations (10−6 to 10−5 M). The coronary constrictive effect of higher DEX (10−5 M) was greater in the endothelium-denuded rings than in the endothelium-intact rings. Yohimbine reduced the coronary constrictive effect of DEX at higher concentrations (10−6 to 10−5 M). TEA and L-NAME significantly reduced the coronary relaxing effect of DEX at lower concentrations (10−9 to 10−7 M) in endothelium-intact rings. TEA attenuated the coronary relaxation induced by DEX in endothelium-denuded rings. Conclusions DEX exerts bidirectional effects on porcine coronary tone. The coronary relaxing effect of DEX at lower concentrations is likely associated with endothelium integrity, NO synthesis and BKCa channel activation, while the coronary constrictive effect of DEX at higher concentrations is mediated by α2 adrenoceptors in the coronary smooth muscle cells. PMID:28369032

  7. Lysis of pig endothelium by IL-2 activated human natural killer cells is inhibited by swine and human major histocompatibility complex (MHC) class I gene products. (United States)

    Itescu, S; Artrip, J H; Kwiatkowski, P A; Wang, S F; Minanov, O P; Morgenthau, A S; Michler, R E


    We have previously described a form of xenograft rejection, mediated by natural killer (NK) cells, occurring in pig-to-primate organ transplants beyond the period of antibody-mediated hyperacute rejection. In this study, two distinct NK activation pathways were identified as mechanisms of pig aortic endotheliual cell (PAEC) lysis by human NK cells. Using an antibody-dependent cellular cytotoxicity (ADCC) assay, a progressive increase in human NK lysis of PAEC was observed following incubation with human IgG at increasing serum titer. In the absence of IgG, a second mechanism of PAEC lysis by human NK cells was observed following activation with IL-2. IL-2 activation of human NK cells increased lysis of PAEC by over 3-fold compared with ADCC. These results indicate that IL-2 activation of human NK cells induces significantly higher levels of lytic activity than does conventional ADCC involving IgG and FcRIII. We next investigated the role of MHC class I molecules in the regulation of NK lysis following IL-2 activation. PAEC expression of SLA class I molecules was increased by up to 75% by treatment with human TNFa. Following treatment with TNFa at 1 u/ml, IL-2 activated human NK lysis of PAEC was inhibited at every effector:target (E:T) ratio tested. Maximal effect occurred at an E:T ratio of 10:1, with TNFa inhibiting specific lysis by 59% (p < 0.01). Incubation with an anti-SLA class I Mab, but not IgG isotype control, abrogated the protective effects of TNFa on NK lysis of PAEC, suggesting direct inhibitory effects of SLA class I molecules on human NK function. To investigate whether human MHC class I molecules might have similar effects on human NK lysis of PAEC, further experiments were performed using a soluble peptide derived from the alpha-helical region of HLA-B7. Incubation with the HLA-B7 derived peptide significantly reduced the IL-2 activated NK lytic activity against PAEC in a dose-dependent fashion. Maximal effect occurred at a concentration of 10 mg

  8. Topographic association of angioscopic yellow plaques with coronary atherosclerotic plaque: assessment with quantitative colorimetry in human coronary artery autopsy specimens. (United States)

    Ishibashi, Fumiyuki; Lisauskas, Jennifer B; Kawamura, Akio; Waxman, Sergio


    Yellow plaques seen during coronary angioscopy are thought to be the surrogates for superficial intimal lipids in coronary plaque. Given diffuse and heterogeneous nature of atherosclerosis, yellow plaques in coronaries may be seen as several yellow spots on diffuse coronary plaque. We examined the topographic association of yellow plaques with coronary plaque. In 40 non-severely stenotic ex-vivo coronary segments (average length: 52.2 +/- 3.1 mm), yellow plaques were examined by angioscopy with quantitative colorimetry. The segments were cut perpendicular to the long axis of the vessel at 2 mm intervals, and 1045 slides with 5 microm thick tissue for whole segments were prepared. To construct the plaque surface, each tissue slice was considered to be representative of the adjacent 2 mm. The circumference of the lumen and the lumen border of plaque were measured in each slide, and the plaque surface region was constructed. Coronary plaque was in 37 (93%) of 40 segments, and consisted of a single mass [39.9 +/- 3.9 (0-100) mm, 311.3 +/- 47.4 (0.0-1336.2) mm2]. In 30 (75%) segments, multiple (2-9) yellow plaques were detected on a mass of coronary plaque. The number of yellow plaques correlated positively with coronary plaque surface area (r = 0.77, P colorimetry, some of them are associated with lipid cores underneath thin fibrous caps, may be used to assess the extent of coronary plaque. Further research using angioscopy could be of value to study the association of high-risk coronaries with acute coronary syndromes.

  9. Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway. (United States)

    Kurokawa, Hirofumi; Sugiyama, Seigo; Nozaki, Toshimitsu; Sugamura, Koichi; Toyama, Kensuke; Matsubara, Junichi; Fujisue, Koichiro; Ohba, Keisuke; Maeda, Hirofumi; Konishi, Masaaki; Akiyama, Eiichi; Sumida, Hitoshi; Izumiya, Yasuhiro; Yasuda, Osamu; Kim-Mitsuyama, Shokei; Ogawa, Hisao


    Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. Telmisartan is a unique angiotensin II type I receptor blocker that has been shown to prevent cardiovascular events in high risk patients. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. This study assessed whether telmisartan enhances mitochondrial function and alters cellular functions via AMPK in human coronary artery endothelial cells (HCAECs). In cultured HCAECs, telmisartan significantly enhanced mitochondrial activity assessed by mitochondrial reductase activity and intracellular ATP production and increased the expression of mitochondria related genes. Telmisartan prevented cellular senescence and exhibited the anti-apoptotic and pro-angiogenic properties. The expression of genes related anti-oxidant and pro-angiogenic properties were increased by telmisartan. Telmisartan increased endothelial NO synthase and AMPK phosphorylation. Peroxisome proliferator-activated receptor gamma signaling was not involved in telmisartan-induced improvement of mitochondrial function. All of these effects were abolished by inhibition of AMPK. Telmisartan enhanced mitochondrial activity and exhibited anti-senescence effects and improving endothelial function through AMPK in HCAECs. Telmisartan could provide beneficial effects on vascular diseases via enhancement of mitochondrial activity and modulating endothelial function through AMPK activation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Vascular Endothelium and Hypovolemic Shock. (United States)

    Gulati, Anil


    Endothelium is a site of metabolic activity and has a major reservoir of multipotent stem cells. It plays a vital role in the vascular physiological, pathophysiological and reparative processes. Endothelial functions are significantly altered following hypovolemic shock due to ischemia of the endothelial cells and by reperfusion due to resuscitation with fluids. Activation of endothelial cells leads to release of vasoactive substances (nitric oxide, endothelin, platelet activating factor, prostacyclin, mitochondrial N-formyl peptide), mediators of inflammation (tumor necrosis factor α, interleukins, interferons) and thrombosis. Endothelial cell apoptosis is induced following hypovolemic shock due to deprivation of oxygen required by endothelial cell mitochondria; this lack of oxygen initiates an increase in mitochondrial reactive oxygen species (ROS) and release of apoptogenic proteins. The glycocalyx structure of endothelium is compromised which causes an impairment of the protective endothelial barrier resulting in increased permeability and leakage of fluids in to the tissue causing edema. Growth factors such as angiopoetins and vascular endothelial growth factors also contribute towards pathophysiology of hypovolemic shock. Endothelium is extremely active with numerous functions, understanding these functions will provide novel targets to design therapeutic agents for the acute management of hypovolemic shock. Hypovolemic shock also occurs in conditions such as dengue shock syndrome and Ebola hemorrhagic fever, defining the role of endothelium in the pathophysiology of these conditions will provide greater insight regarding the functions of endothelial cells in vascular regulation.

  11. Impacto dos stents e do sirolimus por via oral na vasomotilidade coronariana dependente e independente do endotelio Impact of stenting and oral sirolimus on endothelium-dependent and independent coronary vasomotion

    Directory of Open Access Journals (Sweden)

    Rósley Weber Alvarenga Fernandes


    compared to bare metal stenting (BMS. OBJECTIVE: This study aims to assess the impact of BMS and the effect of oral sirolimus on endothelial function. METHODS: Forty-five patients were randomized into three groups: BMS + high-dose oral sirolimus (initial dose of 15 mg, followed by 6 mg/day for four weeks; BMS + low-dose sirolimus (6 mg followed by 2 mg daily for four weeks; and BMS without sirolimus. Changes in vasoconstriction or vasodilation in a 15 mm segment starting at the distal stent end in response to acetylcholine and nitroglycerin were assessed by quantitative angiography. RESULTS: The groups had similar angiographic characteristics. The percent variation in diameter in response to acetylcholine was similar in all groups at the two time points (p = 0.469. Four hours after stenting, the target segment presented an endothelial dysfunction that was maintained after eight months in all groups. In all groups, endothelium-independent vasomotion in response to nitroglycerin was similar at four hours and eight months, with increased target segment diameter after nitroglycerin infusion (p = 0.001. CONCLUSION: The endothelial dysfunction was similarly present at the 15 mm segment distal to the treated segment, at 4 hours and 8 months after stenting. Sirolimus administered orally during 4 weeks to prevent restenosis did not affect the status of endothelium-dependent and independent vasomotion.

  12. Quantitative Measurement of Dissection Resistance in Intimal and Medial Layers of Human Coronary Arteries. (United States)

    Wang, Ying; Johnson, John A; Spinale, Francis G; Sutton, Michael A; Lessner, Susan M


    The left anterior descending (LAD) coronary artery is the most frequently involved vessel in coronary artery dissection, a cause of acute coronary syndrome or sudden cardiac death. The biomechanical mechanisms underlying arterial dissection are not well understood. This study investigated the dissection properties of LAD specimens harvested from explanted hearts at the time of cardiac transplantation, from patients with primary dilated cardiomyopathy (n=12). Using a previously validated approach uniquely modified for these human LAD specimens, we quantified the local energy release rate, G, within different arterial layers during experimental dissection events (tissue tearing). Results show that the mean values of G during arterial dissection within the intima and within the media in human LADs are 20.7±16.5 J/m(2) and 10.3±5.0 J/m(2), respectively. The difference in dissection resistance between tearing events occurring within the intima and within the media is statistically significant. Our data fall in the same order of magnitude as most previous measurements of adhesive strength in other human arteries, with the differences in measured values of G within the layers most likely due to histologically observed differences in the structure and composition of arterial layers.

  13. NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome. (United States)

    Chaldakov, G N; Fiore, M; Stankulov, I S; Hristova, M; Antonelli, A; Manni, L; Ghenev, P I; Angelucci, F; Aloe, L


    While multiple growth factor, cytokines, and immune cells are identified in atherosclerotic lesions, as well as an essential nonneuronal function of neurotrophins implicated in cardiovascular tissue development and in lipid and glucose metabolism, the role of the neurotrophins NGF and BDNF and also the adipokine leptin in human coronary atherosclerosis and related disorders, such as metabolic syndrome, remains unclear. Here we report that (i) both the amount and the immunoreactivity of NGF was reduced and the expression of p75NGF receptor and the number of mast cell increased in human atherosclerotic coronary arteries (n = 12) compared with control specimens (n = 9) obtained from autopsy cases, and (ii) NGF and BDNF plasma levels were reduced in patients with metabolic syndrome (n = 23) compared with control subjects (n = 10). Also, in metabolic syndrome patients, a positive correlation between the plasma leptin levels and the number of adipose tissue mast cells was found, suggesting that leptin may be a novel adipoimmune mediator. Altogether, the results provide the first correlative evidence for the potential involvement of NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome, implying neuroimmune and adipoimmune pathways in the pathobiology of these cardiovascular disorders.

  14. Subcellular characterization of glucose uptake in coronary endothelial cells. (United States)

    Gaudreault, N; Scriven, D R L; Laher, I; Moore, E D W


    Despite all the evidence linking glucose toxicity to an increased risk of cardiovascular diseases, very little is known about the regulation of glucose uptake in endothelial cells. We have previously reported an asymmetric distribution of the GLUTs (1-5) and SGLT-1 in en face preparations of rat coronary artery endothelia [Gaudreault N., Scriven D.R., Moore E.D., 2004. Characterisation of glucose transporters in the intact coronary artery endothelium in rats: GLUT-2 upregulated by long-term hyperglycaemia. Diabetologia 47(12),2081-2092]. We assessed this time, through immunocytochemistry and wide field fluorescence microscopy coupled to deconvolution, the presence and subcellular distribution of glucose transporters in cultures of human coronary artery endothelial cells (HCAECs). HCAECs express GLUT-1 to 5 and SGLT-1, but their subcellular distribution lacks the luminal/abluminal asymmetry and the proximity to cell-to-cell junctions observed in intact endothelium. To determine the impact of the transporters' distribution on intracellular glucose accumulation, a fluorescent glucose analog (2-NBDG) was used in conjunction with confocal microscopy to monitor uptake in individual cells; the arteries were mounted in an arteriograph chamber with physiological flow rates. The uptake in both preparations was inhibited by cytochalasin-B and d-glucose and stimulated by insulin, but the distribution of the incorporated 2-NBDG mirrored that of the transporters. In HCAEC it was distributed throughout the cell and in the intact arterial endothelium it was restricted to the narrow cytosolic volume adjacent to the cell-to-cell junctions. We suggest that the latter subcellular organization and compartmentalization may facilitate transendothelial transport of glucose in intact coronary artery.

  15. 丹参酮ⅡA 磺酸钠联合氯吡格雷对冠心病心绞痛疗效及血管内皮功能的影响%Effect of TanshinoneIIA Sulfonic Sodium combined with Clopidogrel on coronary heart disease and angina pectoris and vascular endothelium function

    Institute of Scientific and Technical Information of China (English)

    周芸羽; 吴敏; 叶张章; 陈明华


    Objective It is to explore the effect of TanshinoneIIA Sulfonic Sodium combined with Clopidogrel on coronaryheart disease and angina pectoris and vascular endothelium function .Methods 60 patients with coronary heart disease and anginapectoris were randomly divided into experimental group and control group , both the groups were given normal therapy , onthis basis the control group was treated with Clopidogrel , the experimental group was treated with TanshinoneIIA Sulfonic Sodi -um combined with Clopidogrel.The attack times and lasting time of angina pectoris and dosage needed of nitroglycerin beforeand after treatment were observed in both groups , and the levels of NO, ET and TXB2 were determined.Results The attacktimes and lasting time of angina pectoris and dosage needed of nitroglycerin, the levels of ET and TXB2 all decreased aftertreatment while that of NO increased in both groups compared with that before treatment , and the decrease or increase in experimentalgroup was more significant (P <0.05).The total effective rate in experimental group was obviously higher thanthat in control group (P <0.05).Conclusion TanshinoneIIA Sulfonic Sodium combined with Clopidogrel can promote coro -nary artery dilatation, improve vascular endothelium function in the treatment with coronary heart disease and angina pectoris ,the curative effect is good and it is worthy of popularization and application .%目的:探讨丹参酮ⅡA磺酸钠联合氯吡格雷对冠心病心绞痛疗效及血管内皮功能的影响。方法将冠心病心绞痛患者60例随机分为实验组和对照组,均给予常规治疗,对照组在此基础上联合氯吡格雷进行治疗,实验组在对照组治疗基础上加用丹参酮ⅡA磺酸钠进行治疗,观察2组治疗前后心绞痛发作次数、持续时间以及缓解所需硝酸甘油剂量,同时检测2组治疗前后血液内一氢化氮( NO)、内皮素( ET)及血栓素A2( TXB2)水平。结果2组治疗后

  16. An Human-Computer Interactive Augmented Reality System for Coronary Artery Diagnosis Planning and Training. (United States)

    Li, Qiming; Huang, Chen; Lv, Shengqing; Li, Zeyu; Chen, Yimin; Ma, Lizhuang


    In order to let the doctor carry on the coronary artery diagnosis and preoperative planning in a more intuitive and more natural way, and to improve the training effect for interns, an augmented reality system for coronary artery diagnosis planning and training (ARS-CADPT) is designed and realized in this paper. At first, a 3D reconstruction algorithm based on computed tomographic (CT) images is proposed to model the coronary artery vessels (CAV). Secondly, the algorithms of static gesture recognition and dynamic gesture spotting and recognition are presented to realize the real-time and friendly human-computer interaction (HCI), which is the characteristic of ARS-CADPT. Thirdly, a Sort-First parallel rendering and splicing display subsystem is developed, which greatly expands the capacity of student users. The experimental results show that, with the use of ARS-CADPT, the reconstruction accuracy of CAV model is high, the HCI is natural and fluent, and the visual effect is good. In a word, the system fully meets the application requirement.

  17. Ischemic heart disease induces upregulation of endothelin receptor mRNA in human coronary arteries

    DEFF Research Database (Denmark)

    Wackenfors, Angelica; Emilson, Malin; Ingemansson, Richard;


    and controls using real-time polymerase chain reaction (real-time PCR). In addition, the suitability of organ culture as a model mimicking endothelin receptor changes in cardiovascular disease was evaluated by in vitro pharmacology and real-time PCR. Endothelin ETA and ETB receptor mRNA levels were......Endothelin has been implicated in the pathogenesis of ischemic heart disease and congestive heart failure. The aims were to quantify endothelin type A (ETA) and type B (ETB) receptor mRNA levels in human coronary arteries from patients with ischemic heart disease, congestive heart failure...

  18. Detection of Human Cytomegalovirus and Epstein-Barr Virus in Coronary Atherosclerotic Tissue (United States)

    Imbronito, Ana Vitória; Marcelino, Silvia Linardi; Grande, Sabrina Rosa; Nunes, Fabio Daumas; Romito, Giuseppe Alexandre


    Previous studies indicated that patients with atherosclerosis are predominantly infected by human cytomegalovirus (HCMV), but rarely infected by type 1 Epstein-Barr virus (EBV-1). In this study, atheromas of 30 patients who underwent aortocoronary bypass surgery with coronary endartherectomy were tested for the presence of these two viruses. HCMV occurred in 93.3% of the samples and EBV-1 was present in 50% of them. Concurrent presence of both pathogens was detected in 43.3% of the samples. PMID:24031529

  19. Wave speed in human coronary arteries is not influenced by microvascular vasodilation: implications for wave intensity analysis. (United States)

    Rolandi, M Cristina; De Silva, Kalpa; Lumley, Matthew; Lockie, Timothy P E; Clapp, Brian; Spaan, Jos A E; Perera, Divaka; Siebes, Maria


    Wave intensity analysis and wave separation are powerful tools for interrogating coronary, myocardial and microvascular physiology. Wave speed is integral to these calculations and is usually estimated by the single-point technique (SPc), a feasible but as yet unvalidated approach in coronary vessels. We aimed to directly measure wave speed in human coronary arteries and assess the impact of adenosine and nitrate administration. In 14 patients, the transit time Δt between two pressure signals was measured in angiographically normal coronary arteries using a microcatheter equipped with two high-fidelity pressure sensors located Δs = 5 cm apart. Simultaneously, intracoronary pressure and flow velocity were measured with a dual-sensor wire to derive SPc. Actual wave speed was calculated as DNc = Δs/Δt. Hemodynamic signals were recorded at baseline and during adenosine-induced hyperemia, before and after nitroglycerin administration. The energy of separated wave intensity components was assessed using SPc and DNc. At baseline, DNc equaled SPc (15.9 ± 1.8 vs. 16.6 ± 1.5 m/s). Adenosine-induced hyperemia lowered SPc by 40 % (p DNc remained unchanged, leading to marked differences in respective separated wave energies. Nitroglycerin did not affect DNc, whereas SPc transiently fell to 12.0 ± 1.2 m/s (p < 0.02). Human coronary wave speed is reliably estimated by SPc under resting conditions but not during adenosine-induced vasodilation. Since coronary wave speed is unaffected by microvascular dilation, the SPc estimate at rest can serve as surrogate for separating wave intensity signals obtained during hyperemia, thus greatly extending the scope of WIA to study coronary physiology in humans.

  20. X-ray micro computed tomography for the visualization of an atherosclerotic human coronary artery (United States)

    Matviykiv, Sofiya; Buscema, Marzia; Deyhle, Hans; Pfohl, Thomas; Zumbuehl, Andreas; Saxer, Till; Müller, Bert


    Atherosclerosis refers to narrowing or blocking of blood vessels that can lead to a heart attack, chest pain or stroke. Constricted segments of diseased arteries exhibit considerably increased wall shear stress, compared to the healthy ones. One of the possibilities to improve patient’s treatment is the application of nano-therapeutic approaches, based on shear stress sensitive nano-containers. In order to tailor the chemical composition and subsequent physical properties of such liposomes, one has to know precisely the morphology of critically stenosed arteries at micrometre resolution. It is often obtained by means of histology, which has the drawback of offering only two-dimensional information. Additionally, it requires the artery to be decalcified before sectioning, which might lead to deformations within the tissue. Micro computed tomography (μCT) enables the three-dimensional (3D) visualization of soft and hard tissues at micrometre level. μCT allows lumen segmentation that is crucial for subsequent flow simulation analysis. In this communication, tomographic images of a human coronary artery before and after decalcification are qualitatively and quantitatively compared. We analyse the cross section of the diseased human coronary artery before and after decalcification, and calculate the lumen area of both samples.

  1. Investigation of CGRP receptors and peptide pharmacology in human coronary arteries. Characterization with a nonpeptide antagonist

    DEFF Research Database (Denmark)

    Hasbak, Philip; Saetrum Opgaard, Ole; Eskesen, Karen


    in human coronary arteries. Relaxant responses were studied on isolated segments of coronary arteries after precontraction with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha)). The human peptides alphaCGRP, AM, and amylin induced relaxation with mean pEC50 values of 8.6, 6.......8, and 6.3 M, respectively. Preincubation with alphaCGRP(8-37) (10(-7) -10(-5) M) and a novel nonpeptide CGRP antagonist "Compound 1" (WO98/11128) (10(-7)-10(-5) M) caused a dose-dependent rightward shift of the concentration-response curves for alphaCGRP with pA(2) values of 7.0 and 7.1, respectively....... Preincubation with alphaCGRP(8-37) (10(-6) M) and Compound 1 (10(-6) M) caused significant rightward shift of the concentration-response curves for AM and amylin as well with pK B values between 6.6 and 7.5. Preincubation with AM(22-52) had no antagonistic effect on the AM and amylin response, neither did...

  2. Ischemic heart disease down-regulates angiotensin type 1 receptor mRNA in human coronary arteries

    DEFF Research Database (Denmark)

    Wackenfors, Angelica; Emilson, Malin; Ingemansson, Richard;


    Angiotensin II is important in the development of cardiovascular disease. In the present study, angiotensin II receptor mRNA levels were quantified by real-time polymerase chain reaction (real-time PCR) in human coronary arteries from patients with ischemic heart disease and controls. Furthermore......, the suitability of artery culture for studying angiotensin receptor changes was evaluated by in vitro pharmacology and real-time PCR. The angiotensin type 1 (AT1) receptor mRNA levels were down-regulated in human coronary arteries from patients with ischemic heart disease as compared to controls (P

  3. Stromal cell-derived factor-1/CXCR4 signaling modifies the capillary-like organization of human embryonic stem cell-derived endothelium in vitro. (United States)

    Chen, Tong; Bai, Hao; Shao, Ying; Arzigian, Melanie; Janzen, Viktor; Attar, Eyal; Xie, Yi; Scadden, David T; Wang, Zack Z


    The molecular mechanisms that regulate human blood vessel formation during early development are largely unknown. Here we used human ESCs (hESCs) as an in vitro model to explore early human vasculogenesis. We demonstrated that stromal cell-derived factor-1 (SDF-1) and CXCR4 were expressed concurrently with hESC-derived embryonic endothelial differentiation. Human ESC-derived embryonic endothelial cells underwent dose-dependent chemotaxis to SDF-1, which enhanced vascular network formation in Matrigel. Blocking of CXCR4 signaling abolished capillary-like structures induced by SDF-1. Inhibition of the SDF-1/CXCR4 signaling pathway by AMD3100, a CXCR4 antagonist, disrupted the endothelial sprouting outgrowth from human embryoid bodies, suggesting that the SDF-1/CXCR4 axis plays a critical role in regulating initial vessel formation, and may function as a morphogen during human embryonic vascular development.

  4. A functionally significant polymorphism in ID3 is associated with human coronary pathology.

    Directory of Open Access Journals (Sweden)

    Ani Manichaikul

    Full Text Available We previously identified association between the ID3 SNP rs11574 and carotid intima-media thickness in the Diabetes Heart Study, a predominantly White diabetic population. The nonsynonymous SNP rs11574 results in an amino acid substitution in the C-terminal region of ID3, attenuating the dominant negative function of ID3 as an inhibitor of basic HLH factor E12-mediated transcription. In the current investigation, we characterize the association between the functionally significant polymorphism in ID3, rs11574, with human coronary pathology.The Multi-Ethnic Study of Atherosclerosis (MESA is a longitudinal study of subclinical cardiovascular disease, including non-Hispanic White (n = 2,588, African American (n = 2,560 and Hispanic (n = 2,130 participants with data on coronary artery calcium (CAC. The Coronary Assessment in Virginia cohort (CAVA included 71 patients aged 30-80 years, undergoing a medically necessary cardiac catheterization and intravascular ultrasound (IVUS at the University of Virginia. ID3 SNP rs11574 risk allele was associated with the presence of CAC in MESA Whites (P = 0.017. In addition, the risk allele was associated with greater atheroma burden and stenosis in the CAVA cohort (P = 0.003, P = 0.04 respectively. The risk allele remained predictive of atheroma burden in multivariate analysis (Model 1: covariates age, gender, and LDL, regression coefficient = 9.578, SE = 3.657, p = 0.0110; Model 2: covariates Model 1, presence of hypertension, presence of diabetes, regression coefficient = 8.389, SE = 4.788, p = 0.0163.We present additional cohorts that demonstrate association of ID3 SNP rs11574 directly with human coronary artery pathology as measured by CAC and IVUS: one a multiethnic, relatively healthy population with low levels of diabetes and the second a predominantly White population with a higher incidence of T2DM referred for cardiac catheterization.

  5. The transcriptome of human epicardial, mediastinal and subcutaneous adipose tissues in men with coronary artery disease.

    Directory of Open Access Journals (Sweden)

    Sandra Guauque-Olarte

    Full Text Available BACKGROUND: The biological functions of epicardial adipose tissue (EAT remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD. The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT and subcutaneous (SAT and to study their possible relationships with the development of cardiovascular diseases. METHODS AND RESULTS: Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina® HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1, involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT. The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects. CONCLUSIONS: Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD.

  6. The Transcriptome of Human Epicardial, Mediastinal and Subcutaneous Adipose Tissues in Men with Coronary Artery Disease (United States)

    Guauque-Olarte, Sandra; Gaudreault, Nathalie; Piché, Marie-Ève; Fournier, Dominique; Mauriège, Pascale; Mathieu, Patrick; Bossé, Yohan


    Background The biological functions of epicardial adipose tissue (EAT) remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases. Methods and Results Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina® HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT). The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects. Conclusions Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD. PMID:21603615

  7. Endothelium-dependent relaxation of blood vessels

    Energy Technology Data Exchange (ETDEWEB)

    Hynes, M.R.


    Dilation of blood vessels in response to a large number of agents has been shown to be dependent on an intact vascular endothelium. The present studies examine some aspects of endothelium-dependent vasodilation in blood vessels of the rabbit and rat. Using the rabbit ear artery and the subtype-selective muscarinic antagonist pirenzepine, muscarinic receptors of the endothelium and smooth muscle cells were shown to be of the low affinity M/sub 2/ subtype. Inhibition of (/sup 3/H)(-)quinuclidinyl benzilate was used to determine affinity for the smooth muscle receptors while antagonism of methacholine induced vasodilation yielded the endothelial cell receptor affinity. The effect of increasing age (1-27 months) on endothelium-dependent relaxation was studied in aortic rings, perfused tail artery and perfused mesenteric bed of the Fisher 344 rat. The influence of endothelium on contractile responses was examined using the perfused caudal artery.

  8. Intracoronary Blood Flow Velocity and Transstenotic Pressure Drop in an Awake Human Being During Coronary Vasodilation

    NARCIS (Netherlands)

    F. Zijlstra (Felix); P.W.J.C. Serruys (Patrick)


    textabstractThe pressure drop over a coronary stenosis and the intracoronary Doppler blood flow velocity were measured at rest and during coronary vasodilation. We report the first observation that confirms the validity of fluid dynamic equations to describe the hemodynamics of a coronary stenosis b

  9. [Use of the most recent reagent (CuFL) for stimulation of NO synthesis by the medicinal leech salivary cell secretion in the cultures of human endothelium cells (HUVEC) and in rat cardiomiocytes]. (United States)

    Baskova, I P; Alekseeva, A Iu; Kostiuk, S V; Neverova, M E; Smirnova, T D; Veĭko, N N


    The medicinal leech salivary cell secretion (SCS) may stimulate NO-production in cultures of human endothelium cells (HUVEC) and rat cardiomiocytes (RCM). This effect was detected using a NO specific reagent, - the complex Cu2+ with a fluorescein derivative (Cu-Fl). NO had also been detected in the cells by fluorescent electronic microscopy and determined quantitatively in the cells and in culture fluid by the fluorescence method. SCS stimulated NO synthesis in HUVEC cells (but not in RCM) is accompanied by NO release into intercellular space. Localization of NO synthesis centers is presented and it is shown that the increase in NO levels during the SCS action on HUVEC and RCM is associated with the increase in the activity of eNOS/nNOS, but not iNOS. In endothelial cells SCS activates nitrosylation processes, assessed by the increase of nitrite-ions in the culture medium. It is therefore important to use Cu-Fl, other than Griss-reagent, during the first hour of analysis of NO synthesis. The NO-depended mechanism of SCS action on endothelial cells might be a factor in providing of its positive action in hirudotheraphy.

  10. Human Coronary Artery Smooth Muscle Cell Responses to Bioactive Polyelectrolyte Multilayer Interfaces

    Directory of Open Access Journals (Sweden)

    Robert G. Newcomer


    Full Text Available Under normal physiological conditions, mature human coronary artery smooth muscle cells (hCASMCs exhibit a “contractile” phenotype marked by low rates of proliferation and protein synthesis, but these cells possess the remarkable ability to dedifferentiate into a “synthetic” phenotype when stimulated by conditions of pathologic stress. A variety of polyelectrolyte multilayer (PEMU films are shown here to exhibit bioactive properties that induce distinct responses from cultured hCASMCs. Surfaces terminated with Nafion or poly(styrenesulfonic acid (PSS induce changes in the expression and organization of intracellular proteins, while a hydrophilic, zwitterionic copolymer of acrylic acid and 3-[2-(acrylamido-ethyl dimethylammonio] propane sulfonate (PAA-co-PAEDAPS is resistant to cell attachment and suppresses the formation of key cytoskeletal components. Differential expression of heat shock protein 90 and actin is observed, in terms of both their magnitude and cellular localization, and distinct cytoplasmic patterns of vimentin are seen. The ionophore A23187 induces contraction in confluent hCASMC cultures on Nafion-terminated surfaces. These results demonstrate that PEMU coatings exert direct effects on the cytoskeletal organization of attaching hCASMCs, impeding growth in some cases, inducing changes consistent with phenotypic modulation in others, and suggesting potential utility for PEMU surfaces as a coating for coronary artery stents and other implantable medical devices.

  11. Biodegradable Polymers Influence the Effect of Atorvastatin on Human Coronary Artery Cells. (United States)

    Strohbach, Anne; Begunk, Robert; Petersen, Svea; Felix, Stephan B; Sternberg, Katrin; Busch, Raila


    Drug-eluting stents (DES) have reduced in-stent-restenosis drastically. Yet, the stent surface material directly interacts with cascades of biological processes leading to an activation of cellular defense mechanisms. To prevent adverse clinical implications, to date almost every patient with a coronary artery disease is treated with statins. Besides their clinical benefit, statins exert a number of pleiotropic effects on endothelial cells (ECs). Since maintenance of EC function and reduction of uncontrolled smooth muscle cell (SMC) proliferation represents a challenge for new generation DES, we investigated the effect of atorvastatin (ATOR) on human coronary artery cells grown on biodegradable polymers. Our results show a cell type-dependent effect of ATOR on ECs and SMCs. We observed polymer-dependent changes in IC50 values and an altered ATOR-uptake leading to an attenuation of statin-mediated effects on SMC growth. We conclude that the selected biodegradable polymers negatively influence the anti-proliferative effect of ATOR on SMCs. Hence, the process of developing new polymers for DES coating should involve the characterization of material-related changes in mechanisms of drug actions.

  12. Biodegradable Polymers Influence the Effect of Atorvastatin on Human Coronary Artery Cells

    Directory of Open Access Journals (Sweden)

    Anne Strohbach


    Full Text Available Drug-eluting stents (DES have reduced in-stent-restenosis drastically. Yet, the stent surface material directly interacts with cascades of biological processes leading to an activation of cellular defense mechanisms. To prevent adverse clinical implications, to date almost every patient with a coronary artery disease is treated with statins. Besides their clinical benefit, statins exert a number of pleiotropic effects on endothelial cells (ECs. Since maintenance of EC function and reduction of uncontrolled smooth muscle cell (SMC proliferation represents a challenge for new generation DES, we investigated the effect of atorvastatin (ATOR on human coronary artery cells grown on biodegradable polymers. Our results show a cell type-dependent effect of ATOR on ECs and SMCs. We observed polymer-dependent changes in IC50 values and an altered ATOR-uptake leading to an attenuation of statin-mediated effects on SMC growth. We conclude that the selected biodegradable polymers negatively influence the anti-proliferative effect of ATOR on SMCs. Hence, the process of developing new polymers for DES coating should involve the characterization of material-related changes in mechanisms of drug actions.

  13. 人角膜内皮细胞增殖特性及能力的研究进展%Research progress on proliferative property and capacity of human corneal endothelium

    Institute of Scientific and Technical Information of China (English)

    潘飞; 姚玉峰


    Primary and secondary corneal endothelial decompensation leads to stromal edema,corneal opacity and loss of visual acuity. The pathogenesis of corneal endothelial decompensation is that adult corneal endothelium in vivo lacks of a robust proliferative response to injury, does not divide sufficiently to replace the lost cells. Previous studies indicate that cell-cell contact inhibition and transforming growth factor-beta2 (TGF-β2) in aqueous humor may be responsible for maintaining human endothelial cells in a non-replicative state in vivo. The results of the experimental investigation by using immunofluorescent staining of the cell cycle-associated proteins and cell proliferation marker Ki67 in corneal endothelium indicate that human corneal endothelial cells in vivo are arrested in the G1-phase and have not exited from the cell cycle. Successful outgrowth in culture of human corneal endothelial cells in vitro and the establishment of the immortalized human endothelial cell line, provide strong evidence that corneal endothelial cells retain proliferative capacity. Experiments with cell culture ex vivo demonstrate that corneal endothelial cells cultured from young donors grow more robustly than those from older donors, and cells cultured from peripheral area of corneas show greater cell density than central regions. Studies have demonstrated that in vitro human corneal endothelia undergo mitotic changes in response to stimulation of growth promoting agents,such as growth factors, EDTA and extracelluar matrix. Identification of corneal endothelial stem cells and isolation and culture of human endothelial precursor cells in vitro will be beneficial for further investigation regarding the mechanism of corneal endothelial regeneration as well as corneal endothelial cells in vitro culture.%原发性和继发性角膜内皮失代偿导致角膜基质水肿、角膜混浊和视力下降,其发生的病理生理基础在于成年人角膜内皮细胞失去增殖能力,损

  14. Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human coronary atherosclerotic and restenotic lesions

    NARCIS (Netherlands)

    D.C. MacLeod (Donald); B.H. Strauss (Bradley); J. Escaned (Javier); V.A.W.M. Umans (Victor); R-J. van Suylen (Robert-Jan); A. Verkerk (Anton); P.J. de Feyter (Pim); P.W.J.C. Serruys (Patrick); M. de Jong (Marcel)


    textabstractOBJECTIVES. The purpose of this study was to examine the proliferative capacity and extracellular matrix synthesis of human coronary plaque cells in vitro. BACKGROUND. Common to both primary atherosclerosis and restenosis are vascular smooth muscle cell proliferation and production of ex

  15. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease? (United States)

    Chaldakov, George N; Fiore, Marco; Stankulov, Ivan S; Manni, Luigi; Hristova, Mariyana G; Antonelli, Alessia; Ghenev, Peter I; Aloe, Luigi


    The development of atherosclerotic cardiovascular disease is a common comorbidity in patients with the metabolic syndrome, a concurrence of cardiovascular risk factors in one individual. While multiple growth factors and adipokines are identified in atherosclerotic lesions, as well as neurotrophins implicated in both cardiac ischemia and lipid and glucose metabolism, the potential role of neurotrophins in human coronary atherosclerosis and in the metabolic syndrome still remains to be elucidated. Here we describe and discuss our results that represent a novel attempt to study the cardiovascular and metabolic biology of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and mast cells (MC). The local amount of NGF, the immunolocalization of p75 neurotrophin receptor (p75NTR) and the number of MC were correlatively examined in coronary vascular wall and in the surrounding subepicardial adipose tissue, obtained from autopsy cases in humans with advanced coronary atherosclerosis. We also analyzed the plasma levels of NGF, BDNF and leptin and the number of MC in biopsies from abdominal subcutaneous adipose tissue in patients with a severe form of the metabolic syndrome. The results demonstrate that NGF levels are decreased in atherosclerotic coronary vascular tissue but increased in the subepicardial adipose tissue, whereas both tissues express a greater number of MC and a stronger p75NTR immunoreactivity, compared to controls. Metabolic syndrome patients display a significant hyponeurotrophinemia and an increased number of adipose MC; the later correlates with elevated plasma leptin levels. In effect, we provide the first evidence for (i) an altered presence of NGF, p75NTR and MC in both coronary vascular and subepicardial adipose tissue in human coronary atherosclerosis, and (ii) a significant decrease in plasma NGF and BDNF levels and an elevated amount of plasma leptin and adipose MC in metabolic syndrome patients. Together our findings suggest that

  16. VEGF Deficit is Involved in Endothelium Dysfunction in Preeclampsia

    Institute of Scientific and Technical Information of China (English)

    周琼; 刘海意; 乔福元; 吴媛媛; 徐京晶


    This study examined the association of expression of vascular endothelial growth factor(VEGF),a promoter of angiogenesis,with endothelium dysfunction in preeclampsia.The level of VEGF protein and mRNA in the placenta and peripheral blood samples of 30 preeclampsia patients and 30 normotensive pregnant women was measured by immunohistochemistry,real-time reverse transcriptase-polymerase chain reaction(RT-PCR) and enzyme-linked immunosorbent assay(ELISA),respectively.VEGF expression in the human umbilical vei...

  17. STAT6 mediates apoptosis of human coronary arterial endothelial cells by interleukin-13. (United States)

    Nishimura, Yuki; Nitto, Takeaki; Inoue, Teruo; Node, Koichi


    Interleukin (IL)-13 is a cytokine produced by type 2 helper T cells that has pathophysiological roles in allergic inflammation and fibrosis formation. IL-13 shares many functional properties with IL-4, which promotes apoptosis of endothelial cells (ECs). We here investigated the effects of IL-13 on apoptosis using human coronary artery endothelial cells (HCAECs). Assessment by WST-1 assay demonstrated that IL-13 as well as IL-4 significantly inhibited cell growth. IL-13 significantly attenuated the cell viability and induced apoptosis of HCAECs as well. Expression of mRNA for vascular endothelial cell growth factor, which maintains survival of ECs, was significantly diminished by IL-13. The effects of IL-13 and IL-4 were abolished by depletion of STAT6 using RNA interference. These results suggest that IL-13 attenuates EC viability by inducing apoptosis, and that STAT6 plays pivotal roles on IL-13- and IL-4-induced apoptosis in ECs.

  18. Adrenomedullin is a potent inhibitor of angiotensin II-induced migration of human coronary artery smooth muscle cells. (United States)

    Kohno, M; Yokokawa, K; Kano, H; Yasunari, K; Minami, M; Hanehira, T; Yoshikawa, J


    The migration of coronary artery medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerotic lesions. In the current study, we examined the possible interaction of adrenomedullin, a novel vasorelaxant peptide, and angiotensin II (Ang II) on human coronary artery SMC migration using Boyden's chamber method. Ang II stimulated SMC migration in a concentration-dependent manner between 10(6) and 10(8) mol/L. This stimulation was clearly blocked by the Ang II type 1 receptor antagonist losartan but not by the type 2 receptor antagonist PD 123319. The migration stimulatory effect of Ang II was chemotactic in nature for cultured human coronary artery SMCs but was not chemokinetic. Human adrenomedullin clearly inhibited Ang II-induced migration in a concentration-dependent manner. Human adrenomedullin stimulated cAMP formation in these cells. Inhibition by adrenomedullin of Ang II-induced SMC migration was paralleled by an increase in the cellular level of cAMP. 8-Bromo-cAMP, a cAMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the Ang II-induced SMC migration. These results suggest that Ang II stimulates SMC migration via type 1 receptors in human coronary artery and adrenomedullin inhibits Ang II-induced migration at least partly through a cAMP-dependent mechanism. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, this peptide may play a role as a local antimigration factor in certain pathological conditions.

  19. Impact of Human Development Index on the profile and outcomes of patients with acute coronary syndrome. (United States)

    Roy, Ambuj; Roe, Matthew T; Neely, Megan L; Cyr, Derek D; Zamoryakhin, Dmitry; Fox, Keith A A; White, Harvey D; Armstrong, Paul W; Ohman, E Magnus; Prabhakaran, Dorairaj


    To study the impact of national economic and human development status on patient profiles and outcomes in the setting of acute coronary syndrome (ACS). We conducted a retrospective analysis of the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial (TRILOGY ACS) population (51 countries; 9301 patients). Outcome measures compared baseline characteristics and clinical outcomes through 30 months by 2010 country-level United Nations Human Development Indices (HDIs) and per-capita gross national income. TRILOGY ACS enrolled 3659 patients from 27 very-high HDI countries, 3744 from 18 high-HDI countries and 1898 from 6 medium-HDI countries. Baseline characteristics of groups varied significantly, with the medium-HDI group having a lower mean age (63.0 years, vs 65.0 and 68.0 years for high-HDI and very-high HDI, respectively; p<0.001), lower baseline Global Registry of Acute Coronary Events risk score and lower rate of non-ST-segment elevation myocardial infarction (58.0%, vs 62.2% and 83.9% among high-HDI and very-high HDI, respectively). Medium-HDI and high-HDI patients had lower unadjusted 30-month rates for the composite of cardiovascular death/myocardial infarction/stroke (17.6%, 16.9% and 23.1% for medium-HDI, high-HDI and very-high HDI, respectively); this difference disappeared after adjusting for baseline characteristics. Adjusted HRs for the composite endpoint were lower in lower-income/middle-income countries vs upper-income/middle-income (0.791(95% CI 0.632 to 0.990)) and high-income countries (0.756 (95% CI 0.616 to 0.928)), with differences largely attributable to myocardial infarction rates. Clinical patient profiles differed substantially by country HDI groupings. Lower unadjusted event rates in medium-HDI countries may be explained by younger age and lower comorbidity burden among these countries' patients. This heterogeneity in patient recruitment across country HDI groupings may have

  20. Aggressive restenosis after percutaneous intervention in two coronary loci in a patient with human immunodeficiency virus infection (United States)

    Alkhalil, Mohammad; Conlon, Christopher P; Ashrafian, Houman; Choudhury, Robin P


    A 54-year-old black African woman, 22 years human immunodeficiency virus (HIV)-positive, presented with an acute coronary syndrome. She was taking two nucleoside reverse transcriptase inhibitors and two protease inhibitors. Viral load and CD4 count were stable. Angiography revealed a right coronary artery lesion, which was treated with everolimus eluting stent. She also underwent balloon angioplasty to the first diagonal. She re-presented on three different occasions and technically successful coronary intervention was performed. The patient has reported satisfactory compliance with dual anti platelet therapy throughout. She was successfully treated with surgical revascularisation. The patient did not experience any clinical recurrence on follow up. This case demonstrates exceptionally aggressive multifocal and recurrent instent restenosis in a patient treated for HIV infection, raising the possibility of an association with HIV infection or potentially components of retro viral therapy. PMID:28255546

  1. Perturbation of human coronary artery endothelial cell redox state and NADPH generation by methylglyoxal.

    Directory of Open Access Journals (Sweden)

    Philip E Morgan

    Full Text Available Diabetes is associated with elevated plasma glucose, increased reactive aldehyde formation, oxidative damage, and glycation/glycoxidation of biomolecules. Cellular detoxification of, or protection against, such modifications commonly requires NADPH-dependent reducing equivalents (e.g. GSH. We hypothesised that reactive aldehydes may modulate cellular redox status via the inhibition of NADPH-generating enzymes, resulting in decreased thiol and NADPH levels. Primary human coronary artery endothelial cells (HCAEC were incubated with high glucose (25 mM, 24 h, 37°C, or methylglyoxal (MGO, glyoxal, or glycolaldehyde (100-500 µM, 1 h, 37°C, before quantification of intracellular thiols and NADPH-generating enzyme activities. Exposure to MGO, but not the other species examined, significantly (P<0.05 decreased total thiols (∼35%, further experiments with MGO showed significant losses of GSH (∼40% and NADPH (∼10%; these changes did not result in an immediate loss of cell viability. Significantly decreased (∼10% NADPH-producing enzyme activity was observed for HCAEC when glucose-6-phosphate or 2-deoxyglucose-6-phosphate were used as substrates. Cell lysate experiments showed significant MGO-dose dependent inhibition of glucose-6-phosphate-dependent enzymes and isocitrate dehydrogenase, but not malic enzyme. Analysis of intact cell or lysate proteins showed that arginine-derived hydroimidazolones were the predominant advanced glycation end-product (AGE formed; lower levels of N(ε-(carboxyethyllysine (CEL and N(ε-(carboxymethyllysine (CML were also detected. These data support a novel mechanism by which MGO exposure results in changes in redox status in human coronary artery endothelial cells, via inhibition of NADPH-generating enzymes, with resultant changes in reduced protein thiol and GSH levels. These changes may contribute to the endothelial cell dysfunction observed in diabetes-associated atherosclerosis.

  2. Localization of oxidized low-density lipoprotein and its relation to plaque morphology in human coronary artery.

    Directory of Open Access Journals (Sweden)

    Yasumi Uchida

    Full Text Available OBJECTIVES: Oxidized low-density lipoprotein (oxLDL plays a key role in the formation of atherosclerotic plaques. However, its localization in human coronary arterial wall is not well understood. The present study was performed to visualize deposition sites and patterns of native oxLDL and their relation to plaque morphology in human coronary artery. METHODS: Evans blue dye (EB elicits a violet fluorescence by excitation at 345-nm and emission at 420-nm, and a reddish-brown fluorescence by excitation at 470-nm and emission at 515-nm characteristic of oxLDL only. Therefore, native oxLDL in excised human coronary artery were investigated by color fluorescent microscopy (CFM using EB as a biomarker. RESULTS: (1 By luminal surface scan with CFM, the % incidence of oxLDL in 38 normal segments, 41 white plaques and 32 yellow plaques that were classified by conventional angioscopy, was respectively 26, 44 and 94, indicating significantly (p<0.05 higher incidence in the latter than the former two groups. Distribution pattern was classified as patchy, diffuse and web-like. Web-like pattern was observed only in yellow plaques with necrotic core. (2 By transected surface scan, oxLDL deposited within superficial layer in normal segments and diffusely within both superficial and deep layers in white and yellow plaques. In yellow plaques with necrotic core, oxLDL deposited not only in the marginal zone of the necrotic core but also in the fibrous cap. CONCLUSION: Taken into consideration of the well-known process of coronary plaque growth, the results suggest that oxLDL begins to deposit in human coronary artery wall before plaque formation and increasingly deposits with plaque growth, exhibiting different deposition sites and patterns depending on morphological changes.

  3. Chronic Kidney Disease and Endothelium

    Directory of Open Access Journals (Sweden)

    Damir Rebić


    Full Text Available The endothelial cell layer is responsible for molecular traffic between the blood and surrounding tissue, and endothelial integrity plays a pivotal role in many aspects of vascular function. Cardiovascular disease (CVD is the main cause of death in patients with chronic kidney disease (CKD and its incidence and severity increase in direct proportion with kidney function decline. Non-traditional risk factors for CVDs, including endothelial dysfunction (ED, are highly prevalent in this population and play an important role in cardiovascular (CV events. ED is the first step in the development of atherosclerosis and its severity has prognostic value for CV events. Several risk markers have been associated with ED. Reduced bioavailability of nitric oxide plays a central role, linking kidney disease to ED, atherosclerosis, and CV events. Inflammation, loss of residual renal function, and insulin resistance are closely related to ED in CKD. ED may be followed by structural damage and remodelling that can precipitate both bleeding and thrombotic events. The endothelium plays a main role in vascular tone and metabolic pathways. ED is the first, yet potentially reversible step in the development of atherosclerosis and its severity has prognostic value for CV events.

  4. Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. (United States)

    Joshi, Mandar S; Mineo, Chieko; Shaul, Philip W; Bauer, John Anthony


    Human endothelial nitric oxide synthase (NOS3) gene polymorphism at Exon 7 (Glu298Asp) has been linked to vascular endothelial dysfunction, but the mechanisms are not defined. Shear is a key modulator of NOS3 function in vivo and association with caveolae is important for the control of NOS3 protein activity. Here we tested the hypothesis that altered enrichment of NOS3 in the caveolar membrane defines Glu298Asp genotype-specific responses and NOS3 activity. Basal caveolar membrane enrichment was carried out to quantitate the NOS3 enrichment in caveolae. Cells were subjected to shear and NOS3 protein levels, phosphorylation, enzyme function were investigated. Variant genotypes had lower NOx production pre- and post-shear, but no genotype-dependent alterations in pNOS3 were observed. Asp variants had significantly lower NOS3 enrichment in the caveolar membrane fraction. Further, immunoprecipitation studies demonstrated that Asp variants had substantially less NOS3/Cav-1 association (approximately 40%) during static conditions. Furthermore, acute shear causes impaired NOS3/Cav-1 dissociation in Asp variants. The results from immunoprecipitation studies were in complete agreement with caveolar membrane preparation findings. Collectively, these data demonstrate functional consequences of the Glu298Asp NOS3 variation and further define disruption of NOS3 caveolar localization and shear-induced mobilization as the primary mechanism responsible for these differences.

  5. Translating the microRNA signature of microvesicles derived from human coronary artery smooth muscle cells in patients with familial hypercholesterolemia and coronary artery disease. (United States)

    de Gonzalo-Calvo, David; Cenarro, Ana; Garlaschelli, Katia; Pellegatta, Fabio; Vilades, David; Nasarre, Laura; Camino-Lopez, Sandra; Crespo, Javier; Carreras, Francesc; Leta, Rubén; Catapano, Alberico Luigi; Norata, Giuseppe Danilo; Civeira, Fernando; Llorente-Cortes, Vicenta


    To analyze the impact of atherogenic lipoproteins on the miRNA signature of microvesicles derived from human coronary artery smooth muscle cells (CASMC) and to translate these results to familial hypercholesterolemia (FH) and coronary artery disease (CAD) patients. Conditioned media was collected after exposure of CASMC to atherogenic lipoproteins. Plasma samples were collected from two independent populations of diagnosed FH patients and matched normocholesterolemic controls (Study population 1, N=50; Study population 2, N=24) and a population of patients with suspected CAD (Study population 3, N=50). Extracellular vesicles were isolated and characterized using standard techniques. A panel of 30 miRNAs related to vascular smooth muscle cell (VSMC) (patho-)physiology was analyzed using RT-qPCR. Atherogenic lipoproteins significantly reduced levels of miR-15b-5p, -24-3p, -29b-3p, -130a-3p, -143-3p, -146a-3p, -222-3p, -663a levels (Pmicrovesicles (0.1μm-1μm in diameter) released by CASMC. Two of these miRNAs, miR-24-3p and miR-130a-3p, were reduced in circulating microvesicles from FH patients compared with normocholesterolemic controls in a pilot study (Study population 1) and in different validation studies (Study populations 1 and 2) (Pmicrovesicles and these alterations are reflected in patients with FH. Circulating miR-130a-3p emerges as a potential biomarker for coronary atherosclerosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Integration of multi-modality imaging for accurate 3D reconstruction of human coronary arteries in vivo (United States)

    Giannoglou, George D.; Chatzizisis, Yiannis S.; Sianos, George; Tsikaderis, Dimitrios; Matakos, Antonis; Koutkias, Vassilios; Diamantopoulos, Panagiotis; Maglaveras, Nicos; Parcharidis, George E.; Louridas, George E.


    In conventional intravascular ultrasound (IVUS)-based three-dimensional (3D) reconstruction of human coronary arteries, IVUS images are arranged linearly generating a straight vessel volume. However, with this approach real vessel curvature is neglected. To overcome this limitation an imaging method was developed based on integration of IVUS and biplane coronary angiography (BCA). In 17 coronary arteries from nine patients, IVUS and BCA were performed. From each angiographic projection, a single end-diastolic frame was selected and in each frame the IVUS catheter was interactively detected for the extraction of 3D catheter path. Ultrasound data was obtained with a sheath-based catheter and recorded on S-VHS videotape. S-VHS data was digitized and lumen and media-adventitia contours were semi-automatically detected in end-diastolic IVUS images. Each pair of contours was aligned perpendicularly to the catheter path and rotated in space by implementing an algorithm based on Frenet-Serret rules. Lumen and media-adventitia contours were interpolated through generation of intermediate contours creating a real 3D lumen and vessel volume, respectively. The absolute orientation of the reconstructed lumen was determined by back-projecting it onto both angiographic planes and comparing the projected lumen with the actual angiographic lumen. In conclusion, our method is capable of performing rapid and accurate 3D reconstruction of human coronary arteries in vivo. This technique can be utilized for reliable plaque morphometric, geometrical and hemodynamic analyses.

  7. The impact of scaled boundary conditions on wall shear stress computations in atherosclerotic human coronary bifurcations. (United States)

    Schrauwen, Jelle T C; Schwarz, Janina C V; Wentzel, Jolanda J; van der Steen, Antonius F W; Siebes, Maria; Gijsen, Frank J H


    The aim of this study was to determine if reliable patient-specific wall shear stress (WSS) can be computed when diameter-based scaling laws are used to impose the boundary conditions for computational fluid dynamics. This study focused on mildly diseased human coronary bifurcations since they are predilection sites for atherosclerosis. Eight patients scheduled for percutaneous coronary intervention were imaged with angiography. The velocity proximal and distal of a bifurcation was acquired with intravascular Doppler measurements. These measurements were used for inflow and outflow boundary conditions for the first set of WSS computations. For the second set of computations, absolute inflow and outflow ratios were derived from geometry-based scaling laws based on angiography data. Normalized WSS maps per segment were obtained by dividing the absolute WSS by the mean WSS value. Absolute and normalized WSS maps from the measured-approach and the scaled-approach were compared. A reasonable agreement was found between the measured and scaled inflows, with a median difference of 0.08 ml/s [-0.01; 0.20]. The measured and the scaled outflow ratios showed a good agreement: 1.5 percentage points [-19.0; 4.5]. Absolute WSS maps were sensitive to the inflow and outflow variations, and relatively large differences between the two approaches were observed. For normalized WSS maps, the results for the two approaches were equivalent. This study showed that normalized WSS can be obtained from angiography data alone by applying diameter-based scaling laws to define the boundary conditions. Caution should be taken when absolute WSS is assessed from computations using scaled boundary conditions.

  8. Endothelium-dependent vasodilation in response to Pseudomonas aeruginosa lipopolysaccharide: an in vitro study on canine arteries

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    P.R.B. Evora


    Full Text Available Early systemic arterial hypotension is a common clinical feature of Pseudomonas septicemia. To determine if Pseudomonas aeruginosa endotoxin induces the release of endothelium-derived nitric oxide (EDNO, an endogenous nitrovasodilator, segments of canine femoral, renal, hepatic, superior mesenteric, and left circumflex coronary arteries were suspended in organ chambers (physiological salt solution, 95% O2/5% CO2, pH 7.4, 37oC to measure isometric force. In arterial segments contracted with 2 µM prostaglandin F2a, Pseudomonas endotoxin (lipopolysaccharide (LPS serotype 10(Habs from Pseudomonas aeruginosa (0.05 to 0.50 mg/ml induced concentration-dependent relaxation of segments with endothelium (P<0.05 but no significant change in tension of arteries without endothelium. Endothelium-dependent relaxation in response to Pseudomonas LPS occurred in the presence of 1 µM indomethacin, but could be blocked in the coronary artery with 10 µM NG-monomethyl-L-arginine (L-NMMA, a competitive inhibitor of nitric oxide synthesis from L-arginine. The inhibitory effect of L-NMMA on LPS-mediated vasorelaxation of the coronary artery could be reversed by exogenous 100 µM L-arginine but not by 100 µM D-arginine. These experiments indicate that Pseudomonas endotoxin induces synthesis of nitric oxide from L-arginine by the vascular endothelium. LPS-mediated production of EDNO by the endothelium, possibly through the action of constitutive nitric oxide synthase (NOSc, may decrease systemic vascular resistance and may be the mechanism of early hypotension characteristic of Pseudomonas septicemia.

  9. Angioscopic observation of coronary lesions in Kawasaki disease (United States)

    Ishikawa, Hiromi


    Kawasaki disease is an acute systematic angiitis, specifically affecting the coronary arteries in young children. Coronary aneurysms develop in 10 to 15% of patients with Kawasaki disease. The coronary aneurysm frequently changes into coronary stenosis and obstruction. Hitherto, we could observe and access the severity of these coronary lesions with the use of two dimensional echocardiography and selective coronary angiography. Angiography is the most sensitive means available for diagnosing significant coronary lesions and their severity. However, it is insensitive for detecting intraluminal minute and pathologic changes such as intimal thickening, regeneration of endothelium and thrombus. Recent advance in fiberscopie technology, enabled us to observe the inside of coronary artery percutaneously. We tried to use this angioscopic technique for the observation of coronary lesions in eight patients with Kawasaki disease at chronic stage.

  10. Scutellarin Reduces Endothelium Dysfunction through the PKG-I Pathway

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    Xiaohua Du


    Full Text Available Purpose. In this report, we investigated the protective mechanism of scutellarin (SCU in vitro and in vivo which could be involved in endothelial cGMP-dependent protein kinase (PKG, vasodilator stimulated phosphoprotein (VASP pathway, and vascular endothelium dysfunction (EtD. Method. Human brain microvascular endothelial cells (HBMECs with hypoxia reoxygenation (HR treatment and rats with cerebral ischemia reperfusion (CIR treatment were applied. Protein and mRNA expression of PKG, VASP, and p-VASP were evaluated by Western blot and RT-PCR methods. Vascular EtD was assessed by using wire myography to determine endothelium-dependent vasorelaxation in isolated rat basilar artery (BA. Result. In cultured HBMECs, SCU (0.1, 1, and 10 μM increased cell viability, mRNA, protein level, and phosphorylative activity of PKG and VASP against HR injury. In HR model of BA, SCU increased protein level of P-VASP. In rat CIR model, wire myography demonstrated that SCU (45 and 90 mg/kg, i.v. significantly reduced ischemic size by partially restoring the endothelium dependent vasodilation of BA; PKG inhibitor Rp-8-Br-cGMPS (50 μg/kg, i.v. reversed this protection of SCU in CIR rats. Conclusion. SCU protects against cerebral vascular EtD through endothelial PKG pathway activation.

  11. Augmented TLR2 Expression on Monocytes in both Human Kawasaki Disease and a Mouse Model of Coronary Arteritis


    I-Chun Lin; Ho-Chang Kuo; Ying-Jui Lin; Feng-Shen Wang; Lin Wang; Shun-Chen Huang; Shao-Ju Chien; Chien-Fu Huang; Chih-Lu Wang; Hong-Ren Yu; Rong-Fu Chen; Yang, Kuender D.


    BACKGROUND: Kawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis. METHODS: Recruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globul...

  12. Augmented TLR2 expression on monocytes in both human Kawasaki disease and a mouse model of coronary arteritis.

    Directory of Open Access Journals (Sweden)

    I-Chun Lin

    Full Text Available BACKGROUND: Kawasaki disease (KD of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE-induced coronary arteritis. METHODS: Recruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globulin (IVIG treatment at the Kaohsiung Chang Gung Memorial Hospital from 2001 to 2009. Blood samples from KD patients were collected before and after IVIG treatment, and cardiovascular abnormalities were examined by transthoracic echocardiography. Wild-type male BALB/c mice (4-week-old were intraperitoneally injected with LCWE (1 mg/mL to induce coronary arteritis. The induced immune response in mice was examined on days 1, 3, 7, and 14 post injections, and histopathology studies were performed on days 7 and 14. RESULTS: Both human KD patients and LCWE-treated mice developed coronary arteritis, myocarditis, valvulitis, and pericarditis, as well as elevated plasma levels of interleukin (IL-2, IL-6, IL-10, monocyte chemoattractant protein (MCP-1, and tumor necrosis factor (TNF-α in acute phase. Most of these proinflammatory cytokines declined to normal levels in mice, whereas normal levels were achieved in patients only after IVIG treatment, with a few exceptions. Toll-like receptor (TLR-2, but not TLR4 surface enhancement on circulating CD14+ monocytes, was augmented in KD patients before IVIG treatment and in LCWE-treated mice, which declined in patients after IVIG treatment. CONCLUSION: This result suggests that that not only TLR2 augmentation on CD14+ monocytes might be an inflammatory marker for both human KD patients and LCWE-induced CAL mouse model but also this model is feasible for studying therapeutic strategies of coronary arteritis in human KD by

  13. Augmented TLR2 expression on monocytes in both human Kawasaki disease and a mouse model of coronary arteritis. (United States)

    Lin, I-Chun; Kuo, Ho-Chang; Lin, Ying-Jui; Wang, Feng-Shen; Wang, Lin; Huang, Shun-Chen; Chien, Shao-Ju; Huang, Chien-Fu; Wang, Chih-Lu; Yu, Hong-Ren; Chen, Rong-Fu; Yang, Kuender D


    Kawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis. Recruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globulin (IVIG) treatment at the Kaohsiung Chang Gung Memorial Hospital from 2001 to 2009. Blood samples from KD patients were collected before and after IVIG treatment, and cardiovascular abnormalities were examined by transthoracic echocardiography. Wild-type male BALB/c mice (4-week-old) were intraperitoneally injected with LCWE (1 mg/mL) to induce coronary arteritis. The induced immune response in mice was examined on days 1, 3, 7, and 14 post injections, and histopathology studies were performed on days 7 and 14. Both human KD patients and LCWE-treated mice developed coronary arteritis, myocarditis, valvulitis, and pericarditis, as well as elevated plasma levels of interleukin (IL)-2, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α in acute phase. Most of these proinflammatory cytokines declined to normal levels in mice, whereas normal levels were achieved in patients only after IVIG treatment, with a few exceptions. Toll-like receptor (TLR)-2, but not TLR4 surface enhancement on circulating CD14+ monocytes, was augmented in KD patients before IVIG treatment and in LCWE-treated mice, which declined in patients after IVIG treatment. This result suggests that that not only TLR2 augmentation on CD14+ monocytes might be an inflammatory marker for both human KD patients and LCWE-induced CAL mouse model but also this model is feasible for studying therapeutic strategies of coronary arteritis in human KD by modulating TLR2-mediated immune activation on CD14

  14. Structure of the Proboscis Endothelium in Nemertea. (United States)

    Magarlamov, Timur Yu; Chernyshev, Alexei V


    We studied the ultrastructure of the proboscis endothelium of 14 nemertean species. In all nemerteans examined, the endothelium is organized as a pseudostratified myoepithelium consisting of two types of cells resting on the basal extracellular matrix: apically situated supportive cells and subapical myocytes covered by cytoplasmic sheets of the supportive cells. Myocytes form the inner circular musculature of the proboscis; the endothelium in the bulb of monostiliferous nemerteans lacks myocytes. The endothelium of the studied species differs in the number of rows of muscle fibres (one vs. several rows), the number of myofibrils in myocytes (one vs. two to five), the number of processes of myocytes covered by one supportive cell (one vs. two to 23), and in the number of processes in supportive cells (one vs. two to five). In some of the species, rudimentary cilia of supportive cells were revealed by using cLSM and an antibody against tubulin. The data obtained indicate that the proboscis endothelium in nemerteans is in fact a coelothelium, but recognition of the ancestral state of the coelomic lining in Nemertea is problematic, as the rhynchocoel peritoneum lacks myocytes.

  15. Effects of Dietary Decosahexaenoic Acid (Dha) on eNOS in Human Coronary Artery Endothelial Cells (United States)

    Stebbins, Charles L.; Stice, James P.; Hart, C. Michael; Mbai, Fiona N.; Knowlton, Anne A.


    Endothelial dysfunction occurs in heart disease, and may reduce functional capacity via attenuations in peripheral blood flow. Dietary DHA may improve this dysfunction, but the mechanism is unknown. We determined if DHA enhances expression and activity of eNOS in cultured human coronary artery endothelial cells (HCAEC). HCAEC from 4 donors were treated with 5 nM, 50 nM, or 1 μM DHA for 7 days to model chronic DHA exposure. A trend for increased expression of eNOS and phospho-eNOS was observed with 5 and 50 nM DHA. DHA also enhanced expression of two proteins instrumental in activation of eNOS; phospho-Akt (5 and 50 nM) and HSP90 (50 nM and 1 μM). VEGF-induced activation of Akt increased NOx in treated (50 nM DHA) vs. untreated HCAEC (9.2±1.0 vs. 3.3±1.1 μmols/μg protein/μl). Findings suggest that DHA enhances eNOS and Akt activity, augments HSP90 expression, and increases NO bioavailability in response to Akt kinase activation PMID:18682551

  16. Intracellular Ca(2+) remodeling during the phenotypic journey of human coronary smooth muscle cells. (United States)

    Muñoz, Eva; Hernández-Morales, Miriam; Sobradillo, Diego; Rocher, Asunción; Núñez, Lucía; Villalobos, Carlos


    Vascular smooth muscle cells undergo phenotypic switches after damage which may contribute to proliferative disorders of the vessel wall. This process has been related to remodeling of Ca(2+) channels. We have tested the ability of cultured human coronary artery smooth muscle cells (hCASMCs) to return from a proliferative to a quiescent behavior and the contribution of intracellular Ca(2+) remodeling to the process. We found that cultured, early passage hCASMCs showed a high proliferation rate, sustained increases in cytosolic [Ca(2+)] in response to angiotensin II, residual voltage-operated Ca(2+) entry, increased Stim1 and enhanced store-operated currents. Non-steroidal anti-inflammatory drugs inhibited store-operated Ca(2+) entry and abolished cell proliferation in a mitochondria-dependent manner. After a few passages, hCASMCs turned to a quiescent phenotype characterized by lack of proliferation, oscillatory Ca(2+) response to angiotensin II, increased Ca(2+) store content, enhanced voltage-operated Ca(2+) entry and Cav1.2 expression, and decreases in Stim1, store-operated current and store-operated Ca(2+) entry. We conclude that proliferating hCASMCs return to quiescence and this switch is associated to a remodeling of Ca(2+) channels and their control by subcellular organelles, thus providing a window of opportunity for targeting phenotype-specific Ca(2+) channels involved in proliferation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Colocalization of Serum Amyloid A with Microtubules in Human Coronary Artery Endothelial Cells

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    Katja Lakota


    Full Text Available Serum amyloid A (SAA acts as a major acute phase protein and represents a sensitive and accurate marker of inflammation. Besides its hepatic origin, as the main source of serum SAA, this protein is also produced extrahepatically. The mRNA levels of SAA become significantly elevated following proinflammatory stimuli, as well as, are induced through their own positive feedback in human primary coronary artery endothelial cells. However, the intracellular functions of SAA are so far unknown. Colocalization of SAA with cytoskeletal filaments has previously been proposed, so we analyzed the colocalization of SAA with all three cytoskeletal elements: actin filaments, vimentin filaments, and microtubules. Immunofluorescent double-labeling analyses confirmed by PLA method revealed a strict colocalization of SAA with microtubules and a very infrequent attachment to vimentin while the distribution of actin filaments appeared clearly separated from SAA staining. Also, no significant colocalization was found between SAA and endomembranes labeled with the fluorescent lipid stain DiO6. However, SAA appears to be located also unbound in the cytosol, as well as inside the nucleus and within nanotubes extending from the cells or bridging neighboring cells. These different locations of SAA in endothelial cells strongly indicate multiple potential functions of this protein.

  18. Markers of inflammation collocate with increased wall stress in human coronary arterial plaque. (United States)

    Hallow, Karen Melissa; Taylor, W Robert; Rachev, Alexander; Vito, Raymond Peter


    In this study, we hypothesized that spatial relationships exist between the local mechanical environment and inflammatory marker expression in atherosclerotic plaques, and that these relationships are plaque-progression dependent. Histologic cross-sections were collected at regular intervals along the length of diseased human coronary arteries and classified as early, intermediate, advanced, or mature based on their morphological features. For each cross-section, the spatial distribution of stress was determined using a 2D heterogeneous finite element model, and the corresponding distribution of selected inflammatory markers (macrophages, matrix metalloproteinase-1 [MMP-1], and nuclear factor-kappa B [NF-κB]) were determined immunohistochemically. We found a monotonic spatial relationship between mechanical stress and activated NF-κB that was consistent in all stages of plaque progression. We also identified progression-dependent relationships between stress and both macrophage presence and MMP-1 expression. These findings add to our understanding of the role of mechanical stress in stimulating the inflammatory response, and help explain how mechanical factors may regulate complex biological changes in remodeling.

  19. The endothelium - the cardiovascular health barometer. (United States)

    Herrmann, Joerg; Lerman, Amir


    Once considered to fulfill no other purpose than that of a physical barrier between blood and tissue, the multifunctional nature of the endothelium was discovered in the later half of the 20th century. In cardiology, the dysfunctional nature of the endothelium has received even more attention, initially mainly within the research community but later also in the clinical community, serving as a prime example for the translation of bench research to patient care. In this review, the entity of endothelial dysfunction, its modes of diagnosis in clinical practice, its prognostic implications, and its treatment options will be defined. From past conceptual ideas to current practical applications to the road ahead, the endothelium is to be viewed as the cardiovascular health barometer.

  20. Effect of Nateglinide and Glibenclamide on Endothelial Cells and Smooth Muscle Cells from Human Coronary Arteries

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    Seeger H


    Full Text Available In the present work the effect of nateglinide and glibenclamide, two different substances used for therapy of diabetes mellitus type 2, were investigated on the synthesis of markers of endothelial function and on the proliferation of smooth muscle cells in vitro. As cell models endothelial and smooth muscle cells from human coronary arteries were used. Both substances were tested at concentrations of 0.1, 1 and 10 mmol/l. As markers of endothelial function prostacyclin, endothelin and plasminogen-activator-inhibitor-1 (PAI-1 were tested. Nateglinide and glibenclamide were similarly able to inhibit endothelial endothelin and PAI-1 synthesis, but only at the highest concentration tested. Endothelial prostacyclin synthesis and proliferation of smooth muscle cells were not significantly changed by both substances. These results indicate that both nateglinide and glibenclamide may have potential in reducing negative long-term effects of diabetes such as atherogenesis. Kurzfassung: Effekt von Nateglinid und Glibenclamid auf Endothel- und Muskelzellen humaner Koronararterien. In der vorliegenden Arbeit wurde die Wirkung von Nateglinid und Glibenclamid, zweier unterschiedlicher Substanzen zur Behandlung des Diabetes mellitus Typ 2, auf die Synthese von Markern der Endothelfunktion und auf die Proliferation glatter Muskelzellen untersucht. Als Zellmodell dienten Endothelzellen und glatte Muskelzellen menschlicher Koronararterien. Beide Substanzen wurden in den Konzentrationen 0,1, 1 und 10 mmol/l getestet. Als Marker der Endothelfunktion dienten Prostazyklin, Endothelin und Plasminogen-Aktivator-Inhibitor-1 (PAI-1. Sowohl Nateglinid als auch Glibenclamid konnten die endotheliale Endothelin- und PAI-1-Produktion in ähnlichem Ausmaß senken, allerdings nur in der höchsten Konzentration. Die Prostazyklinsynthese und die Muskelzellproliferation wurden nicht signifikant beeinflußt. Diese Ergebnisse deuten daraufhin, daß sowohl Nateglinid als auch

  1. Characterization of plaque components with intravascular ultrasound elastography in human femoral and coronary arteries in vitro

    NARCIS (Netherlands)

    C.L. de Korte (Chris); G. Pasterkamp (Gerard); H.A. Woutman; N. Bom (Klaas); A.F.W. van der Steen (Ton)


    textabstractBACKGROUND: The composition of plaque is a major determinant of coronary-related clinical syndromes. Intravascular ultrasound (IVUS) elastography has proven to be a technique capable of reflecting the mechanical properties of phantom material and the femoral arterial

  2. Coexpression Analysis Reveals Key Gene Modules and Pathway of Human Coronary Heart Disease. (United States)

    Tang, Yu; Ke, Zun-Ping; Peng, Yi-Gen; Cai, Ping-Tai


    Coronary heart disease is a kind of disease which causes great injury to people world-widely. Although gene expression analyses had been performed previously, to our best knowledge, systemic co-expression analysis for this disease is still lacking to date. Microarray data of coronary heart disease was downloaded from NCBI with the accession number of GSE20681. Co-expression modules were constructed by WGCNA. Besides, the connectivity degree of eigengenes was analyzed. Furthermore, GO and KEGG enrichment analysis was performed on these eigengenes in these constructed modules. A total of 11 co-expression modules were constructed by the 3,000 up-regulated genes from the 99 samples with coronary heart disease. The average number of genes in these modules was 270. The interaction analysis indicated the relative independence of gene expression in these modules. The functional enrichment analysis showed that there was a significant difference in the enriched terms and degree among these 11 modules. The results showed that module 9 and module 10 played critical roles in the occurrence of coronary disease. Pathways of hsa00190(Oxidative phosphorylation)and (hsa01130: Biosynthesis of antibiotics) were thought to be closely related to the occurrence and development of coronary heart disease. Our result demonstrated that module 9 and module 10 were the most critical modules in the occurrence of coronary heart disease. Pathways as hsa00190(Oxidative phosphorylation) and (hsa01130: Biosynthesis of antibiotics) had the potential to serve as the prognostic and predictive marker of coronary heart disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  3. Stimulatory interactions between human coronary smooth muscle cells and dendritic cells.

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    Sara Paccosi

    Full Text Available Despite inflammatory and immune mechanisms participating to atherogenesis and dendritic cells (DCs driving immune and non-immune tissue injury response, the interactions between DCs and vascular smooth muscle cells (VSMCs possibly relevant to vascular pathology including atherogenesis are still unclear. To address this issue, immature DCs (iDCs generated from CD14+ cells isolated from healthy donors were matured either with cytokines (mDCs, or co-cultured (ccDCs with human coronary artery VSMCs (CASMCs using transwell chambers. Co-culture induced DC immunophenotypical and functional maturation similar to cytokines, as demonstrated by flow cytometry and mixed lymphocyte reaction. In turn, factors from mDCs and ccDCs induced CASMC migration. MCP-1 and TNFα, secreted from DCs, and IL-6 and MCP-1, secreted from CASMCs, were primarily involved. mDCs adhesion to CASMCs was enhanced by CASMC pre-treatment with IFNγ and TNFα ICAM-1 and VCAM-1 were involved, since the expression of specific mRNAs for these molecules increased and adhesion was inhibited by neutralizing antibodies to the counter-receptors CD11c and CD18. Adhesion was also inhibited by CASMC pre-treatment with the HMG-CoA-reductase inhibitor atorvastatin and the PPARγ agonist rosiglitazone, which suggests a further mechanism for the anti-inflammatory action of these drugs. Adhesion of DCs to VSMCs was shown also in vivo in rat carotid 7 to 21 days after crush and incision injury. The findings indicate that DCs and VSMCs can interact with reciprocal stimulation, possibly leading to perpetuate inflammation and vascular wall remodelling, and that the interaction is enhanced by a cytokine-rich inflammatory environment and down-regulated by HMGCoA-reductase inhibitors and PPARγ agonists.

  4. Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration. (United States)

    Kohno, M; Yokokawa, K; Yasunari, K; Minami, M; Kano, H; Hanehira, T; Yoshikawa, J


    The objectives of the present study were (1) to determine whether lysophosphatidylcholine (lyso-PC), a prominent component of oxidatively modified LDL, induces migration of human coronary artery smooth muscle cells (SMCs) and, if so, to clarify the mechanism, and (2) to investigate the possible interactions of lyso-PC and platelet-derived growth factor (PDGF)-BB, endothelin- (ET-1), adrenomedullin (AM), or vitamin E on SMC migration by the Boyden's chamber method. Lyso-PC induced SMC migration in a concentration-dependent manner between 10(-6) and 5 x 10(-5) mol/L. By contrast, phosphatidylcholine was without significant activity, and lysophosphatidylinositol and lysophosphatidylserine were much less effective than lyso-PC. Lyso-PC increased basic fibroblast growth factor (bFGF) production in a concentration-dependent manner between 10(-6) and 5 x 10(-5) mol/L in these cells. Furthermore, lyso-PC-induced SMC migration was inhibited by neutralizing antibody to bFGF but not by neutralizing antibody to transforming growth factor-beta1. Lyso-PC-induced migration was significantly enhanced by PDGF-BB or ET-1 but was clearly inhibited by human AM and vitamin E. These results indicate that (1) lyso-PC induces human coronary artery SMC migration at least in part through release of endogenous bFGF and (2) this lyso-PC-induced migration can be further induced by PDGF-BB and ET-1 and can be inhibited by human AM and vitamin E. Lyso-PC may recruit medial SMCs during the process of coronary atherosclerosis in part by releasing bFGF in concert with PDGF-BB or ET-1 in vascular tissues. This lyso-PC-induced SMC migration may be suppressed by AM and vitamin E under certain pathological conditions.

  5. Key role of endothelium in the eNOS-dependent cardioprotection with exercise training. (United States)

    Farah, C; Nascimento, A; Bolea, G; Meyer, G; Gayrard, S; Lacampagne, A; Cazorla, O; Reboul, C


    Modulation of endothelial nitric oxide synthase (eNOS) activation is recognized as a main trigger of the cardioprotective effects of exercise training on heart vulnerability to ischemia-reperfusion (IR). However, this enzyme is expressed both in coronary endothelial cells and cardiomyocytes and the contribution of each one to such cardioprotection has never been challenged. The aim of this study was to investigate the role of eNOS from the cardiomyocytes vs. the endothelium in the exercise cardioprotection. Male Wistar rats were assigned to a chronic aerobic training (Ex) (vs. sedentary group; Sed) and we investigated the role of eNOS in the effects of exercise on sensitivity to IR or anoxia-reoxygenation (A/R) at whole heart, isolated cardiomyocytes and left coronary artery (LCA) levels. We observed that exercise increased eNOS activation (Ser1177 phosphorylation) and protein S-nitrosylation in whole heart but not at cardiomyocyte level, suggesting the specific target of endothelial cells by exercise. Consistently, in isolated cardiomyocytes submitted to the A/R procedure, exercise reduced cell death and improved cells contractility, but independently of the eNOS pathway. Next, to evaluate the contribution of endothelial cells in exercise cardioprotection, LCA were isolated before and after an IR procedure performed on Langendorff hearts. Exercise improved basal relaxation sensitivity to acetylcholine and markedly reduced the alteration of endothelium-dependent coronary relaxation induced by IR. Furthermore, inactivation of coronary endothelial cells activity just before IR, obtained with a bolus of Triton X-100, totally suppressed cardioprotective effects of exercise on both left ventricular functional recovery after IR and infarct size, whereas no effect of Triton X-100 was observed in Sed group. In conclusion, these results show that coronary endothelial cells rather than cardiomyocytes play a key role in the eNOS-dependent cardioprotection of exercise.

  6. Systolic and diastolic changes in human coronary blood flow during Valsalva manoeuvre. (United States)

    Federici, A; Ciccone, M; Gattullo, D; Losano, G


    Valsalva manoeuvre is reported to be sometimes successful for the relief of angina pectoris. The present study investigated how haemodynamic changes produced by Valsalva manoeuvre can interact to improve the relationship between cardiac work and coronary blood flow. Ten male subjects aged 53 +/- 12 years (SD) were considered. Blood velocity in the internal mammary artery, previously anastomosed to the left descending coronary artery, was studied with Doppler technique. The subjects performed Valsalva manoeuvres by expiring into a tube connected to a mercury manometer, to develop a pressure of 40 mmHg. The arterial blood pressure curve was continuously monitored with a Finapres device from a finger of the left hand. During expiratory effort, an increase in heart rate and a decrease in arterial pulse pressure were followed by a more delayed and progressive increase in mean and diastolic pressures. Systolic blood velocity markedly decreased along with the reduction in pulse pressure and increase in heart rate. By contrast, diastolic and mean coronary blood velocities did not show any significant change. Since it is known that the Valsalva manoeuvre strongly reduces stroke volume and cardiac output, it is likely that a reduction in cardiac work also takes place. Since in diastole, i.e. when the myocardial wall is better perfused, coronary blood velocity did not show any significant reduction, it is likely that unchanged perfusion in the presence of reduced cardiac work is responsible for the relief from angina sometimes observed during Valsalva manoeuvre. It is also likely that the increase in heart rate prevents the diastolic and mean blood coronary velocity from decreasing during the expiratory strain, when an increased sympathetic discharge could cause vasoconstriction through the stimulation of the coronary alpha-receptors.

  7. Interaction of variable bacterial outer membrane lipoproteins with brain endothelium.

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    Gaurav Gandhi

    Full Text Available BACKGROUND: Previously we reported that the variable outer membrane lipoprotein Vsp1 from the relapsing fever spirochete Borrelia turicatae disseminates from blood to brain better than the closely related Vsp2 [1]. Here we studied the interaction between Vsp1 and Vsp2 with brain endothelium in more detail. METHODOLOGY/PRINCIPAL FINDINGS: We compared Vsp1 to Vsp2 using human brain microvascular endothelial cell (HBMEC association assays with aminoacid radiolabeled Vsp-expressing clones of recombinant Borrelia burgdorferi and lanthanide-labeled purified lipidated Vsp1 (LVsp1 and Vsp2 (LVsp2 and inoculations of the lanthanide-labeled proteins into mice. The results showed that heterologous expression of LVsp1 or LVsp2 in B. burgdorferi increased its association with HBMEC to a similar degree. Purified lanthanide-labeled lipidated Vsp1 (LVsp1 and LVsp2 by themselves were capable of associating with HBMEC. The association of LVsp1 with brain endothelium was time-dependent, saturable, and required the lipidation. The association of Vsp1 with HBMEC was inhibited by incubation at lower temperature or with excess unlabeled LVsp1 or LVsp2 but not with excess rVsp1 or mouse albumin or an anti Vsp1 monoclonal antibody. The association of LVsp2 with HBMEC and its movement from blood to brain parenchyma significantly increased in the presence of LVsp1. CONCLUSIONS/SIGNIFICANCE: Variable bacterial outer membrane lipoproteins interact with brain endothelium differently; the lipidation and variable features at the protein dome region are key modulators of this interaction.

  8. Coronary Artery Anomalies in Animals

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    Brian A. Scansen


    Full Text Available Coronary artery anomalies represent a disease spectrum from incidental to life-threatening. Anomalies of coronary artery origin and course are well-recognized in human medicine, but have received limited attention in veterinary medicine. Coronary artery anomalies are best described in the dog, hamster, and cow though reports also exist in the horse and pig. The most well-known anomaly in veterinary medicine is anomalous coronary artery origin with a prepulmonary course in dogs, which limits treatment of pulmonary valve stenosis. A categorization scheme for coronary artery anomalies in animals is suggested, dividing these anomalies into those of major or minor clinical significance. A review of coronary artery development, anatomy, and reported anomalies in domesticated species is provided and four novel canine examples of anomalous coronary artery origin are described: an English bulldog with single left coronary ostium and a retroaortic right coronary artery; an English bulldog with single right coronary ostium and transseptal left coronary artery; an English bulldog with single right coronary ostium and absent left coronary artery with a prepulmonary paraconal interventricular branch and an interarterial circumflex branch; and a mixed-breed dog with tetralogy of Fallot and anomalous origin of all coronary branches from the brachiocephalic trunk. Coronary arterial fistulae are also described including a coronary cameral fistula in a llama cria and an English bulldog with coronary artery aneurysm and anomalous shunting vessels from the right coronary artery to the pulmonary trunk. These examples are provided with the intent to raise awareness and improve understanding of such defects.

  9. Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement

    NARCIS (Netherlands)

    Z. Zhou (Zhichao); O. Sorop (Oana); V.J. de Beer (Vincent Jacob); I. Heinonen (Ilkka); C. Cheng (Caroline); A.H.J. Danser (Jan); D.J.G.M. Duncker (Dirk); D. Merkus (Daphne)


    textabstractWe previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of

  10. Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus. (United States)

    Yahagi, Kazuyuki; Kolodgie, Frank D; Lutter, Christoph; Mori, Hiroyoshi; Romero, Maria E; Finn, Aloke V; Virmani, Renu


    The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification.

  11. Activation of endothelium by immunotherapy with interleukin-2 in patients with malignant disorders. (United States)

    Locker, G J; Kapiotis, S; Veitl, M; Mader, R M; Stoiser, B; Kofler, J; Sieder, A E; Rainer, H; Steger, G G; Mannhalter, C; Wagner, O F


    Treatment with intravenous recombinant human interleukin-2 (rh IL-2) is frequently accompanied by the capillary leak syndrome and disturbances of the coagulation system. Although the exact mechanisms are still not fully understood, the involvement of the endothelium is proven. This investigation aimed to elucidate more precisely the role of the endothelium in the generation of IL-2-based side-effects. In nine tumour patients receiving intravenous rh IL-2, parameters characterizing endothelial cell activation as well as activation of the coagulation system were evaluated. A significant increase of the circulating endothelial leucocyte adhesion molecule-1 (cELAM-1) and the vasoconstrictor peptide endothelin-1 (ET-1) was observed (P<0.05), indicating activation of endothelial cells. The simultaneous increase of tissue-plasminogen activator and plasminogen activator inhibitor type-1 during therapy (P<0.05) corroborated this observation. A decrease in platelet count parallelled by an increase of fibrin degradation products, the prolongation of partial thromboplastin time, and the decrease of fibrinogen (P<0.05) suggested the development of disseminated intravascular coagulation (DIC), induced by activated endothelium and intensified by transient hepatic failure. We concluded that activation of the endothelium mediated by IL-2 was accompanied by a loss of endothelial integrity and capillary leak. The activated endothelium can trigger DIC via activation of the coagulation cascade. The increased ET-1 might act as an endogenous counter-regulator of the disadvantageous haemodynamic side-effects induced by IL-2.

  12. Measurement of the ultrasonic properties of human coronary arteries in vitro with a 50-MHz acoustic microscope

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    Machado J.C.


    Full Text Available Ultrasonic attenuation coefficient, wave propagation speed and integrated backscatter coefficient (IBC of human coronary arteries were measured in vitro over the -6 dB frequency bandwidth (36 to 67 MHz of a focused ultrasound transducer (50 MHz, focal distance 5.7 mm, f/number 1.7. Corrections were made for diffraction effects. Normal and diseased coronary artery sub-samples (N = 38 were obtained from 10 individuals at autopsy. The measured mean ± SD of the wave speed (average over the entire vessel wall thickness was 1581.04 ± 53.88 m/s. At 50 MHz, the average attenuation coefficient was 4.99 ± 1.33 dB/mm with a frequency dependence term of 1.55 ± 0.18 determined over the 36- to 67-MHz frequency range. The IBC values were: 17.42 ± 13.02 (sr.m-1 for thickened intima, 11.35 ± 6.54 (sr.m-1 for fibrotic intima, 39.93 ± 50.95 (sr.m-1 for plaque, 4.26 ± 2.34 (sr.m-1 for foam cells, 5.12 ± 5.85 (sr.m-1 for media and 21.26 ± 31.77 (sr.m-1 for adventitia layers. The IBC results indicate the possibility for ultrasound characterization of human coronary artery wall tissue layer, including the situations of diseased arteries with the presence of thickened intima, fibrotic intima and plaque. The mean IBC normalized with respect to the mean IBC of the media layer seems promising for use as a parameter to differentiate a plaque or a thickened intima from a fibrotic intima.

  13. Tibolone and its metabolites acutely relax rabbit coronary arteries in vitro

    DEFF Research Database (Denmark)

    Lund, Claus Otto; Nilas, Lisbeth; Pedersen, Susan Helene


    OBJECTIVES: To compare the acute effects of estradiol, tibolone and its metabolites on coronary arteries in vitro and to investigate possible vascular mechanisms. METHODS: Coronary artery ring segments from female rabbits were mounted in myographs for isometric tension recordings. Concentration.......05, ANOVA). CONCLUSIONS: Our data indicate that the acute relaxation induced by tibolone and its metabolites in coronary arteries in vitro are probably mediated by endothelium independent inhibition of calcium channels but may also involve an endothelium-dependent mechanism via nitric oxide. The effect...

  14. Dehydroepiandrosterone (DHEA) inhibition of monocyte binding by vascular endothelium is associated with sialylation of neural cell adhesion molecule. (United States)

    Curatola, Anna-Maria; Huang, Kui; Naftolin, Frederick


    Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects. (1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence-labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting. Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by ≥50% (P DHEA's inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane. In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen- and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis.

  15. 焦虑状态的干预对急性冠脉综合征患者血管内皮功能及血小板活化的影响%The imapct of anti-anxiety therapy on vascular endothelium function and platelet activation in patients with acute coronary syndrome

    Institute of Scientific and Technical Information of China (English)

    袁敏; 杨国灿; 郭航远; 彭放; 裘宇芳; 房溶娟; 周妍; 孙勇; 周国忠; 王兴木


    目的 探讨焦虑情绪障碍和抗焦虑治疗对急性冠脉综合征(ACS)患者血管内皮功能及血小板活化状态的影响及其临床意义.方法 前瞻、对照方法观察2009年1月至2010年12月入住绍兴人民医院心内科的ACS患者139例,排除严重心衰、肝肾功能不全、炎性感染、苯二氮卓类药物过敏、2周内服用过任何抗精神类药物、无法完成问卷调查者.经汉密尔顿焦虑量表(HAMA)评定,入选焦虑组患者68例,非焦虑组患者71例.检测两组患者血清一氧化氮(NO)、内皮素(ET)、活化血小板CD62p、CD63水平和肱动脉血流介导的血管舒张功能(FMD);并将68例焦虑患者随机分为焦虑A组和焦虑B组,在基础治疗同时分别给予劳拉西泮片0.5 mg,2次/d和安慰剂(维生素B6片)10 mg,2次/d治疗,2周后再次检测上述指标并进行HAMA评定.采用独立样本t检验和x2检验进行组间计量资料及计数资料的比较.结果 焦虑组与非焦虑组ACS患者相比,NO水平和FMD明显降低(t=2.090和2.558,P=0.038和0.012),ET、CD62p、CD63的水平明显升高(t=2.082,2.042和2.145,P=0.039,0.043和0.034).抗焦虑治疗前焦虑A组和焦虑B组上述参数以及HAMA评分比较差异无统计学意义;经劳拉西泮2周治疗后,焦虑A组与焦虑B组相比较,NO水平和FMD明显升高(t=2.821和2.246,P=0.006和0.028),而ET,CD62p,CD63水平和HAMA评分则显著降低(t=2.107,3.242,2.079,7.779,P=0.039,0.002,0.041,0.001).结论 焦虑情绪障碍可明显加重ACS患者血管内皮功能紊乱,激活血小板,而积极的抗焦虑干预,则可有效地改善内皮功能和血小板的活化,从而改善ACS患者的临床预后.%Objective To investigate the effects of anxiety and anti - anxiety therapy on vascular endothelium function and platelet activation in patients with acute coronary syndrome (ACS).Methods One hundred and thirty -nine ACS patients were enrolled in this prospective and controlled clinical study from January

  16. Resistin Enhances Inflammatory Cytokine Production in Coronary Artery Tissues by Activating the NF-κB Signaling

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    Fang Gao


    Full Text Available Purpose. Kawasaki disease (KD is a systemic vasculitis and is a leading cause of coronary artery lesions (CALs in childhood. Our previous study has shown higher levels of serum Resistin in KD patients with coronary aneurysm. This study aimed at examining the association of Resistin with inflammatory cytokine expression in mouse model of coronary arteritis and determining the potential mechanisms. Methods. C57BL/6 mice were injected with Lactobacillus cell wall extract (LCWE to induce coronary arteritis. The relative levels of Resistin, TNF-α, IL-1β, and MMP-9 expression and inflammatory infiltrates in the coronary arteries were determined longitudinally by quantitative RT-PCR, ELISA, and histology. The effect of TLR4 and NF-κB activation on Resistin-induced TNF-α and IL-1β expression in human coronary artery endothelium cells (HCAECs was examined by quantitative RT-PCR. Results. Higher levels of Resistin, TNF-α, IL-1β, and MMP-9 expression were associated with the degrees of inflammatory infiltrates in the coronary artery walls of the LCWE-injected mice. Resistin enhanced TNF-α and IL-1β expression in HCAECs at 18 or 24 hours after stimulation. Pretreatment with anti-TLR4 attenuated Resistin-enhanced IL-1β, but not TNF-α, expression and pretreatment with parthenolide or QNZ demolished Resistin-enhanced TNF-α expression in HACECs. Pretreatment with parthenolide, but not QNZ, blocked Resistin-enhanced IL-1β expression in HCAECs. Conclusion. Resistin may enhance inflammation by cross-talking with TLR4/NF-κB signaling during the development of coronary arteritis in mice.

  17. Coronary microembolization. (United States)

    Skyschally, Andreas; Leineweber, Kkirsten; Gres, Petra; Haude, Michael; Erbel, Raimund; Heusch, Gerd


    Atherosclerotic plaque rupture is the key event in the pathogenesis of acute coronary syndromes and it also occurs during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. This review summarizes the present experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and highlights the main consequences of coronary microembolization--reduced coronary reserve, microinfarction, inflammation and oxidative modification of contractile proteins, contractile dysfunction and perfusion-contraction mismatch.Furthermore, the review presents the available clinical evidence for coronary microembolization in patients and compares the clinical observations with observations in the experimental model.

  18. Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease.

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    Yijing Zhang

    Full Text Available Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell

  19. Scientific Opinion on the substantiation of a health claim related to cocoa flavanols and maintenance of normal endothelium-dependent vasodilation pursuant to Article 13(5 of Regulation (EC No 1924/2006

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    EFSA Panel on Dietetic Products, Nutrition and Allergies


    Full Text Available

    Following an application from Barry Callebaut Belgium nv, submitted pursuant to Article 13(5 of Regulation (EC No 1924/2006 via the Competent Authority of Belgium, the Panel on Dietetic Products, Nutrition and Allergies (NDA was asked to deliver an opinion on the scientific substantiation of a health claim related to cocoa flavanols and maintenance of normal endothelium-dependent vasodilation. Cocoa flavanols are sufficiently characterised. The claimed effect is “help maintain endothelium-dependent vasodilation which contributes to healthy blood flow”. The target population proposed by the applicant is the general healthy adult population. The Panel considers that maintenance of normal endothelium-dependent vasodilation is a beneficial physiological effect. In weighing the evidence, the Panel took into account that cocoa flavanols consumed for 12 weeks have been shown to increase fasting ED-FMD significantly in the target population in one human intervention study, that in another study the effect was dose-dependent and occurred after one week of consumption, that the effect was supported by two additional studies, and that it was also observed in two out of three studies in patients under pharmacological treatment for coronary artery disease, although the mechanisms by which regular consumption of cocoa flavanols may induce a sustained effect on fasting ED-FMD are unknown. The Panel concludes that a cause and effect relationship has been established between the consumption of cocoa flavanols and maintenance of normal endothelium-dependent vasodilation. The following wording reflects the scientific evidence: “Cocoa flavanols help maintain endothelium-dependent vasodilation, which contributes to normal blood flow”. In order to obtain the claimed effect, 200 mg of cocoa flavanols should be consumed daily. This amount could be provided by 2.5 g of high-flavanol cocoa powder or 10 g of high-flavanol dark chocolate, both of which can be

  20. Binding of human coronary artery endothelial cells to plasma-treated titanium dioxide nanotubes of different diameters. (United States)

    Flašker, Ajda; Kulkarni, Mukta; Mrak-Poljšak, Katjuša; Junkar, Ita; Čučnik, Saša; Žigon, Polona; Mazare, Anca; Schmuki, Patrik; Iglič, Aleš; Sodin-Semrl, Snezna


    Nanoscale topography in improving vascular response in vitro was established previously on various titanium surfaces. In the present study different surface nanotopographies that is different diameters of titanium dioxide (TiO2 ) nanotubes (NTs) were fabricated by electrochemical anodization and conditioned with highly reactive gaseous oxygen plasma. The morphology of different diameter NTs was studied by scanning electron microscopy and atomic force microscopy, while changes in chemical composition on the surface before and after plasma treatment were determined by X-ray photoelectron spectroscopy. Performance of human coronary artery endothelial cells (HCAEC) on those conditioned surfaces was studied in regard to cell proliferation, released IL-6 protein and immunofluorescence microscopy (IFM). We show that HCAEC function is dependent on the diameter of the TiO2 NTs, functioning far less optimally when bound to 100 nm TiO2 NTs as compared to Ti foil, 15 nm NTs or 50 nm NTs. There were improved, morphological cell shape changes, observed with IFM, between HCAEC growing on oxygen-rich plasma-treated versus nontreated 100 nm NTs. These endothelialized conditioned Ti nanosurfaces could elucidate optimization conditions necessary for vascular implants in coronary arteries.

  1. Effects of abciximab on key pattern of human coronary restenosis in vitro: impact of the SI/MPL-ratio

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    Baur Regine


    Full Text Available Abstract Background The significant reduction of angiographic restenosis rates in the ISAR-SWEET study (intracoronary stenting and antithrombotic regimen: is abciximab a superior way to eliminate elevated thrombotic risk in diabetes raises the question of whether abciximab acts on clopidogrel-independent mechanisms in suppressing neointimal hyperplasia. The current study investigates the direct effect of abciximab on ICAM-1 expression, migration and proliferation. Methods ICAM-1: Part I of the study investigates in cytoflow studies the effect of abciximab (0.0002, 0.002, 0.02, 0.2, 2.0, and 20.0 μg/ml on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1. Migration: Part II of the study explored the effect of abciximab (0.0002, 0.002, 0.02, 0.2, 2.0, and 20.0 μg/ml on migration of HCMSMC over a period of 24 h. Proliferation: Part III of the study investigated the effect of abciximab (0.0002, 0.002, 0.02, 0.2, 2.0, and 20.0 μg/ml on proliferation of HUVEC, HCAEC, and HCMSMC after an incubation period of 5 days. Results ICAM-1: In human venous endothelial cells (HUVEC, human coronary endothelial cells (HCAEC and human coronary medial smooth muscle cells (HCMSMC no inhibitory or stimulatory effect on expression of ICAM-1 was detected. Migration: After incubation of HCMSMC with abciximab in concentrations of 0.0002 – 2 μg/ml a stimulatory effect on cell migration was detected, statistical significance was achieved after incubation with 0.002 μg/ml (p 1. Conclusion Thus, the anti-restenotic effects of systemically administered abciximab reported in the ISAR-SWEET-study were not caused by a direct inhibitory effect on ICAM-1 expression, migration or proliferation.

  2. Toxicological effects of beryllium on platelets and vascular endothelium. (United States)

    Togna, G; Togna, A R; Russo, P; Caprino, L


    Although ample research has described the toxic effects of the metal beryllium on the respiratory apparatus, less is known about its effects on the vascular apparatus, including pulmonary blood vessels. We investigated the in vitro effects of beryllium on endothelial vascular adenosine diphosphatase activity and prostacyclin production in bovine aortic endothelium, and on nitric oxide release in isolated rabbit arteries. Rabbit and human platelet responsiveness was also evaluated. Beryllium inhibited vascular endothelial adenosine diphosphatase activity, prostacyclin production, and nitric oxide release, thus inducing functional alterations in vascular endothelial cells. It also induced platelet hyperreactivity to arachidonic acid, as shown by a lowering of the threshold of aggregating concentration and by concurrently increasing thromboxane production. In contrast, beryllium left the response to aggregating and nonaggregating concentrations of ADP and collagen unchanged. These findings show that beryllium may impair some vascular endothelial functions and alter the interaction between platelet and endothelial mediators.


    NARCIS (Netherlands)



    Background. At present, there is extensive knowledge on the clinical course of coronary artery disease (CAD), whereas data on the underlying anatomical changes and their relation to clinical events are still limited. Methods and Results. We investigated progression and regression of CAD prospectivel

  4. Unsteady Integrodifferential Equation of Fluid-Structure Interaction in Constricted Collapsible Tube Model of Diseased Human Coronary Artery

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    Eric Velaski Tuema


    Full Text Available Unsteady flow in a collapsible tube is analyzed to simulate a diseased human coronary artery. The novelty of the approach is that the set of equations governing the fluid-structure interaction is reduced to a single integrodifferential equation in the transient state. The equation is then solved using the finite difference method to obtain the flow characteristics and compliant wall behavior. Three control parameters are investigated, namely, Reynolds number, inlet transmural pressure, and the wall thickness. The predicted wall deflection is quite large at low Reynolds numbers, suggesting possible approach to breakdown in equilibrium. The transmural pressure increases with wall deflection and bulges appear at the ends of the membrane indicating critical stage of stability, consistent with previous studies. Increase in wall thickness reduces the wall deflection and ultimately results in its collapse which may indicate another breakdown in equilibrium. An increase in internal pressure is required to maintain membrane stability.

  5. Comparison between Adventitial and Intimal Inflammation of Ruptured and Nonruptured Atherosclerotic Plaques in Human Coronary Arteries

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    Higuchi Maria L.


    Full Text Available OBJECTIVE: To verify the possible role of adventitial inflammation in atherosclerotic plaque vulnerability and coronary artery remodelling. METHODS: We compared the mean numbers of lymphocytes in the adventitia and in the plaque of ruptured thrombosed and stable equi-stenotic coronary segments of 34 patients who died due to acute myocardial infarction. We also analysed adventitial microvessels, adventitial fibrosis and the external elastic membrane. RESULTS: In the adventitia, the numbers of lymphocytes and microvessels/mm² were 69.5±88.3 and 60.9± 32.1 in culprit lesions and 16.4 ± 21.1 and 44.3±16.1 in stable lesions (p<0.05; within the plaques, the mean number of lymphocytes was 24±40.8 in culprit lesions and 10.9±13.2 in stable ones (p=0.17. The mean percent area of adventitial fibrosis/cross-sectional area of the vessel was significantly lower in unstable plaques (p<0.001. The confocal images showed holes in the external elastic membrane. CONCLUSION: Unstable plaques exhibit chronic pan-arteritis, accompanied by enlargement, medial thinning, and less fibrosis than in stable lesions, which is compatible with vessel aneurysm. Adventitial inflammation may contribute significantly to atheroma instability.

  6. Endothelium attenuates ethanol induced vasoconstriction of arteries

    Energy Technology Data Exchange (ETDEWEB)

    Morley, D.; Bove, A.A.; Walter, J. (Temple School of Medicine, Philadelphia, PA (United States))


    The authors have previously demonstrated that clinically relevant doses of ethanol (ETH) caused significant vasoconstriction of rabbit thoracic aorta. This study examined the role of endothelium in ethanol vasoconstriction. Thoracic aorta was harvested from 3 New Zealand White rabbits after anesthetization with sodium pentobarbital. Twelve aortic 3 mm rings were mounted in organ baths attached to force transducers and recording apparatus. Six of the twelve rings were denuded. Denudation was confirmed by challenge with acetylcholine (10-4 M). Resting tension was set at 10 grams and the rings equilibrated in 37 C Krebs-Heinsleit solution for 2 hours. Then, the response to norepinephrine (NE) was established (10-8 to 10-5 M). After reattaining resting tension, the response to ETH (500-2,500 ug/ml) was recorded. ETH produced significant vasoconstriction in both non-denuded (48{plus minus}7% of NE max) and denuded (58{plus minus}2% of NE max) arteries. Vasoconstriction was significantly higher in the denuded condition. The authors conclude that the predominant ETH action on arteries is based in vascular smooth muscle although endothelium acts to attenuate the ETH induced vasoconstrictor response.

  7. Electrical resistance of a capillary endothelium (United States)


    The electrical resistance of consecutive segments of capillaries has been determined by a method in which the microvessels were treated as a leaky, infinite cable. A two-dimensional analytical model to describe the potential field in response to intracapillary current injection was formulated. The model allowed determination of the electrical resistance from four sets of data: the capillary radius, the capillary length constant, the length constant in the mesentery perpendicular to the capillary, and the relative potential drop across the capillary wall. Of particular importance were the mesothelial membranes covering the mesenteric capillaries with resistances several times higher than that of the capillary endothelium. 27 frog mesenteric capillaries were characterized. The average resistance of the endothelium was 1.85 omega cm2, which compares well with earlier determinations of the ionic permeability of such capillaries. However, heterogeneity with respect to resistance was observed, that of 10 arterial capillaries being 3.0 omega cm2 as compared with 0.95 omega cm2 for 17 mid- and venous capillaries. The average in situ length constant was 99 micrometers for the arterial capillaries and 57 micrometers for the mid- and venous capillaries. It is likely that the ions that carry the current must move paracellularly, through junctions that are leaky to small solutes. PMID:7241087


    Feoktistova, V S; Vavilkova, T V; Sirotkina, O V; Boldueva, S A; Gaikovaia, L B; Leonova, I A; Laskovets, A B; Ermakov, A I


    The endothelium dysfunction takes leading place in pathogenesis of development of cardiovascular diseases. The circulating endothelium cells of peripheral blood can act as a direct cell marker of damage and remodeling of endothelium. The study was carried out to develop a new approach to diagnose of endothelium dysfunction by force of determination of number of circulating endothelium cells using flow cytometry technique and to apply determination of circulating endothelium cells for evaluation of risk of development of ischemic heart disease in women of young and middle age. The study embraced 62 female patients with angiography confirmed ischemic heart disease, exertional angina pectoris at the level of functional class I-II (mean age 51 ± 6 years) and 49 women without anamnesis of ischemic heart disease (mean age 52 ± 9 years). The occurrence of more than three circulating endothelium cells by 3 x 105 leukocytes in peripheral blood increases relative risk of development of ischemic heart disease up to 4 times in women of young and middle age and risk of development of acute myocardial infarction up to 8 times in women with ischemic heart disease. The study demonstrated possibility to apply flow cytometry technique to quantitatively specify circulating endothelium cells in peripheral blood and forecast risk of development of ischemic heart disease in women of young and middle age depending on level of circulating endothelium cells.

  9. Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated up-regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto-placental endothelium. (United States)

    Hiden, U; Lassance, L; Tabrizi, N Ghaffari; Miedl, H; Tam-Amersdorfer, C; Cetin, I; Lang, U; Desoye, G


    Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion. Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis. Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors. Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, Pfeto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature.

  10. Coronary hemodynamics and myocardial metabolism during and after pacing stress in normal humans. (United States)

    Camici, P; Marraccini, P; Marzilli, M; Lorenzoni, R; Buzzigoli, G; Puntoni, R; Boni, C; Bellina, C R; Klassen, G A; L'Abbate, A


    We investigated coronary hemodynamics, myocardial utilization of circulating substrates (by coronary sinus catheterization), and overall use of oxidative fuels (by regional indirect calorimetry) in healthy adults during incremental atrial pacing (up to 159 +/- 9 beats/min), and during 25 min of recovery. Great cardiac vein flow (thermodilution) increased from 52 +/- 9 to 115 +/- 15 ml/min (P less than 0.001) with pacing; myocardial O2 uptake (301 +/- 53 to 593 +/- 71 mumol/min, P less than 0.001) and CO2 production (225 +/- 37 to 518 +/- 66 mumol/min, P less than 0.005) paralleled the pacing-induced rise in rate-pressure product (9.4 +/- 0.9 to 21.1 +/- 1.1 mmHg.beat. min-1.10(-3), P less than 0.001). During recovery, all the above variables returned to base line within 5 min, but myocardial O2 extraction remained depressed (67 +/- 2 vs. 71 +/- 3%, P less than 0.05). Circulating glucose uptake rose linearly with pacing (P less than 0.05) and remained above base line throughout recovery. By contrast, free fatty acid (FFA) uptake (10 mumol/min) did not increase with pacing and fell during recovery (P less than 0.01). Calorimetry, however, showed that net lipid oxidation exceeded FFA uptake throughout the study, whereas net carbohydrate oxidation was small at base line, rose significantly at maximal pacing (62% of myocardial energy output), and remained above base line during recovery (32% of energy output). In the basal state as well as during recovery, myocardial uptake of glucose equivalents (lactate plus glucose plus pyruvate) was in excess of carbohydrate oxidation, indicating nonoxidative disposal of these substrates.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Comprehensive metabolomics identified lipid peroxidation as a prominent feature in human plasma of patients with coronary heart diseases

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    Jianhong Lu


    Full Text Available Coronary heart disease (CHD is a complex human disease associated with inflammation and oxidative stress. The underlying mechanisms and diagnostic biomarkers for the different types of CHD remain poorly defined. Metabolomics has been increasingly recognized as an enabling technique with the potential to identify key metabolomic features in an attempt to understand the pathophysiology and differentiate different stages of CHD. We performed comprehensive metabolomic analysis in human plasma from 28 human subjects with stable angina (SA, myocardial infarction (MI, and healthy control (HC. Subsequent analysis demonstrated a uniquely altered metabolic profile in these CHD: a total of 18, 37 and 36 differential metabolites were identified to distinguish SA from HC, MI from SA, and MI from HC groups respectively. Among these metabolites, glycerophospholipid (GPL metabolism emerged as the most significantly disturbed pathway. Next, we used a targeted metabolomic approach to systematically analyze GPL, oxidized phospholipid (oxPL, and downstream metabolites derived from polyunsaturated fatty acids (PUFAs, such as arachidonic acid and linoleic acid. Surprisingly, lipids associated with lipid peroxidation (LPO pathways including oxidized PL and isoprostanes, isomers of prostaglandins, were significantly elevated in plasma of MI patients comparing to HC and SA, consistent with the notion that oxidative stress-induced LPO is a prominent feature in CHD. Our studies using the state-of-the-art metabolomics help to understand the underlying biological mechanisms involved in the pathogenesis of CHD; LPO metabolites may serve as potential biomarkers to differentiation MI from SA and HC.

  12. 内皮源性缩血管因子花生四烯酸代谢物的作用多样性%Diversity of endothelium-derived vasocontracting factors--arachidonic acid metabolites

    Institute of Scientific and Technical Information of China (English)

    KURAHASHI Kazuyoshi; NISHIHASHI Tsuyoshi; TRANDAFIR Cristina Corina; WANG Ai-Min; MURAKAMI Shizuka; JI Xu


    Vascular endothelium releases vasocontracting and/or vasorelaxing substances. Here, we report the diversity of endothelium-derived vasocontracting factors (EDCFs), arachidonic acid metabolites, and discuss the pathophysiological significance. In the canine basilar artery and the rabbit intrapulmonary artery, acetylcholine-induced contractions (Ach-induced EDC) are due to endothelial thromboxane A2 (TXA2) (TXA2-type). The Ach-induced EDC in the rabbit coronary artery is due to endothelial leukotrienes (LTs) (LTs-type). In addition, in the rat coronary artery, nicotine and noradrenaline (Nad)-induced EDCs are due to endothelial COX-metabolites (COX metabolite-type). These arachidonic acid metabolites derived from endothelium (activation by vasoactive substances including Ach, Nad and nicotine) cause a contraction of vascular smooth muscle cells and may disturb the local circulation. These EDCFs (TXA2, LTs and COX-metabolites) may be involved in the pathophysiology of cardiovascular immuno-inflammatory diseases.

  13. Vascular endothelium receptors and transduction mechanisms

    CERN Document Server

    Gillis, C; Ryan, Una; Proceedings of the Advanced Studies Institute on "Vascular Endothelium: Receptors and Transduction Mechanisms"


    Beyond their obvious role of a barrier between blood and tissue, vascular endothelial cells are now firmly established as active and essential participants in a host of crucial physiological and pathophysiological functions. Probably the two most important factors responsible for promoting the current knowledge of endothelial functions are 1) observations in the late sixties-early seventies that many non-ventilatory properties of the lung could be attributed to the pulmonary endothelium and 2) the establishment, in the early and mid-seventies of procedures for routine culture of vascular endothelial cells. Many of these endothelial functions require the presence of receptors on the surface of the plasma membrane. There is now evidence for the existence among others of muscarinic, a-and /3-adrenergic, purine, insulin, histamine, bradykinin, lipoprotein, thrombin, paf, fibronectin, vitronectin, interleukin and albumin receptors. For some of these ligands, there is evidence only for the existence of endothelial ...

  14. Pressure promotes angiotensin II--mediated migration of human coronary smooth muscle cells through increase in oxidative stress. (United States)

    Yasunari, Kenichi; Maeda, Kensaku; Nakamura, Munehiro; Yoshikawa, Junichi


    Angiotensin II--mediated oxidative stress may play a role in the pathogenesis of coronary atherosclerosis. We examined the effects of pressure on the angiotensin II--mediated increase in oxidative stress and migration of cultured human coronary smooth muscle cells (SMCs). Increased pressure (100 mm Hg) by helium gas for 48 hours increased angiotensin II--mediated oxidative stress as evaluated by flow cytometry and SMC migration (from 15.9 +/- 2.2 to 32.0 +/- 2.4 cells per 4 high-power fields, P<0.05; n=8). The pressure-induced increases in oxidative stress observed appear to involve phospholipase D (PLD) and protein kinase C (PKC), inasmuch as the indirect PLD inhibitor suramin, at 100 micromol/L, and the PKC inhibitor chelerythrine, at 1 micromol/L, completely blocked the increase in angiotensin II--mediated oxidative stress induced by pressure. Pressure-induced increase in angiotensin II--mediated oxidative stress was inhibited by diphenylene iodonium chloride, an NADPH oxidase inhibitor, by 79% (P<0.05, n=8). Losartan (1 micromol/L), its active metabolite E3174 (1 micromol/L), and the antioxidant N-acetylcysteine (100 mmol/L) but not PD123319 (1 micromol/L) also blocked pressure-induced increases in angiotensin II--mediated oxidative stress and SMC migration (P<0.05, n=8). These findings suggest a novel cellular mechanism whereby pressure regulates the angiotensin II--mediated migration of SMCs, possibly via angiotensin II type 1 receptors, and which involves PLD-mediated, PKC-mediated, and NADPH oxidase--mediated increases in oxidative stress.

  15. Microvascular Coronary Artery Spasm Presents Distinctive Clinical Features With Endothelial Dysfunction as Nonobstructive Coronary Artery Disease (United States)

    Ohba, Keisuke; Sugiyama, Seigo; Sumida, Hitoshi; Nozaki, Toshimitsu; Matsubara, Junichi; Matsuzawa, Yasushi; Konishi, Masaaki; Akiyama, Eiichi; Kurokawa, Hirofumi; Maeda, Hirofumi; Sugamura, Koichi; Nagayoshi, Yasuhiro; Morihisa, Kenji; Sakamoto, Kenji; Tsujita, Kenichi; Yamamoto, Eiichiro; Yamamuro, Megumi; Kojima, Sunao; Kaikita, Koichi; Tayama, Shinji; Hokimoto, Seiji; Matsui, Kunihiko; Sakamoto, Tomohiro; Ogawa, Hisao


    Background Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers. Methods and Results Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor–borderline ischemic electrocardiogram findings at rest, limited–baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate–induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular

  16. Increased TRPC3 expression in vascular endothelium of patients with malignant hypertension

    DEFF Research Database (Denmark)

    Thilo, Florian; Loddenkemper, Christoph; Berg, Erika


    An increased expression of transient receptor potential canonical type 3 (TRPC3) cation channels has been proposed as one of the factors contributing to the pathogenesis of hypertension. To test that hypothesis we compared the expression of TRPC3 and TRPC6 as an endogenous control in human vascular...... endothelium of preglomerular arterioles in kidney biopsies from six patients with malignant hypertension and from four patients with diarrhea-associated hemolytic-uremic syndrome. Patients with malignant hypertension showed significantly higher systolic blood pressure and more prominent expression of TRPC3...... in vascular endothelium of preglomerular arterioles compared to patients with hemolytic-uremic syndrome. The expression of TRPC6 was not different between the two groups. The study supports the hypothesis that the increased expression of TRPC3 is associated with malignant hypertension in humans....

  17. Activation of group IVC phospholipase A2 by polycyclic aromatic hydrocarbons induces apoptosis of human coronary artery endothelial cells (United States)

    Richards, Sean M.; Elgayyar, Mona A.; Menn, Fu-Minn; Vulava, Vijay M.; McKay, Larry; Sanseverino, John; Sayler, Gary; Tucker, Dawn E.; Leslie, Christina C.; Lu, Kim P.; Ramos, Kenneth S.


    Exposure to environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs) found in coal tar mixtures and tobacco sources, is considered a significant risk factor for the development of heart disease in humans. The goal of this study was to determine the influence of PAHs present at a Superfund site on human coronary artery endothelial cell (HCAEC) phospholipase A2 (PLA2) activity and apoptosis. Extremely high levels of 12 out of 15 EPA high-priority PAHs were present in both the streambed and floodplain sediments at a site where an urban creek and its adjacent floodplain were extensively contaminated by PAHs and other coal tar compounds. Nine of the 12 compounds and a coal tar mixture (SRM 1597A) activated group IVC PLA2 in HCAECs, and activation of this enzyme was associated with histone fragmentation and poly (ADP) ribose polymerase (PARP) cleavage. Genetic silencing of group IVC PLA2 inhibited both 3H-fatty acid release and histone fragmentation by PAHs and SRM 1597A, indicating that individual PAHs and a coal tar mixture induce apoptosis of HCAECs via a mechanism that involves group IVC PLA2. Western blot analysis of aortas isolated from feral mice (Peromyscus leucopus) inhabiting the Superfund site showed increased PARP and caspase-3 cleavage when compared to reference mice. These data suggest that PAHs induce apoptosis of HCAECs via activation of group IVC PLA2. PMID:21132278

  18. Metabolic Characteristics of Human Hearts Preserved for 12 Hours by Static Storage, Antegrade Perfusion or Retrograde Coronary Sinus Perfusion (United States)

    Cobert, Michael L.; Merritt, Matthew E.; West, LaShondra M.; Ayers, Colby; Jessen, Michael E.; Peltz, Matthias


    Objective(s) Machine perfusion of donor hearts is a promising strategy to increase the donor pool. Antegrade perfusion is effective but can lead to aortic valve incompetence and non-nutrient flow. Experience with retrograde coronary sinus perfusion of donor hearts has been limited. We tested the hypothesis that retrograde perfusion could support myocardial metabolism over an extended donor ischemic interval. Methods Human hearts from donors rejected or not offered for transplantation were preserved for 12 hours in University of Wisconsin Machine Perfusion Solution by: 1. Static hypothermic storage 2. Hypothermic antegrade machine perfusion or 3. Hypothermic retrograde machine perfusion. Myocardial oxygen consumption (MVO2), and lactate accumulation were measured. Ventricular tissue was collected for proton (1H) and phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) to evaluate the metabolic state of the myocardium. Myocardial water content was determined at end-experiment. Results Stable perfusion parameters were maintained throughout the perfusion period with both perfusion techniques. Lactate/alanine ratios were lower in perfused hearts compared to static hearts (pperfused groups. High energy phosphates were better preserved in both perfused groups (pperfused (80.2±.8%) compared to both antegrade perfused (76.6±.8%, p=.02) and static storage hearts (76.7±1%, p=.02). Conclusions In conclusion, machine perfusion by either the antegrade or the retrograde technique can support myocardial metabolism over long intervals. Machine perfusion appears promising for long term preservation of human donor hearts. PMID:24642559

  19. Spectral characteristics of normal and atherosclerotic human coronary artery intima and media (United States)

    Morcos, N. C.; Levy, Guy C.; Rizoiu, Ioana-Mihaela; Tomita, M.


    Efficient use and specific targeting of laser energy to atherosclerotic lesions necessitate understanding of spectral characteristics of intima and media from normal and diseased segments. We report absorption, transmission, and reflectance spectra from 19 normal and 21 diseased coronary artery segments which were obtained at autopsy within 5 to 10 h post mortem and submerged in oxygenated Ringer's solution. Spectra were obtained from the luminal surface of 1 X 1 cm full thickness arteries or bluntly dissected intima and media segments in the range 250 to 2500 nm. Water peaks were subtracted. Absorption and transmission for full thickness artery, intima, and media from normal and atherosclerotic arteries shared main bands at 1150 and 1700 nm with variation in intensity. Significant differences in reflectance showed bands at 1080, 1340, 1600, 1739 nm in normal intima and media and atherosclerotic intima but absent in media from atherosclerotic arteries. Peaks at 1340, 1600, and 1739 nm in normal intima and media are equalized in atherosclerotic intima and absent in atherosclerotic media. In conclusion, absence of reflectance at 1080, 1340, 1600, and 1739 nm in atherosclerotic media may be selectively utilized to target laser energy and ablation at intimal plaque and spare media of atherosclerotic arteries.

  20. IVUS-based FSI models for human coronary plaque progression study: components, correlation and predictive analysis. (United States)

    Wang, Liang; Wu, Zheyang; Yang, Chun; Zheng, Jie; Bach, Richard; Muccigrosso, David; Billiar, Kristen; Maehara, Akiko; Mintz, Gary S; Tang, Dalin


    Atherosclerotic plaque progression is believed to be associated with mechanical stress conditions. Patient follow-up in vivo intravascular ultrasound coronary plaque data were acquired to construct fluid-structure interaction (FSI) models with cyclic bending to obtain flow wall shear stress (WSS), plaque wall stress (PWS) and strain (PWSn) data and investigate correlations between plaque progression measured by wall thickness increase (WTI), cap thickness increase (CTI), lipid depth increase (LDI) and risk factors including wall thickness (WT), WSS, PWS, and PWSn. Quarter average values (n = 178-1016) of morphological and mechanical factors from all slices were obtained for analysis. A predictive method was introduced to assess prediction accuracy of risk factors and identify the optimal predictor(s) for plaque progression. A combination of WT and PWS was identified as the best predictor for plaque progression measured by WTI. Plaque WT had best overall correlation with WTI (r = -0.7363, p WTI: (r = -0.3208, p < 1E-10); cap thickness: (r = 0.4541, p < 1E-10); CTI: (r = -0.1719, p = 0.0190); LD: (r = -0.2206, p < 1E-10); LDI: r = 0.1775, p < 0.0001). WSS had mixed correlation results.

  1. 21 CFR 250.102 - Drug preparations intended for human use containing certain “coronary vasodilators”. (United States)


    ... any representations that such drugs are effective in the management of hypertension; in the management... useful as employed under medical supervision for the management of angina pectoris in some patients: Amyl... the management of the post coronary state, except angina pectoris present after coronary occlusion...

  2. Role of Myoendothelial Gap Junctions in the Regulation of Human Coronary Artery Smooth Muscle Cell Differentiation by Laminar Shear Stress

    Directory of Open Access Journals (Sweden)

    Zongqi Zhang


    Full Text Available Background/Aims: Smooth muscle cells may dedifferentiate into the synthetic phenotype and promote atherosclerosis. Here, we explored the role of myoendothelial gap junctions in phenotypic switching of human coronary artery smooth muscle cells (HCASMCs co-cultured with human coronary artery endothelial cells (HCAECs exposed to shear stress. Methods: HCASMCs and HCAECs were seeded on opposite sides of Transwell inserts, and HCAECs were exposed to laminar shear stress of 12 dyn/cm2 or 5 dyn/cm2. The myoendothelial gap junctions were evaluated by using a multi-photon microscope. Results: In co-culture with HCAECs, HCASMCs exhibited a contractile phenotype, and maintained the expression of differentiation markers MHC and H1-calponin. HCASMCs and HCAECs formed functional intercellular junctions, as evidenced by colocalization of connexin(Cx40 and Cx43 on cellular projections inside the Transwell membrane and biocytin transfer from HCAECs to HCASMCs. Cx40 siRNA and 18-α-GA attenuated protein expression of MHC and H1-calponin in HCASMCs. Shear stress of 5 dyn/cm2 increased Cx43 and decreased Cx40 expression in HCAECs, and partly inhibited biocytin transfer from HCAECs to HCASMCs, which could be completely blocked by Cx43 siRNA or restored by Cx40 DNA transfected into HCAECs. The exposure of HCAECs to shear stress of 5 dyn/cm2 promoted HCASMC phenotypic switching, manifested by morphological changes, decrease in MHC and H1-calponin expression, and increase in platelet-derived growth factor (PDGF-BB release, which was partly rescued by Cx43 siRNA or Cx40 DNA or PDGF receptor signaling inhibitor. Conclusions: The exposure of HCAECs to shear stress of 5 dyn/cm2 caused the dysfunction of Cx40/Cx43 heterotypic myoendothelial gap junctions, which may be replaced by homotypic Cx43/Cx43 channels, and induced HCASMC transition to the synthetic phenotype associated with the activation of PDGF receptor signaling, which may contribute to shear stress

  3. Anatomic Fat Depots and Coronary Plaque Among Human Immunodeficiency Virus-Infected and Uninfected Men in the Multicenter AIDS Cohort Study. (United States)

    Palella, Frank J; McKibben, Rebeccah; Post, Wendy S; Li, Xiuhong; Budoff, Matthew; Kingsley, Lawrence; Witt, Mallory D; Jacobson, Lisa P; Brown, Todd T


    Methods.  In a cross-sectional substudy of the Multicenter AIDS Cohort Study, noncontrast cardiac computed tomography (CT) scanning for coronary artery calcium (CAC) scoring was performed on all men, and, for men with normal renal function, coronary CT angiography (CTA) was performed. Associations between fat depots (visceral adipose tissue [VAT], abdominal subcutaneous adipose tissue [aSAT], and thigh subcutaneous adipose tissue [tSAT]) with coronary plaque presence and extent were assessed with logistic and linear regression adjusted for age, race, cardiovascular disease (CVD) risk factors, body mass index (BMI), and human immunodeficiency virus (HIV) parameters. Results.  Among HIV-infected men (n = 597) but not HIV-uninfected men (n = 343), having greater VAT was positively associated with noncalcified plaque presence (odds ratio [OR] = 1.04, P aSAT and tSAT and greater median VAT among men with BMI aSAT and extent of total plaque among HIV-infected men, but not among HIV-uninfected men. Lower tSAT was associated with greater CAC and total plaque score extent regardless of HIV serostatus. Conclusions.  The presence of greater amounts of VAT and lower SAT may contribute to increased risk for coronary artery disease among HIV-infected persons.

  4. Stunning and Right Ventricular Dysfunction Is Induced by Coronary Balloon Occlusion and Rapid Pacing in Humans: Insights From Right Ventricular Conductance Catheter Studies. (United States)

    Axell, Richard G; Giblett, Joel P; White, Paul A; Klein, Andrew; Hampton-Til, James; O'Sullivan, Michael; Braganza, Denise; Davies, William R; West, Nick E J; Densem, Cameron G; Hoole, Stephen P


    We sought to determine whether right ventricular stunning could be detected after supply (during coronary balloon occlusion [BO]) and supply/demand ischemia (induced by rapid pacing [RP] during transcatheter aortic valve replacement) in humans. Ten subjects with single-vessel right coronary artery disease undergoing percutaneous coronary intervention with normal ventricular function were studied in the BO group. Ten subjects undergoing transfemoral transcatheter aortic valve replacement were studied in the RP group. In both, a conductance catheter was placed into the right ventricle, and pressure volume loops were recorded at baseline and for intervals over 15 minutes after a low-pressure BO for 1 minute or a cumulative duration of RP for up to 1 minute. Ischemia-induced diastolic dysfunction was seen 1 minute after RP (end-diastolic pressure [mm Hg]: 8.1±4.2 versus 12.1±4.1, Pright coronary artery balloon occlusion both cause ischemic right ventricular dysfunction with stunning observed later during the procedure. This may have intraoperative implications in patients without right ventricular functional reserve. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  5. [Clinicofunctional evaluation of ischemic episodes and vascular endothelium in patients with type 2 diabetes]. (United States)

    Tatarchenko, I P; Pozdniakova, N V; Dudukina, E A; Morozova, O I


    The aim of the investigation was to study the significance of the functional condition of endothelium for the evaluation of ischemic episodes in patients with type 2 diabetes mellitus (DM2). Ninety-three patients (52 men; 41 women; mean age 58.3+/-4.8 years) were examined. Group 1 consisted of 47 patients with coronary heart disease (CHD) and CD2; group 2 consisted of 46 CAD patients without carbohydrate exchange disorder. Both groups were comparable by gender, age, and the main risk factors. The patients were examined using Holter monitoring, physical load test, EchoCG, reactive hyperemia test (ultrasound evaluation of the endothelium-dependent brachial artery dilation). The number of painless ischemic episodes (PIE), the total duration of ischemia, the maximum degree of ST depression prevailed in group 1 patients. Correlation analysis demonstrated a significant negative correlation between endothelial dysfunction, one the one part, and the number and duration of PIE and the time between the ischemic ST depression and pain syndrome, on the other, in group 1 patients.

  6. Asymmetric subcellular distribution of glucose transporters in the endothelium of small contractile arteries. (United States)

    Gaudreault, N; Scriven, D R L; Moore, E D W


    The authors have recently reported the presence and asymmetric distribution of the glucose transporters GLUT-1 to -5 and SGLT-1 in the endothelium of rat coronary artery (Gaudreault et al. 2004, Diabetologica, 47, 2081-2092). In the present study the authors investigate and compare the presence and subcellular distribution of the classic glucose transporter isoforms in endothelial cells of cerebral, renal, and mesenteric arteries. The GLUTs and SGLT-1 were examined with immunohistochemistry and wide-field fluorescence microscopy coupled to deconvolution in en face preparation of intact artery. We identified GLUT-1 to -5 and SGLT-1 in the endothelial cells of all three vascular beds. The relative level of expression for each isoform was found comparable amongst arteries. Clusters of the glucose transporter isoforms were found at a high density in proximity to the cell-to-cell junctions. In addition, a consistent asymmetric distribution of GLUT-1 to -5 was found, predominantly located on the abluminal side of the endothelium in all three vascular beds examined (ranging from 68% to 91%, p<.05). The authors conclude that the expression and subcellular distribution of glucose transporters are similar in endothelial cells from vascular beds of comparable diameter and suggest that their subcellular organization may facilitate transendothelial transport of glucose in small contractile arteries.

  7. Influence of acute renal failure on coronary vasoregulation in dogs. (United States)

    Kingma, John G; Vincent, Chantal; Rouleau, Jacques R; Kingma, Iris


    Impaired renal function is associated with an increased risk for cardiovascular events and death, but the pathophysiology is poorly defined. The hypothesis that coronary blood flow regulation and distribution of ventricular blood flow could be compromised during acute renal failure (ARF) was tested. In two separate groups (n = 14 each) of dogs with ARF, (1) coronary autoregulation (pressure-flow relations), vascular reserve (reactive hyperemia), and myocardial blood flow distribution (microspheres) and (2) coronary vessel responses to intracoronary infusion of select endothelium-dependent and -independent vasodilators were evaluated. In addition, coronary pressure-flow relations and vascular reserve after inhibition of nitric oxide and prostaglandin release were evaluated. Under resting conditions, myocardial oxygen consumption increased in dogs with ARF compared with no renal failure (NRF; 11.8 +/- 9.2 versus 5.0 +/- 1.5 ml O(2)/min per 100 g; P = 0.01), and the autoregulatory break point of the coronary pressure-flow relation was shifted to higher diastolic coronary pressures (60 +/- 17 versus 52 +/- 8 mmHg in NRF; P = 0.003); the latter was shifted further rightward after inhibition of both nitric oxide and prostaglandin release. The endocardial/epicardial blood flow ratio was comparable for both groups, suggesting preserved ventricular distribution of blood flow. In dogs with ARF, coronary vascular conductance also was reduced (P = 0.001 versus NRF), but coronary zero-flow pressure was unchanged. Vessel reactivity to each endothelium-dependent/independent compound also was blunted significantly. In conclusion, under resting conditions, coronary vascular tone, reserve, and vessel reactivity are markedly diminished with ARF, suggesting impaired vascular function. Consequently, during ARF, small increases in myocardial oxygen demand would induce subendocardial ischemia as a result of a limited capacity to increase oxygen supply and thereby contribute to higher

  8. Endothelial and non-endothelial coronary blood flow reserve and left ventricular dysfunction in systemic hypertension

    Directory of Open Access Journals (Sweden)

    Aloísio Marchi Rocha


    Full Text Available OBJECTIVES: We evaluated the impairment of endothelium-dependent and endothelium-independent coronary blood flow reserve after administration of intracoronary acetylcholine and adenosine, and its association with hypertensive cardiac disease. INTRODUCTION: Coronary blood flow reserve reduction has been proposed as a mechanism for the progression of compensated left ventricular hypertrophy to ventricular dysfunction. METHODS: Eighteen hypertensive patients with normal epicardial coronary arteries on angiography were divided into two groups according to left ventricular fractional shortening (FS. Group 1 (FS >0.25: n=8, FS=0.29 ± 0.03; Group 2 (FS <0.25: n=10, FS= 0.17 ± 0.03. RESULTS: Baseline coronary blood flow was similar in both groups (Group 1: 80.15 ± 26.41 mL/min, Group 2: 100.09 ± 21.51 mL/min, p=NS. In response to adenosine, coronary blood flow increased to 265.1 ± 100.2 mL/min in Group 1 and to 300.8 ± 113.6 mL/min (p <0.05 in Group 2. Endothelium-independent coronary blood flow reserve was similar in both groups (Group 1: 3.31 ± 0.68 and Group 2: 2.97 ± 0.80, p=NS. In response to acetylcholine, coronary blood flow increased to 156.08 ± 36.79 mL/min in Group 1 and to 177.8 ± 83.6 mL/min in Group 2 (p <0.05. Endothelium-dependent coronary blood flow reserve was similar in the two groups (Group 1: 2.08 ± 0.74 and group Group 2: 1.76 ± 0.61, p=NS. Peak acetylcholine/peak adenosine coronary blood flow response (Group 1: 0.65 ± 0.27 and Group 2: 0.60 ± 0.17 and minimal coronary vascular resistance (Group 1: 0.48 ± 0.21 mmHg/mL/min and Group 2: 0.34 ± 0.12 mmHg/mL/min were similar in both groups (p= NS. Casual diastolic blood pressure and end-systolic left ventricular stress were independently associated with FS. CONCLUSIONS: In our hypertensive patients, endothelium-dependent and endothelium-independent coronary blood flow reserve vasodilator administrations had similar effects in patients with either normal or decreased left

  9. Identification of a potent endothelium-derived angiogenic factor.

    Directory of Open Access Journals (Sweden)

    Vera Jankowski

    Full Text Available The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up4U from the secretome of human endothelial cells. The angiogenic effect of the endothelial secretome was partially reduced after incubation with alkaline phosphatase and abolished in the presence of suramin. In one fraction, purified to homogeneity by reversed phase and affinity chromatography, Up4U was identified by MALDI-LIFT-fragment-mass-spectrometry, enzymatic cleavage analysis and retention-time comparison. Beside a strong angiogenic effect on the yolk sac membrane and the developing rat embryo itself, Up4U increased the proliferation rate of endothelial cells and, in the presence of PDGF, of vascular smooth muscle cells. Up4U stimulated the migration rate of endothelial cells via P2Y2-receptors, increased the ability of endothelial cells to form capillary-like tubes and acts as a potent inducer of sprouting angiogenesis originating from gel-embedded EC spheroids. Endothelial cells released Up4U after stimulation with shear stress. Mean total plasma Up4U concentrations of healthy subjects (N=6 were sufficient to induce angiogenic and proliferative effects (1.34 ± 0.26 nmol L(-1. In conclusion, Up4U is a novel strong human endothelium-derived angiogenic factor.

  10. Lipid-soluble smoke particles damage endothelial cells and reduce endothelium-dependent dilatation in rat and man

    DEFF Research Database (Denmark)

    Zhang, Jin-Yan; Cao, Yong-Xiao; Xu, Cang-Bao;


    BACKGROUND: Cigarette smoking is a strong risk factor for vascular disease and known to cause dysfunction of the endothelium. However, the molecular mechanisms involved are still not fully understood. METHODS: In order to reveal the direct effects of lipid-soluble smoke particles on the endothelium......, ring segments isolated from rat mesenteric arteries and human middle cerebral arteries (MCA) obtained at autopsy were incubated for 6 to 48 hrs in the presence of dimethylsulphoxide (DMSO)-soluble particles from cigarette smoke (DSP), i.e. lipid-soluble smoke particles. The endothelial microstructure...

  11. Inhibition of Endothelium-dependent Vasodilatation by Asymmetric Dimethyl Arginine in Human Resistance Vessels%非对称性二甲基精氨酸对人阻力血管EDVD的抑制作用

    Institute of Scientific and Technical Information of China (English)

    张东亮; 廖华; 张莉; 刘文虎


    目的 探讨非对称性二甲基精氨酸(ADMA)对人离体阻力血管环内皮依赖性舒张(endothelium-dependent vasodilatation,EDVD)的抑制作用.方法在血液透析患者行动-静脉内瘘成形术时留取桡动脉,制备血管环,用机械法去内皮并设立内皮存在组和内皮缺失组.应用离体血管张力记录仪观察2组血管环在不同质量浓度ADMA(10-7 mol/L、10-6 mol/L、10-5 mol/L、10-4 mol/L和10-3 mol/L)作用下张力的变化.内皮存在组用10-5 mol/L苯肾上腺素(phenylephrine,PE)引发血管环收缩,再用质量浓度为10-5 mol/L的乙酰胆碱(ACh)引发EDVD,然后用不同质量浓度ADMA处理,观察ADMA在内皮存在情况下对ACh所引起EDVD的抑制作用.内皮缺失组用质量浓度为10-5 mol/L的PE引发血管环收缩后,再用质量浓度为10-7 mol/L的硝普钠(SNP)引发非内皮依赖性血管舒张(EIVD),然后用不同质量浓度ADMA处理,观察ADMA在内皮缺失情况下对SNP引起EIVD的抑制作用.结果内皮存在组用10-5 mol/L的ACh处理可使67.10%±18.63%因PE(10-5 mol/L)引起收缩的血管舒张, ADMA对ACh引起的EDVD呈浓度依赖性抑制作用,相对收缩幅度依次为EDVD幅度的7.32%±8.60%(10-7 mol/L)、20.03%±13.49%(10-6 mol/L)、29.93%±11.78%(10-5 mol/L)、43.30%±11.29%(10-4 mol/L)和80.21%±18.16%(10-3 mol/L).在内皮缺失组,ADMA对SNP引起的EIVD呈微弱的抑制作用,且不表现为浓度依赖性.相对收缩幅度为EIVD的2.76%±1.98%(10-7 mol/L)、2.27%±1.82%(10-6 mol/L)、3.38%±2.99%(10-5 mol/L)、3.59%±3.66%(10-4 mol/L)和4.16%±3.67%(10-3 mol/L).结论 ADMA可以有效地抑制ACh引发的EDVD反应,该抑制作用呈浓度依赖性和内皮依赖性.

  12. Toxicity of methods of implant material sterilization on corneal endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Singh, G.; Boehnke, Mv.; von Domarus, D.; Draeger, J.


    The toxicity of different procedures utilized for the sterilization of intraocular implant material was assessed on the endothelium of organ-cultured porcine corneas. Polymethylmethacrylate lenses sterilized by treatment with sodium hydroxide (NaOH), ethylene oxide, formaldehyde, and gamma radiation were added to a culture medium containing normal porcine corneas. Considering the viability of endothelial cells, appearance of intracellular degenerative vacuoles, and denudation of corneal Descemet's membrane as criterion for the evaluation of toxicity of different methods of sterilization, the NaOH-treated lenses were found to be the least toxic to porcine corneal endothelium. Phase-contrast microscopy and vital staining of the endothelium permitted direct viewing of the endothelium aiding in the assessment of toxicity.

  13. Role of the endothelium in inflammatory bowel diseases

    Institute of Scientific and Technical Information of China (English)

    Walter E Cromer; J Michael Mathis; Daniel N Granger; Ganta V Chaitanya; J Steven Alexander


    Inflammatory bowel diseases (IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease. At the core of these alterations are endothelial cells, whose continual adjustments in structure and function coordinate vascular supply, immune cell emigration, and regulation of the tissue environment. Expansion of the endothelium in IBD (angiogenesis), mediated by inflammatory growth factors, cytokines and chemokines, is a hallmark of active gut disease and is closely related to disease severity. The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors, and adhesion molecules, altering coagulant capacity, barrier function and blood cell recruitment in injury. This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.

  14. microRNAs in the Lymphatic Endothelium: Master Regulators of Lineage Plasticity and Inflammation (United States)

    Yee, Daniel; Coles, Mark C.; Lagos, Dimitris


    microRNAs (miRNAs) are highly conserved, small non-coding RNAs that regulate gene expression at the posttranscriptional level. They have crucial roles in organismal development, homeostasis, and cellular responses to pathological stress. The lymphatic system is a large vascular network that actively regulates the immune response through antigen trafficking, cytokine secretion, and inducing peripheral tolerance. Here, we review the role of miRNAs in the lymphatic endothelium with a particular focus on their role in lymphatic endothelial cell (LEC) plasticity, inflammation, and regulatory function. We highlight the lineage plasticity of LECs during inflammation and the importance of understanding the regulatory role of miRNAs in these processes. We propose that targeting miRNA expression in lymphatic endothelium can be a novel strategy in treating human pathologies associated with lymphatic dysfunction.

  15. Coronary pressure and flow relationships in humans: phasic analysis of normal and pathological vessels and the implications for stenosis assessment: a report from the Iberian–Dutch–English (IDEAL) collaborators (United States)

    Nijjer, Sukhjinder S.; de Waard, Guus A.; Sen, Sayan; van de Hoef, Tim P.; Petraco, Ricardo; Echavarría-Pinto, Mauro; van Lavieren, Martijn A.; Meuwissen, Martijn; Danad, Ibrahim; Knaapen, Paul; Escaned, Javier; Piek, Jan J.; Davies, Justin E.; van Royen, Niels


    Background Our understanding of human coronary physiological behaviour is derived from animal models. We sought to describe physiological behaviour across a large collection of invasive pressure and flow velocity measurements, to provide a better understanding of the relationships between these physiological parameters and to evaluate the rationale for resting stenosis assessment. Methods and results Five hundred and sixty-seven simultaneous intracoronary pressure and flow velocity assessments from 301 patients were analysed for coronary flow velocity, trans-stenotic pressure gradient (TG), and microvascular resistance (MVR). Measurements were made during baseline and hyperaemic conditions. The whole cardiac cycle and the diastolic wave-free period were assessed. Stenoses were assessed according to fractional flow reserve (FFR) and quantitative coronary angiography DS%. With progressive worsening of stenoses, from unobstructed angiographic normal vessels to those with FFR ≤ 0.50, hyperaemic flow falls significantly from 45 to 19 cm/s, Ptrend stenosis severity and was consistent across all strata of stenosis (Ptrend > 0.05 for all). Trans-stenotic pressure gradient rose with stenosis severity for both rest and hyperaemic measures (Ptrend stenosis severity under resting conditions (Ptrend stenosis severity, TG rises. However, while hyperaemic flow falls significantly, resting coronary flow is maintained by compensatory reduction of MVR, demonstrating coronary auto-regulation. These data support the translation of coronary physiological concepts derived from animals to patients with coronary artery disease and furthermore, suggest that resting pressure indices can be used to detect the haemodynamic significance of coronary artery stenoses. PMID:26612582

  16. Antibodies directed against antigens on the endothelium of peritubular capillaries in patients with rejecting renal allografts. (United States)

    Paul, L C; van Es, L A; van Rood, J J; van Leeuwen, A; de la Rivière, G B; de Graeff, J


    This study was undertaken to examine the humoral immune response against endothelial antigens of the donor kidney in human renal allograft recipients. Sera from 61 transplant recipients who received 62 grafts were studied for the presence of circulating endothelial antibodies (CEAb) using an indirect immunofluorescence technique with a pretransplant biopsy of the graft as a substrate. IgG antibodies directed against the endothelium of peritubular capillaries were found in the sera of 6 of the 10 patients with graft rejection within 7 weeks after transplantation, whereas these antibodies were not found in the absence of rejection (P less than 0.001). Immunofluorescence studies of post-transplant biopsies showed IgG along the endothelium of peritubular capillaries only in the grafts of patients with CEAb. Eluates from these grafts contained IgG antibodies that bound to the endothelium of the donor as shown by the indirect immunofluorescence technique. Absorption of endothelial antibody (EAb)-positive sera with human platelets or Wistar strain rat erythrocytes showed that the EAb were not directed against serologically defined HLA antigens or against heterophile antigens on rat erythrocytes. We conclude from this study that the presence of antibodies directed against endothelial antigens is associated with poor graft prognosis and that these antibodies may be responsible for the rejection process.

  17. The development of 3-D, in vitro, endothelial culture models for the study of coronary artery disease

    Directory of Open Access Journals (Sweden)

    Fraser Richard


    Full Text Available Abstract The response of the vascular endothelium to wall shear stress plays a central role in the development and progression of atherosclerosis. Current studies have investigated endothelial response using idealized in vitro flow chambers. Such cell culture models are unable to accurately replicate the complex in vivo wall shear stress patterns arising from anatomical geometries. To better understand this implication, we have created both simplified/tubular and anatomically realistic in vitro endothelial flow models of the human right coronary artery. A post-mortem vascular cast of the human left ventricular outflow tract was used to create geometrically accurate silicone elastomer models. Straight, tubular models were created using a custom made mold. Following the culture of human abdominal aortic endothelial cells within the inner lumen, cells were exposed to steady flow (Re = 233 for varying time periods. The resulting cell morphology was analyzed in terms of shape index and angle of orientation relative to the flow direction. In both models a progressive elongation and alignment of the endothelium in the flow direction was observed following 8, 12, and 24 hours. This change, however, was significantly less pronounced in the anatomical model (as observed from morphological variations indicative of localized flow features. Differences were also observed between the inner and outer walls at the disease-prone proximal region. Since morphological adaptation is a visual indication of endothelial shear stress activation, the use of anatomical models in endothelial genetic and biochemical studies may offer better insight into the disease process.

  18. Oxidation modifies the structure and function of the extracellular matrix generated by human coronary artery endothelial cells. (United States)

    Chuang, Christine Y; Degendorfer, Georg; Hammer, Astrid; Whitelock, John M; Malle, Ernst; Davies, Michael J


    ECM (extracellular matrix) materials, such as laminin, perlecan, type IV collagen and fibronectin, play a key role in determining the structure of the arterial wall and the properties of cells that interact with the ECM. The aim of the present study was to investigate the effect of peroxynitrous acid, an oxidant generated by activated macrophages, on the structure and function of the ECM laid down by HCAECs (human coronary artery endothelial cells) in vitro and in vivo. We show that exposure of HCAEC-derived native matrix components to peroxynitrous acid (but not decomposed oxidant) at concentrations >1 μM results in a loss of antibody recognition of perlecan, collagen IV, and cell-binding sites on laminin and fibronectin. Loss of recognition was accompanied by decreased HCAEC adhesion. Real-time PCR showed up-regulation of inflammation-associated genes, including MMP7 (matrix metalloproteinase 7) and MMP13, as well as down-regulation of the laminin α2 chain, in HCAECs cultured on peroxynitrous acid-treated matrix compared with native matrix. Immunohistochemical studies provided evidence of co-localization of laminin with 3-nitrotyrosine, a biomarker of peroxynitrous acid damage, in type II-III/IV human atherosclerotic lesions, consistent with matrix damage occurring during disease development in vivo. The results of the present study suggest a mechanism through which peroxynitrous acid modifies endothelial cell-derived native ECM proteins of the arterial basement membrane in atherosclerotic lesions. These changes to ECM and particularly perlecan and laminin may be important in inducing cellular dysfunction and contribute to atherogenesis.

  19. A Case of Isolated Coronary Artery Ectasia in the Setting of Chronic Inflamation From human Immunodeficiency Virus Infection. (United States)

    Heckle, Mark R; Askari, Raza; Morsy, Mohamed; Ibebuogu, Uzoma N


    Coronary artery ectasia also known as dilated coronopathy is a relatively rare finding that is most commonly associated with atherosclerosis. Several alternative reasons including congenital malformations and chronic inflammation have been identified as a cause of CAE. In this case, we discuss a 61-year-old male with postoperative chest pain who was found to have localized CAE in the absence of significant atherosclerosis. We also elucidate the recently proposed markers of chronic inflammation that might be associated with coronary artery ectasia.

  20. Traction force dynamics predict gap formation in activated endothelium. (United States)

    Valent, Erik T; van Nieuw Amerongen, Geerten P; van Hinsbergh, Victor W M; Hordijk, Peter L


    In many pathological conditions the endothelium becomes activated and dysfunctional, resulting in hyperpermeability and plasma leakage. No specific therapies are available yet to control endothelial barrier function, which is regulated by inter-endothelial junctions and the generation of acto-myosin-based contractile forces in the context of cell-cell and cell-matrix interactions. However, the spatiotemporal distribution and stimulus-induced reorganization of these integral forces remain largely unknown. Traction force microscopy of human endothelial monolayers was used to visualize contractile forces in resting cells and during thrombin-induced hyperpermeability. Simultaneously, information about endothelial monolayer integrity, adherens junctions and cytoskeletal proteins (F-actin) were captured. This revealed a heterogeneous distribution of traction forces, with nuclear areas showing lower and cell-cell junctions higher traction forces than the whole-monolayer average. Moreover, junctional forces were asymmetrically distributed among neighboring cells. Force vector orientation analysis showed a good correlation with the alignment of F-actin and revealed contractile forces in newly formed filopodia and lamellipodia-like protrusions within the monolayer. Finally, unstable areas, showing high force fluctuations within the monolayer were prone to form inter-endothelial gaps upon stimulation with thrombin. To conclude, contractile traction forces are heterogeneously distributed within endothelial monolayers and force instability, rather than force magnitude, predicts the stimulus-induced formation of intercellular gaps. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. A tale of two ligands: angiopoietins, the endothelium, and outcomes. (United States)

    Siner, Jonathan M


    Angiopoietins signal via the Tie-2 receptor and are essential molecules for vasculogenesis during development and in the adult state play roles in vascular stability as well as inflammation and appear to be involved in the dysregulation of the endothelium in illness. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are, respectively, agonists and competitive partial agonists, which have been found to undergo alterations in individuals with sepsis. In sepsis, Ang-2 levels are elevated and Ang-1 is decreased. In the previous issue of Critical Care, Fiusa and colleagues measure circulating Ang-1 and Ang-2 along with other growth factors in humans with febrile neutropenia. The authors found that an increased Ang-2/Ang-1 ratio, or an elevated Ang-2 level, at the time of an initial fever, is associated with subsequent development of septic shock and death. These findings validate that the Ang-2/Ang-1 balance, which is thought to reflect overall signaling via the Tie-2 receptor, is relevant to outcomes in patients with sepsis. Importantly, the specimens were obtained far in advance of the development of septic shock, suggesting that detectable alterations in this pathway may provide early clues regarding outcomes. This study adds to the evidence that angiopoietins are early markers of endothelial dysfunction in sepsis and provide prognostic information regarding outcomes.

  2. The effect of mepivacaine on swine lingual, pulmonary and coronary arteries


    Satoh, Kenichi; Chikuda, Mami; Ohashi, Ayako; Kumagai, Miho; Sato, Masahito; Joh, Shigeharu


    Background Although mepivacaine has a known biphasic action on the aortic and coronary artery in several animal species, its effects on the lingual and pulmonary artery are not well understood and it is not yet known whether mepivacaine produces vasoconstriction in these vessels. The present study aims to investigate the direct effects of mepivacaine on swine lingual, pulmonary and coronary arterial endothelium-denuded rings. Methods Artery rings were perfused with isotonic 40 mM KCl until a ...

  3. Myocardial bridges of the coronary arteries in the human fetal heart. (United States)

    Cakmak, Yusuf Ozgür; Cavdar, Safiye; Yalin, Aymelek; Yener, Nuran; Ozdogmus, Omer


    During the last century, many investigators reported on myocardial bridges in the adult human heart. In the present study, 39 human fetal hearts (the mean gestastional age was 30 weeks) were studied for myocardial bridging, and the results were correlated with adult data. Among the 39 (27 male and 12 female) fetal hearts studied, 26 bridges were observed on 18 fetal hearts (46.2%). Ten of the bridges had one myocardial bridge, whereas double myocardial bridges were observed in eight fetal hearts. The most frequent myocardial bridges were observed on the left anterior descending artery (LAD), which had 13 bridges (50%). Eight (30.7%) myocardial bridges were on the diagonal artery, and on the posterior descending artery there were five (19.3%). Myocardial bridges were not observed on the circumflex artery. The data presented in this study may provide potentially useful information for the preoperative evaluation of the newborn and may have a clinical implication for sudden fetal death.

  4. Testosterone-derived estradiol production by male endothelium is robust and dependent on p450 aromatase via estrogen receptor alpha. (United States)

    Villablanca, Amparo C; Tetali, Sarada; Altman, Robin; Ng, Kenneth F; Rutledge, John C


    Vascular endothelium expresses both the estrogen receptors (ERs) α and β, and ERα mediates development of early atherosclerosis in male mice. This process is thought to be testosterone-dependent. We hypothesized that male murine aortic endothelium produces robust levels of estradiol by aromatase conversion of testosterone, and that regulation of this process is mediated by the presence of ERs, primarily ERα. Aortic endothelium was isolated from ERα knockout (ERα -/-) and wild-type (ERα +/+) male mice and treated with testosterone or the 5α reduction product dihydrotestosterone (DHT), with or without the P450 aromatase inhibitor anastrazole, or a non-specific estrogen receptor antagonist. Aromatase gene expression and estradiol production were assayed. Treatment with testosterone, but not DHT, caused increased aromatase expression and estradiol production in ERα +/+ endothelium that was attenuated by disruption of ERα in the ERα -/- group. Anastrazole inhibition of aromatase reduced testosterone-induced aromatase expression and estradiol levels in both ERα -/- and ERα +/+ endothelium. Antagonism of both ERs decreased testosterone-induced aromatase expression in both wild-type and knockout groups. The effects of the receptor antagonist on estradiol production differed between the two groups, however, with a reduction in estradiol release from the ERα +/+ cells and complete abolition of estradiol release from the ERα -/- cells. Thus, estradiol production in vascular endothelium from male mice is robust, depends on the aromatic conversion of testosterone and requires functional ERα to achieve maximal levels of estradiol generation. Local vascular production of aromatase-mediated estradiol in response to circulating testosterone may affect ERα-dependent mechanisms to increase susceptibility to early atheroma formation in male mice. This pathway may have important therapeutic relevance for reducing the risk of atherosclerotic cardiovascular disease in

  5. Bone marrow X kinase-mediated signal transduction in irradiated vascular endothelium. (United States)

    Tu, Tianxiang; Thotala, Dinesh; Geng, Ling; Hallahan, Dennis E; Willey, Christopher D


    Radiation-induced activation of the phosphatidyl inositol-3 kinase/Akt signal transduction pathway requires Akt binding to phosphatidyl-inositol phosphates (PIP) on the cell membrane. The tyrosine kinase bone marrow X kinase (Bmx) binds to membrane-associated PIPs in a manner similar to Akt. Because Bmx is involved in cell growth and survival pathways, it could contribute to the radiation response within the vascular endothelium. We therefore studied Bmx signaling within the vascular endothelium. Bmx was activated rapidly in response to clinically relevant doses of ionizing radiation. Bmx inhibition enhanced the efficacy of radiotherapy in endothelial cells as well as tumor vascular endothelium in lung cancer tumors in mice. Retroviral shRNA knockdown of Bmx protein enhanced human umbilical vascular endothelial cell (HUVEC) radiosensitization. Furthermore, pretreatment of HUVEC with a pharmacologic inhibitor of Bmx, LFM-A13, produced significant radiosensitization of endothelial cells as measured by clonogenic survival analysis and apoptosis as well as functional assays including cell migration and tubule formation. In vivo, LFM-A13, when combined with radiation, resulted in significant tumor microvascular destruction as well as enhanced tumor growth delay. Bmx therefore represents a molecular target for the development of novel radiosensitizing agents.

  6. Comparative reactivity of the myeloperoxidase-derived oxidants hypochlorous acid and hypothiocyanous acid with human coronary artery endothelial cells. (United States)

    Lloyd, Mitchell M; Grima, Michael A; Rayner, Benjamin S; Hadfield, Katrina A; Davies, Michael J; Hawkins, Clare L


    In the immune response, hypohalous acids are generated by activated leukocytes via the release of myeloperoxidase and the formation of H2O2. Although these oxidants have important bactericidal properties, they have also been implicated in causing tissue damage in inflammatory diseases, including atherosclerosis. Hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) are the major oxidants formed by myeloperoxidase under physiological conditions, with the ratio of these oxidants dependent on diet and smoking status. HOCl is highly reactive and causes marked cellular damage, but few data are available on the effects of HOSCN on mammalian cells. In this study, we have compared the actions of HOCl and HOSCN on human coronary artery endothelial cells (HCAEC). HOCl reacts rapidly with the cells, resulting in extensive cell death by both apoptosis and necrosis, with necrosis dominating at higher oxidant doses. In contrast, HOSCN is consumed more slowly, with cell death occurring only by apoptosis. Exposure of HCAEC to HOCl and HOSCN induces changes in mitochondrial membrane permeability, which, in the case of HOSCN, is associated with mitochondrial release of proapoptotic factors, including cytochrome c, apoptosis-inducing factor, and endonuclease G. With each oxidant, apoptosis appears to be caspase-independent, with the inactivation of caspases 3/7 observed, and pretreatment of the cells with the caspase inhibitor Z-VAD-fmk having no effect on the extent of cell death. Loss of cellular thiols, depletion of glutathione, and the inactivation of thiol-dependent enzymes, including glyceraldehyde-3-phosphate dehydrogenase, were seen with both oxidants, though to a much greater extent with HOCl. The ability of myeloperoxidase-derived oxidants to induce endothelial cell apoptosis may contribute to the formation of unstable lesions in atherosclerosis. The results with HOSCN may be particularly significant for smokers, who have elevated plasma levels of SCN(-), the precursor

  7. Beta Blockers Suppress Dextrose-Induced Endoplasmic Reticulum Stress, Oxidative Stress, and Apoptosis in Human Coronary Artery Endothelial Cells. (United States)

    Haas, Michael J; Kurban, William; Shah, Harshit; Onstead-Haas, Luisa; Mooradian, Arshag D

    Beta blockers are known to have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. To determine whether beta blockers can also prevent dextrose-induced endoplasmic reticulum (ER) stress in addition to their antioxidative effects, human coronary artery endothelial cells and hepatocyte-derived HepG2 cells were treated with 27.5 mM dextrose for 24 hours in the presence of carvedilol (a lipophilic beta blockers with alpha blocking activity), propranolol (a lipophilic nonselective beta blockers), and atenolol (a water-soluble selective beta blockers), and ER stress, oxidative, stress and cell death were measured. ER stress was measured using the placental alkaline phosphatase assay and Western blot analysis of glucose regulated protein 78, c-Jun-N-terminal kinase (JNK), phospho-JNK, eukaryotic initiating factor 2α (eIF2α), and phospho-eIF2α and measurement of X-box binding protein 1 (XBP1) mRNA splicing using reverse transcriptase-polymerase chain reaction. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. Cell viability was measured by propidium iodide staining method. The ER stress, SO production, and cell death induced by 27.5 mM dextrose were inhibited by all 3 beta blockers tested. The antioxidative and ER stress reducing effects of beta blockers were also observed in HepG2 cells. The salutary effects of beta blockers on endothelial cells in reducing both ER stress and oxidative stress may contribute to the cardioprotective effects of these agents.

  8. Evaluation of endoscopic vein extraction on structural and functional viability of saphenous vein endothelium

    Directory of Open Access Journals (Sweden)

    Lu Xiu-Gui


    Full Text Available Abstract Objectives Endothelial injury during harvest influences graft patency post CABG. We have previously shown that endoscopic harvest causes structural and functional damage to the saphenous vein (SV endothelium. However, causes of such injury may depend on the extraction technique. In order to assess this supposition, we evaluated the effect of VirtuoSaph endoscopic SV harvesting technique (VsEVH on structural and functional viability of SV endothelium using multiphoton imaging, biochemical and immunofluorescence assays. Methods Nineteen patients scheduled for CABG were prospectively identified. Each underwent VsEVH for one portion and "No-touch" open SV harvesting (OSVH for another portion of the SV. A two cm segment from each portion was immersed in GALA conduit preservation solution and transported overnight to our lab for processing. The segments were labeled with fluorescent markers to quantify cell viability, calcium mobilization and generation of nitric oxide. Morphology, expression, localization and stability of endothelial caveolin, eNOS, von Willebrand factor and cadherin were evaluated using immunofluorescence, Western blot and multiphoton microscopy (MPM. Results Morphological, biochemical and immunofluorescence parameters of viability, structure and function were well preserved in VsEVH group as in OSVH group. However, tonic eNOS activity, agonist-dependent calcium mobilization and nitric oxide production were partially attenuated in the VsEVH group. Conclusions This study indicates that VirtuoSaph endoscopic SV harvesting technique preserves the structural and functional viability of SV endothelium, but may differentially attenuate the vasomotor function of the saphenous vein graft. Ultramini-Abstract Endoscopic extraction preserved the structure and function, but attenuated the calcium mobilization and nitric oxide generation in human SV endothelium.

  9. Coronary artery fistula (United States)

    Congenital heart defect - coronary artery fistula; Birth defect heart - coronary artery fistula ... A coronary artery fistula is often congenital, meaning that it is present at birth. It generally occurs when one of the coronary arteries ...

  10. Evaluation of circulating microRNA-92a for endothelial damage induced by percuatenous coronary intervention

    Institute of Scientific and Technical Information of China (English)



    Objective To explore the role of microRNA-92a(miR-92a) in evaluating endothelium damage induced by percutaneous coronary intervention(PCI). Methods A case control study was prospectively conducted. Fifty-eight patients with ST-segment elevation acute myocardial

  11. Coronary MR angiography using citrate-coated very small superparamagnetic iron oxide particles as blood-pool contrast agent: initial experience in humans. (United States)

    Wagner, Moritz; Wagner, Susanne; Schnorr, Jörg; Schellenberger, Eyk; Kivelitz, Dietmar; Krug, Lasse; Dewey, Marc; Laule, Michael; Hamm, Bernd; Taupitz, Matthias


    To evaluate very small superparamagnetic iron oxide particles (VSOP-C184) as blood-pool contrast agent for coronary MR angiography (CMRA) in humans. Six healthy volunteers and 14 patients with suspected coronary artery disease underwent CMRA after administration of VSOP-C184 at the following doses: 20 μmol Fe/kg (4 patients), 40 μmol Fe/kg (5 patients), 45 μmol Fe/kg (6 healthy volunteers), and 60 μmol Fe/kg (5 patients). In healthy volunteers, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and vessel edge definition (VED) of contrast-enhanced CMRA were compared with non-contrast-enhanced CMRA. In patients, a per-segment intention-to-diagnose evaluation of contrast-enhanced CMRA for detection of significant coronary stenosis (≥50%) was performed. Three healthy volunteers (45 μmol Fe/kg VSOP-C184) and two patients (60 μmol Fe/kg VSOP-C184) had adverse events of mild or moderate intensity. VSOP-C184 significantly increased CNR (15.1 ± 4.6 versus 6.9 ± 1.9; P = 0.010), SNR (21.7 ± 5.3 versus 15.4 ± 1.6; P = 0.048), and VED (2.3 ± 0.6 versus 1.2 ± 0.2; P VSOP-C184 was feasible and yielded moderate diagnostic accuracy for detection of significant coronary stenosis within this proof-of-concept setting. Copyright © 2011 Wiley-Liss, Inc.

  12. Oxidative Stress-Dependent Coronary Endothelial Dysfunction in Obese Mice. (United States)

    Gamez-Mendez, Ana María; Vargas-Robles, Hilda; Ríos, Amelia; Escalante, Bruno


    Obesity is involved in several cardiovascular diseases including coronary artery disease and endothelial dysfunction. Endothelial Endothelium vasodilator and vasoconstrictor agonists play a key role in regulation of vascular tone. In this study, we evaluated coronary vascular response in an 8 weeks diet-induced obese C57BL/6 mice model. Coronary perfusion pressure in response to acetylcholine in isolated hearts from obese mice showed increased vasoconstriction and reduced vasodilation responses compared with control mice. Vascular nitric oxide assessed in situ with DAF-2 DA showed diminished levels in coronary arteries from obese mice in both basal and acetylcholine-stimulated conditions. Also, released prostacyclin was decreased in heart perfusates from obese mice, along with plasma tetrahydrobiopterin level and endothelium nitric oxide synthase dimer/monomer ratio. Obesity increased thromboxane A2 synthesis and oxidative stress evaluated by superoxide and peroxynitrite levels, compared with control mice. Obese mice treated with apocynin, a NADPH oxidase inhibitor, reversed all parameters to normal levels. These results suggest that after 8 weeks on a high-fat diet, the increase in oxidative stress lead to imbalance in vasoactive substances and consequently to endothelial dysfunction in coronary arteries.

  13. Magnetic characterization of human blood in the atherosclerotic process in coronary arteries

    Energy Technology Data Exchange (ETDEWEB)

    Janus, B. [Institute of Environmental Engineering PAS, ul. SkLodowskiej-Curie 34, 41-819 Zabrze (Poland); Bucko, M.S., E-mail: michal.bucko@helsinki.f [Institute of Environmental Engineering PAS, ul. SkLodowskiej-Curie 34, 41-819 Zabrze (Poland); Division of Geophysics and Astronomy, P.O. Box 64, Gustaf Haellstroemin katu 2, 00014 University of Helsinki (Finland); Chrobak, A. [University of Silesia, Institute of Physics, ul. Uniwersytecka 4, 40-007 Katowice (Poland); Wasilewski, J. [3rd Chair and Clinical Ward of Cardiology, Medical University of Silesia, Katowice, Silesian Centre of Heart Diseases, ul. Szpitalna 2, 41-800 Zabrze (Poland); Zych, M. [Department of Pharmacognosy and Phytochemistry, Medical University of Silesia, ul. Jagiellonska 4, 41-200 Sosnowiec (Poland)


    In the last decades there has been an increasing interest in biomagnetism-a field of biophysics concerned with the magnetic properties of living organisms. Biomagnetism focuses on the measurement of magnetic properties of biological samples in the clinical environment. Progress in this field can provide new data for the understanding of the pathomechanism of atherosclerosis and support the diagnostic options for the evaluation and treatment of atherothrombotic complications. Lyophilized human blood samples from patients with atherosclerotic lesions (calcium scoring (CS) CS>0) and without atherosclerotic lesions (CS=0) were magnetically investigated. Magnetic measurements (performed in room and low temperature) indicated significant magnetic differences between these two groups of patients. Atherosclerotic blood samples are characterized by higher concentration of ferrimagnetic particles (magnetite and/or maghemite) and significant changes in the superparamagnetic behaviour. This research presents that magnetometry, in combination with medical research can lead to a better understanding of iron physiology in the atherosclerotic process. - Research Highlights: {yields}Blood samples are characterized by higher concentration of ferrimagnetic particles. {yields}Atherosclerotic blood samples consist of larger superparamagnetic clusters. {yields}Superparamagnetic particles in pathological samples are considered to be magnetite. {yields}The formation of ferrimagnetic particles is favoured in the atherosclerotic patients. {yields}Magnetite may play a role in the progression of atherosclerosis.

  14. Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque

    NARCIS (Netherlands)

    P.W.J.C. Serruys (Patrick); H.M. Garcia-Garcia (Hector); P. Buszman (Pawel); P. Erne (Paul); S. Verheye (Stefan); M. Aschermann (Michael); H.J. Duckers (Henricus); O. Bleie (Oyvind); D. Dudek (Dariusz); H.E. Bøtker (Hans); C. von Birgelen (Clemens); D. D'Amico (Don); T. Hutchinson (Tammy); A. Zambanini (Andrew); F. Mastik (Frits); G.A. van Es (Gerrit Anne); A.F.W. van der Steen (Ton); D.G. Vince (Geoffrey); P. Ganz (Peter); C.W. Hamm (Christian); W. Wijns (William); A. Zalewski (Andrew)


    textabstractBackground - Lipoprotein-associated phospholipase A2 (Lp-PLA2) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results - This study

  15. Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque

    NARCIS (Netherlands)

    P.W.J.C. Serruys (Patrick); H.M. Garcia-Garcia (Hector); P. Buszman (Pawel); P. Erne (Paul); S. Verheye (Stefan); M. Aschermann (Michael); H.J. Duckers (Henricus); O. Bleie (Oyvind); D. Dudek (Dariusz); H.E. Bøtker (Hans); C. von Birgelen (Clemens); D. D'Amico (Don); T. Hutchinson (Tammy); A. Zambanini (Andrew); F. Mastik (Frits); G.A. van Es (Gerrit Anne); A.F.W. van der Steen (Ton); D.G. Vince (Geoffrey); P. Ganz (Peter); C.W. Hamm (Christian); W. Wijns (William); A. Zalewski (Andrew)


    textabstractBackground - Lipoprotein-associated phospholipase A2 (Lp-PLA2) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results - This study

  16. Human plasma complement C3 is independently associated with coronary heart disease, but only in heavy smokers (the CODAM study)

    NARCIS (Netherlands)

    Greevenbroek, van M.M.J.; Jacobs, M.; Kallen, van der C.J.H.; Blaak, E.E.; Jansen, E.H.J.M.; Schalkwijk, C.G.; Feskens, E.J.M.; Stehouwer, C.D.A.


    Background - Complement C3 is an emerging risk factor for coronary heart disease (CHD) and is particularly increased in the metabolic syndrome. A direct effect of smoking on structure and function of complement C3 has been suggested. Hypothesis - Smoking behavior may affect the cardiovascular risk t

  17. Patient-Specific Simulation of Coronary Artery Pressure Measurements: An In Vivo Three-Dimensional Validation Study in Humans

    Directory of Open Access Journals (Sweden)

    Panagiotis K. Siogkas


    Full Text Available Pressure measurements using finite element computations without the need of a wire could be valuable in clinical practice. Our aim was to compare the computed distal coronary pressure values with the measured values using a pressure wire, while testing the effect of different boundary conditions for the simulation. Eight coronary arteries (lumen and outer vessel wall from six patients were reconstructed in three-dimensional (3D space using intravascular ultrasound and biplane angiographic images. Pressure values at the distal and proximal end of the vessel and flow velocity values at the distal end were acquired with the use of a combo pressure-flow wire. The 3D lumen and wall models were discretized into finite elements; fluid structure interaction (FSI and rigid wall simulations were performed for one cardiac cycle both with pulsatile and steady flow in separate simulations. The results showed a high correlation between the measured and the computed coronary pressure values (coefficient of determination [r2] ranging between 0.8902 and 0.9961, while the less demanding simulations using steady flow and rigid walls resulted in very small relative error. Our study demonstrates that computational assessment of coronary pressure is feasible and seems to be accurate compared to the wire-based measurements.

  18. Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation. (United States)

    Colussi, Gian Luca; Di Fabio, Alessandro; Catena, Cristiana; Chiuch, Alessandra; Sechi, Leonardo A


    Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 μmol l(-1) midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 μmol l(-1) midazolam. Only the low concentration of midazolam (10 μmol l(-1)) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 μmol l(-1)) reduced the CaCl(2)-induced vasoconstriction of aortic rings with EC(50) (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l(-1) for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally

  19. Clinical CVVH model removes endothelium-derived microparticles from circulation

    Directory of Open Access Journals (Sweden)

    Abdelhafeez H. Abdelhafeez


    Full Text Available Background: Endothelium-derived microparticles (EMPs are submicron vesicles released from the plasma membrane of endothelial cells in response to injury, apoptosis or activation. We have previously demonstrated EMP-induced acute lung injury (ALI in animal models and endothelial barrier dysfunction in vitro. Current treatment options for ALI are limited and consist of supportive therapies. We hypothesize that standard clinical continuous venovenous hemofiltration (CVVH reduces serum EMP levels and may be adapted as a potential therapeutic intervention. Materials and methods: EMPs were generated from plasminogen activation inhibitor-1 (PAI-1-stimulated human umbilical vein endothelial cells (HUVECs. Flow cytometric analysis was used to characterize EMPs as CD31- and annexin V-positive events in a submicron size gate. Enumeration was completed against a known concentration of latex beads. Ultimately, a concentration of ~650,000 EMP/mL perfusate fluid (total 470 mL was circulated through a standard CVVH filter (pore size 200 μm, flow rate 250 mL/hr for a period of 70 minutes. 0.5 mL aliquots were removed at 5- to 10-minute intervals for flow cytometric analysis. EMP concentration in the dialysate was measured at the end of 4 hours to better understand the fate of EMPs. Results: A progressive decrease in circulating EMP concentration was noted using standard CVVH at 250 mL/hr (a clinical standard rate from a 470 mL volume modelling a patient's circulation. A 50% reduction was noted within the first 30 minutes. EMPs entering the dialysate after 4 hours were 5.7% of the EMP original concentration. Conclusion: These data demonstrate that standard CVVH can remove EMPs from circulation in a circuit modelling a patient. An animal model of hemofiltration with induction of EMP release is required to test the therapeutic potential of this finding and potential of application in early treatment of ALI.

  20. Electric Impedance Spectroscopy for On-Chip Analysis of Human Trabecular Meshwork Endothelium%阻抗谱芯片用于人眼小梁网细胞分析

    Institute of Scientific and Technical Information of China (English)

    顾雯雯; 赵毅


    The in vitro cultured human trabecular meshwork (TM) was investigated using electric impedance spectroscopy (EIS) in real time.TM is a critical determinant of intraocular pressure (IOP),the increase of which is the main cause of glaucoma.An array of interdigitated microelectrodes (IMEs) was fabricated for electric impedance sensing.An equivalent electric circuit model was proposed to study the cellular activities on the IMEs,showing that the impedance of extracellular matrix (ECM) and the cell coverage ratio have distinct signatures on the spectrum.The utility of the EIS was demonstrated by treating TM cells during their proliferation with dexamethasone (DEX).The impedance measurement at 40 kHz showed that a higher DEX concentration can induce more severe inhibition of cell proliferation.The measurement was validated by AlamarBlue assay.The measurement provided a reasonable explanation on glucocorticoid induced glaucoma,where the glucocorticoid alters the metabolic and physiological functions of TM cells by inhibiting normal cell growth and proliferation.%采用阻抗谱分析法对体外培养人眼小梁网细胞进行实时在线检测.人眼眼压过高将导致青光眼病变,而小梁网对于眼压高低至关重要.制备了叉指式阵列微电极作为阻抗传感器敏感单元.提出了分析小梁网细胞生物行为特征的等效电路模型,通过仿真分析表明该电路模型可在不同频段区分人眼小梁网细胞外基质和细胞繁殖率等阻抗参数值.采用叉指式阻抗谱芯片对经地塞米松药物处理的小梁网细胞进行了实时在线监测,结果表明40 kHz时高浓度地塞米松对小梁网细胞增殖具有较大的抑制作用,该结论与AlamarBlue试剂法得到的结论一致.阻抗测试结果为糖皮质激素诱导的青光眼提供了一种合理的解释,认为该病变与正常细胞增殖率异常有关.

  1. Differential Sensitivities of Pulmonary and Coronary Arteries to Hemoglobin-Based Oxygen Carriers and Nitrovasodilators: Study in a Bovine Ex Vivo Model of Vascular Strips (United States)


    lsev ier.c omflocate/ vph Differential sensitivities of pulmonary and coronary arteries to hemoglobin-based oxygen carriers and nitrovasodilators...preparation has been used extensively in multiple studies that led to the discovery of NO as endothelium-derived relaxing factor (lgnarro et al., 1984...G.M .• Wood, K.S., Chaudhuri, G., 1988a. Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide: use or pyrogallol and

  2. Coronary anomaly: the single coronary artery

    Institute of Scientific and Technical Information of China (English)

    QIN Xu-guang; XIONG Wei-guo; LU Chun-peng; GONG Cheng-jie; SHANG Li-hua


    @@ Single coronary artery (SCA), defined as an artery that arises from the arterial trunk and nourishes the entire myocardium, is rare. We report two cases of SCA, one is the right coronary artery (RCA) originating from the middle of left descending artery (LAD), and the other is the left main coronary artery (LMCA) arising from the proximal right coronary artery.

  3. The immobilization of recombinant human tropoelastin on metals using a plasma-activated coating to improve the biocompatibility of coronary stents. (United States)

    Waterhouse, Anna; Yin, Yongbai; Wise, Steven G; Bax, Daniel V; McKenzie, David R; Bilek, Marcela M M; Weiss, Anthony S; Ng, Martin K C


    Current endovascular stents have sub-optimal biocompatibility reducing their clinical efficacy. We previously demonstrated a plasma-activated coating (PAC) that covalently bound recombinant human tropoelastin (TE), a major regulator of vascular cells in vivo, to enhance endothelial cell interactions. We sought to develop this coating to enhance its mechanical properties and hemocompatibility for application onto coronary stents. The plasma vapor composition was altered by incorporating argon, nitrogen, hydrogen or oxygen to modulate coating properties. Coatings were characterized for 1) surface properties, 2) mechanical durability, 3) covalent protein binding, 4) endothelial cell interactions and 5) thrombogenicity. The N(2)/Ar PAC had optimal mechanical properties and did not delaminate after stent expansion. The N(2)/Ar PAC was mildly hydrophilic and covalently bound the highest proportion of TE, which enhanced endothelial cell proliferation. Acute thrombogenicity was assessed in a modified Chandler loop using human blood. Strikingly, the N(2)/Ar PAC alone reduced thrombus weight by ten-fold compared to 316L SS, a finding unaltered with immobilized TE. Serum soluble P-selectin was reduced on N(2)/Ar PAC and N(2)/Ar PAC + TE (p < 0.05), consistent with reduced platelet activation. We have demonstrated a coating for metal alloys with multifaceted biocompatibility that resists delamination and is non-thrombogenic, with implications for improving coronary stent efficacy.

  4. HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi. (United States)

    Ahrens, Ingo; Chen, Yung-Chih; Topcic, Danijal; Bode, Michael; Haenel, David; Hagemeyer, Christoph E; Seeba, Hannah; Duerschmied, Daniel; Bassler, Nicole; Jandeleit-Dahm, Karin A; Sweet, Matthew J; Agrotis, Alex; Bobik, Alex; Peter, Karlheinz


    High mobility group box 1 (HMGB1) acts as both a nuclear protein that regulates gene expression, as well as a pro-inflammatory alarmin that is released from necrotic or activated cells. Recently, HMGB1-expression in human atherosclerotic plaques was identified. Therapeutic blockade of HMGB1 reduced the development of diet-induced atherosclerosis in ApoE knockout mice. Thus, we hypothesised an interaction between HMGB1 and activated platelets. Binding of recombinant HMGB1 to platelets was assessed by flow cytometry. HMGB1 bound to thrombin-activated human platelets (MFI 2.49 vs 25.01, p=0.0079). Blood from wild-type, TLR4 and RAGE knockout mice was used to determine potential HMGB1 receptors on platelets. HMGB1 bound to platelets from wild type C57Bl6 (MFI 2.64 vs 20.3, p 0.05). RAGE expression on human platelets was detected by RT-PCR with mRNA extracted from highly purified platelets and confirmed by Western blot and immunofluorescence microscopy. Platelet activation increased RAGE surface expression (MFI 4.85 vs 6.74, p< 0.05). Expression of HMGB1 in human coronary artery thrombi was demonstrated by immunohistochemistry and revealed high expression levels. Platelets bind HMGB1 upon thrombin-induced activation. Platelet specific expression of RAGE could be detected at the mRNA and protein level and is involved in the binding of HMGB1. Furthermore, platelet activation up-regulates platelet surface expression of RAGE. HMGB1 is highly expressed in platelet-rich human coronary artery thrombi pointing towards a central role for HMGB1 in atherothrombosis, thereby suggesting the possibility of platelet targeted anti-inflammatory therapies for atherothrombosis.

  5. Endothelium-Derived Hyperpolarizing Factor and Vascular Function

    Directory of Open Access Journals (Sweden)

    Muhiddin A. Ozkor


    Full Text Available Endothelial function refers to a multitude of physiological processes that maintain healthy homeostasis of the vascular wall. Exposure of the endothelium to cardiac risk factors results in endothelial dysfunction and is associated with an alteration in the balance of vasoactive substances produced by endothelial cells. These include a reduction in nitric oxide (NO, an increase in generation of potential vasoconstrictor substances and a potential compensatory increase in other mediators of vasodilation. The latter has been surmised from data demonstrating persistent endothelium-dependent vasodilatation despite complete inhibition of NO and prostaglandins. This remaining non-NO, non-prostaglandin mediated endothelium-dependent vasodilator response has been attributed to endothelium-derived hyperpolarizing factor/s (EDHF. Endothelial hyperpolarization is likely due to several factors that appear to be site and species specific. Experimental studies suggest that the contribution of the EDHFs increase as the vessel size decreases, with a predominance of EDHF activity in the resistance vessels, and a compensatory up-regulation of hyperpolarization in states characterized by reduced NO availability. Since endothelial dysfunction is a precursor for atherosclerosis development and its magnitude is a reflection of future risk, then the mechanisms underlying endothelial dysfunction need to be fully understood, so that adequate therapeutic interventions can be designed.

  6. Effect of hepatoma H22 on lymphatic endothelium in vitro

    Institute of Scientific and Technical Information of China (English)

    Hua Yu; Hong-Zhi Zhou; Chun-Mei Wang; Xiao-Ming Gu; Bo-Rong Pan


    AIM: To determine the effect of metastatic hepatoma cells on lymphangioma-derived endothelium, and to establish in vitro model systems for assessing metastasis-related response of lymphatic endothelium.METHODS: Benign lymphangioma, induced by intraperitonea linjection of the incomplete Freund's adjuvant in BALB/c mice, was embedded in fibrin gel or digested and then cultured in the conditioned medium derived from hepatoma H22. Light and electron microscopy, and the transwell migration assay were used to determine the effect of H22 on tissue or cell culture. Expressions of Flt-4, c-Fos, proliferating cell nuclear antigen (PCNA), and inducible nitric oxide synthase (iNOS) in cultured cells, and content of nitric oxide in culture medium were also examined.RESULTS: The embedded lymphangioma pieces gave rise to array of capillaries, while separated cells from lymphangioma grew to a cobblestone-like monolayer. H22 activated growth and migration of the capillaries and cells, induced expressions of Flt-4, c-Fos, PCNA and iNOS in cultured cells, and significantly increased the content of NO in the culture medium.CONCLUSION: Lymphangioma-derived cells keep the differentiated phenotypes of lymphatic endothelium, and the models established in this study are feasible for in vitro study of metastasis-related response of lymphatic endothelium.

  7. The fine structure of endothelium of large arteries. (United States)

    BUCK, R C


    Endothelium of large arteries from several species was studied in thin sections with the electron microscope. Before sacrifice, some animals received an intravenous injection of colloidal thorium dioxide which was visualized in the sections. Surface replicas were prepared by carbon evaporation on either frozen-dried endothelium or on endothelium dried by sublimation of naphthalene with which the tissue had been impregnated. Cell boundaries, stained with silver, were observed in sections and also from the surface by stripping off the inner part of the endothelium. In addition to the usual cytoplasmic organelles, the endothelial cells showed certain characteristic features, namely, large invaginated pockets communicating with the arterial lumen, numerous much smaller vesicular structures immediately under the plasma membrane and apparently also communicating with the lumen, and inclusions, into which injected thorium particles were incorporated. Intercellular boundaries appeared as regular double membranes in thin sections, and they were outlined by a double row of silver granules after silver staining. No evidence was obtained of permeation of intracellular spaces by colloidal thorium.

  8. Renal and cardiac microvascular endothelium: injury and repair

    NARCIS (Netherlands)

    Oosterhuis, NR


    Injury to the capillary endothelium can be devastating for renal and cardiac function. To halt the progression of chronic kidney disease (CKD) and heart failure (HF) preservation of the microvascular endothelial cell (EC) function and structure is of great importance.1 Increasing knowledge about

  9. Renal and cardiac microvascular endothelium: injury and repair

    NARCIS (Netherlands)

    Oosterhuis, N.R.


    Injury to the capillary endothelium can be devastating for renal and cardiac function. To halt the progression of chronic kidney disease (CKD) and heart failure (HF) preservation of the microvascular endothelial cell (EC) function and structure is of great importance.1 Increasing knowledge about mic


    NARCIS (Netherlands)



    The central corneal endothelium of 13 eyes in 13 subjects was visualized with a non-contact specular microscope. This report describes the computer-assisted morphometric analysis of enhanced digitized images, using a direct input by means of a frame grabber. The output consisted of mean cell area, c

  11. Physical (in)activity and endothelium-derived constricting factors: overlooked adaptations

    National Research Council Canada - National Science Library

    D. H. J. Thijssen; G. A. Rongen; P. Smits; M. T. E. Hopman


    .... In response to physical stimuli, the endothelium varies its release of circulating vasoactive substances and serves as a source of local and systemic endothelium-derived dilator and vasoconstrictor factors...

  12. Lipoxin A4 inhibits immune cell binding to salivary epithelium and vascular endothelium. (United States)

    Chinthamani, Sreedevi; Odusanwo, Olutayo; Mondal, Nandini; Nelson, Joel; Neelamegham, Sriram; Baker, Olga J


    Lipoxins are formed by leukocytes during cell-cell interactions with epithelial or endothelial cells. Native lipoxin A(4) (LXA(4)) binds to the G protein-coupled lipoxin receptors formyl peptide receptor 2 (FPR2)/ALX and CysLT1. Furthermore, LXA(4) inhibits recruitment of neutrophils, by attenuating chemotaxis, adhesion, and transmigration across vascular endothelial cells. LXA(4) thus appears to serve as an endogenous "stop signal" for immune cell-mediated tissue injury (Serhan CN; Annu Rev Immunol 25: 101-137, 2007). The role of LXA(4) has not been addressed in salivary epithelium, and little is known about its effects on vascular endothelium. Here, we determined that interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) receptor activation in vascular endothelium and salivary epithelium upregulated the expression of adhesion molecules that facilitates the binding of immune cells. We hypothesize that the activation of the ALX/FPR2 and/or CysLT1 receptors by LXA(4) decreases this cytokine-mediated upregulation of cell adhesion molecules that enhance lymphocyte binding to both the vascular endothelium and salivary epithelium. In agreement with this hypothesis, we observed that nanomolar concentrations of LXA(4) blocked IL-1β- and TNF-α-mediated upregulation of E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells (HUVECs). Binding of Jurkat cells to stimulated HUVECs was abrogated by LXA(4). Furthermore, LXA(4) preincubation with human submandibular gland cell line (HSG) also blocked TNF-α-mediated upregulation of vascular cell adhesion molecule-1 (VCAM-1) in these cells, and it reduced lymphocyte adhesion. These findings suggest that ALX/FPR2 and/or CysLT1 receptor activation in endothelial and epithelial cells blocks cytokine-induced adhesion molecule expression and consequent binding of lymphocytes, a critical event in the pathogenesis of Sjögren's syndrome (SS).

  13. Coronary collaterals

    NARCIS (Netherlands)

    Koerselman, Jeroen


    Cardiovascular diseases, in particular coronary artery disease, are the leading cause of death and disease in industrialized countries. Atherosclerotic changes of the arterial vessel wall constitute one of the major causes for the occurrence of cardiovascular disease. Important risk factors for

  14. Coronary collaterals

    NARCIS (Netherlands)

    Koerselman, Jeroen


    Cardiovascular diseases, in particular coronary artery disease, are the leading cause of death and disease in industrialized countries. Atherosclerotic changes of the arterial vessel wall constitute one of the major causes for the occurrence of cardiovascular disease. Important risk factors for card

  15. Activation of Poly(ADP-Ribose) Polymerase by Myocardial Ischemia and Coronary Reperfusion in Human Circulating Leukocytes


    Tóth-Zsámboki, Emese; Horváth, Eszter; Vargova, Katarina; Pankotai, Eszter; Murthy, Kanneganti; Zsengellér, Zsuzsanna; Bárány, Tamás; Pék, Tamás; Fekete, Katalin; Kiss, Róbert Gábor; Préda, István; Lacza, Zsombor; Gerö, Domokos; SzabÓ, Csaba


    Reactive free radical and oxidant production leads to DNA damage during myocardial ischemia/reperfusion. Consequent overactivation of poly(ADP-ribose) polymerase (PARP) promotes cellular energy deficit and necrosis. We hypothesized that PARP is activated in circulating leukocytes in patients with myocardial infarction and reperfusion during primary percutaneous coronary intervention (PCI). In 15 patients with ST segment elevation acute myocardial infarction, before and after primary PCI and 2...

  16. [The pattern of Levenberg-Marquardt backpropagation algorithm for recognition of coronary heart disease patients based on microamount of elements in human blood]. (United States)

    Kai, Xiao-ming


    The contents of four microamount elements (Sr, Cu, Mg and Zn) in human blood were chosen as recognition index of coronary heart disease patients and normal persons. The recognition pattern of Levenberg-Marquardt Backpropagation algorithm has been established. The first-layer transfer function is Tansig function; the second-layer transfer function is linear Purelin function. There are four input vectors, eight neurons on hidden layer, and one neuron of output vector. Four samples were chosen as a teat group and 22 samples as a training group. The weights and biases of the neural network were given. The given data could be completely identified, which predicted that this method could be a supplementary tool to diagnose this kind of disease with the determined contents of microamount of elements in human blood.

  17. Role of endothelium-derived hyperpolarization in the vasodilatation of rat intrarenal arteries

    DEFF Research Database (Denmark)

    Pinilla, Estéfano; Sánchez-Pina, Ana; Muñoz Picos, Mercedes


    Background and purpose: Endothelium-dependent vasodilation plays an important role in the regulation of vascular tone in different vascular beds. Besides the release of prostacyclin (PGI2) and nitric oxide (NO), the endothelium mediates vasodilation through endothelium-derived hyperpolarization (...

  18. The endothelin B receptor plays a crucial role for the adhesion of neutrophils to the endothelium in sickle cell disease. (United States)

    Koehl, Bérengère; Nivoit, Pierre; El Nemer, Wassim; Lenoir, Olivia; Hermand, Patricia; Pereira, Catia; Brousse, Valentine; Guyonnet, Léa; Ghinatti, Giulia; Benkerrou, Malika; Colin, Yves; Le Van Kim, Caroline; Tharaux, Pierre-Louis


    Although the primary origin of sickle cell disease is a hemoglobin disorder, several cell types contribute considerably to the physiopathology of the disease. The adhesion of neutrophils to activated endothelium is critical in sickle cell disease pathophysiology and the targeting of neutrophils and their interactions with endothelium represent important opportunities for new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and we investigated the involvement of the endothelin receptors in interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor highly influences neutrophils recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils display functional ETB receptors with calcium signaling capability leading to increased adhesion to the endothelium, through action on both endothelial cells and neutrophils. ETB intact function was also found to be required for TNFα-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1 that may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptor, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises of sickle cell patients.

  19. Effect of basic fibroblast growth factor on the migration of human adipose-derived stem cells toward vascular endothelium%碱性成纤维细胞生长因子影响脂肪干细胞的血管内皮迁移

    Institute of Scientific and Technical Information of China (English)

    朱梦琳; 姜南; 徐扬阳; 曹菁; 杨柳


    labeled by cm-dil was prepared. The working solution containing 2 mg/L basic fibroblast growth factor was prepared. Composite tissue al-lografts which were the mixtures of 0.25 mL sodium hyaluronate, 0.2 mL cellsuspension and 0.05 mL working solution or DMEM were implanted into the subcutaneous site of both sides of the mouse back. Specimens were taken at 6 weeks after operation and were evaluated histological y after hematoxylin-eosin and vascular immunofluorescent staining. RESULTS AND CONCLUSION:No necrosis, liquefaction, nodular tissue or gel remained in operated position. The hematoxylin-eosin staining showed the main components of the specimens were the adipose tissue and the loose connective tissue. The immunofluorescence staining showed the overlaps between the cm-dil fluorescence from human adipose-derived stem cells and the FITC fluorescence from the vascular endothelium in the experimental group were more than those in the control group (P<0.05). Basic fibroblast growth factor promotes the migration and the differentiation of human adipose-derived stem cells in the sodium hyaluronate scaffold into vascular endothelium.

  20. Confocal microscopy and electrophysiological study of single patient corneal endothelium cell cultures (United States)

    Tatini, Francesca; Rossi, Francesca; Coppi, Elisabetta; Magni, Giada; Fusco, Irene; Menabuoni, Luca; Pedata, Felicita; Pugliese, Anna Maria; Pini, Roberto


    The characterization of the ion channels in corneal endothelial cells and the elucidation of their involvement in corneal pathologies would lead to the identification of new molecular target for pharmacological treatments and to the clarification of corneal physiology. The corneal endothelium is an amitotic cell monolayer with a major role in preserving corneal transparency and in regulating the water and solute flux across the posterior surface of the cornea. Although endothelial cells are non-excitable, they express a range of ion channels, such as voltage-dependent Na+ channels and K+ channels, L-type Ca2 channels and many others. Interestingly, purinergic receptors have been linked to a variety of conditions within the eye but their presence in the endothelium and their role in its pathophysiology is still uncertain. In this study, we were able to extract endothelial cells from single human corneas, thus obtaining primary cultures that represent the peculiarity of each donor. Corneas were from tissues not suitable for transplant in patients. We characterized the endothelial cells by confocal microscopy, both within the intact cornea and in the primary endothelial cells cultures. We also studied the functional role of the purinergic system (adenosine, ATP and their receptors) by means of electrophysiological recordings. The experiments were performed by patch clamp recordings and confocal time-lapse microscopy and our results indicate that the application of purinergic compounds modulates the amplitude of outward currents in the isolated endothelial cells. These findings may lead to the proposal of new therapies for endothelium-related corneal diseases.

  1. Embolic capture with updated intra-aortic filter during coronary artery bypass grafting and transaortic transcatheter aortic valve implantation: first-in-human experience. (United States)

    Ye, Jian; Webb, John G


    We report our first-in-human clinical experience in the use of the new version of the EMBOL-X intra-aortic filter (Edwards Lifesciences Corporation, Irvine, Calif) to capture embolic material during transaortic transcatheter aortic valve implantation and cardiac surgery. Five patients were enrolled into the first-in-human clinical assessment of the new version of the EMBOL-X intra-aortic filter. Three patients underwent coronary artery bypass grafting, and 2 patients underwent transaortic transcatheter aortic valve implantation. During coronary artery bypass grafting, the filter was deployed before clamping of the aorta and removal of the aortic clamp. In contrast, the filter was deployed before aortic puncture for transaortic transcatheter aortic valve implantation and kept in the aorta throughout the entire procedure. The filter introducer sheath and filter were easily placed and removed without difficulty. There were no complications related to the use of the filter. Postoperative examination of the retrieved filters revealed the presence of multiple microemboli in the filters from all 5 cases. Histologic study revealed various kinds of tissue and thrombus. This first-in-human clinical experience has demonstrated the safety and feasibility of using the new version of the EMBOL-X intra-aortic filter during either cardiac surgery or transaortic transcatheter aortic valve implantation. We believe that the combination of the transaortic approach without aortic arch manipulation and the use of the EMBOL-X filter with a high capture rate is a promising strategy to reduce the incidence of embolic complications during transcatheter aortic valve implantation. Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  2. The Changes of Vasoactive Substances Originated Endothelium in Patients with Unstable Angina Pectoris Treated by Improved Thrombolytic Therapy

    Institute of Scientific and Technical Information of China (English)

    Wang Congxia; Niu Xiaolin; Li Yongqin; Zhang MingJuan; Ding Kangning


    Objectives To analyze the changes of vasoactive substances originated from endothelium in patients with unstable angina pectoris treated by modified thrombolytic therapy and explore the mechanisms of the drug to treat unstable angina pectoris.Methods 120 patients with unstable angina pectoris who were not well responsed to common medication were studied. Their ECG stress tests were abnormal and there were ischemic changes in Holter. Urokinase 300,000 U was added in 100 ml normal saline and injected within 30 min once a day for 3 days. 300 mg aspirin was administrated a day before and during urokinase applications. Before and after urokinase treatments, endothelin-1, plasma tissue plasminogen activator and its inhibitor-1were determined. Results Compared with pretreatments, after treatments, the activities of tissue plasminogen activator increased, endothelin-1 and the inhibitor-1 decreased. The changes were significant. Conclusions Modified thrombolytic therapy can regulate the vasoactive substances originated endothelium in patients with unstable angina pectoris . The major substances include endothelin-1 ,plasma tissue plasminogen activator and inhibitor-1. This mechanism may suggest that urokinase can treat coronary heart disease effectively.

  3. A Combination of Constitutive Damage Model and Artificial Neural Networks to Characterize the Mechanical Properties of the Healthy and Atherosclerotic Human Coronary Arteries. (United States)

    Karimi, Alireza; Rahmati, Seyed Mohammadali; Sera, Toshihiro; Kudo, Susumu; Navidbakhsh, Mahdi


    It has been indicated that the content and structure of the elastin and collagen of the arterial wall can subject to a significant alteration due to the atherosclerosis. Consequently, a high tissue stiffness, stress, and even damage/rupture are triggered in the arterial wall. Although many studies so far have been conducted to quantify the mechanical properties of the coronary arteries, none of them consider the role of collagen damage of the healthy and atherosclerotic human coronary arterial walls. Recently, a fiber family-based constitutive equation was proposed to capture the anisotropic mechanical response of the healthy and atherosclerotic human coronary arteries via both the histostructural and uniaxial data. In this study, experimental mechanical measurements along with histological data of the healthy and atherosclerotic arterial walls were employed to determine the constitutive damage parameters and remodeling of the collagen fibers. To do this, the preconditioned arterial tissues were excised from human cadavers within 5-h postmortem, and the mean angle of their collagen fibers was precisely determined. Thereafter, a group of quasistatic axial and circumferential loadings were applied to the arterial walls, and the constrained nonlinear minimization method was employed to identify the arterial parameters according to the axial and circumferential extension data. The remodeling of the collagen fibers during the tensile test was also predicted via Artificial Neural Networks algorithm. Regardless of loading direction, the results presented a noteworthy load-bearing capability and stiffness of the atherosclerotic arteries compared to the healthy ones (P < 0.005). Theoretical fiber angles were found to be consistent with the experimental histological data with less than 2 and 5° difference for the healthy and atherosclerotic arterial walls, respectively. The pseudoelastic damage model data were also compared with that of the experimental data, and

  4. Calcification of multipotent prostate tumor endothelium. (United States)

    Dudley, Andrew C; Khan, Zia A; Shih, Shou-Ching; Kang, Soo-Young; Zwaans, Bernadette M M; Bischoff, Joyce; Klagsbrun, Michael


    Solid tumors require new blood vessels for growth and metastasis, yet the biology of tumor-specific endothelial cells is poorly understood. We have isolated tumor endothelial cells from mice that spontaneously develop prostate tumors. Clonal populations of tumor endothelial cells expressed hematopoietic and mesenchymal stem cell markers and differentiated to form cartilage- and bone-like tissues. Chondrogenic differentiation was accompanied by an upregulation of cartilage-specific col2a1 and sox9, whereas osteocalcin and the metastasis marker osteopontin were upregulated during osteogenic differentiation. In human and mouse prostate tumors, ectopic vascular calcification was predominately luminal and colocalized with the endothelial marker CD31. Thus, prostate tumor endothelial cells are atypically multipotent and can undergo a mesenchymal-like transition.

  5. Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa

    Directory of Open Access Journals (Sweden)

    Hisa Hui Ling Tseng


    Full Text Available Calycosin and formononetin are two structurally similar isoflavonoids that have been shown to induce vasodilation in aorta and conduit arteries, but study of their actions on endothelial functions is lacking. Here, we demonstrated that both isoflavonoids relaxed rat mesenteric resistance arteries in a concentration-dependent manner, which was reduced by endothelial disruption and nitric oxide synthase (NOS inhibition, indicating the involvement of both endothelium and vascular smooth muscle. In addition, the endothelium-dependent vasodilation, but not the endothelium-independent vasodilation, was blocked by BKCa inhibitor iberiotoxin (IbTX. Using human umbilical vein endothelial cells (HUVECs as a model, we showed calycosin and formononetin induced dose-dependent outwardly rectifying K+ currents using whole cell patch clamp. These currents were blocked by tetraethylammonium chloride (TEACl, charybdotoxin (ChTX, or IbTX, but not apamin. We further demonstrated that both isoflavonoids significantly increased nitric oxide (NO production and upregulated the activities and expressions of endothelial NOS (eNOS and neuronal NOS (nNOS. These results suggested that calycosin and formononetin act as endothelial BKCa activators for mediating endothelium-dependent vasodilation through enhancing endothelium hyperpolarization and NO production. Since activation of BKCa plays a role in improving behavioral and cognitive disorders, we suggested that these two isoflavonoids could provide beneficial effects to cognitive disorders through vascular regulation.

  6. Cardiovascular and autoimmune diseases in females: The role of microvasculature and dysfunctional endothelium. (United States)

    Gianturco, L; Bodini, B D; Atzeni, F; Colombo, C; Stella, D; Sarzi-Puttini, P; Drago, L; Galaverna, S; Turiel, M


    Cardiovascular (CV) diseases are becoming increasingly frequent and associated with a high incidence of CV events, disability and death. It is known that there is a relationship between CV burden and systemic autoimmune diseases (SADs) that is mainly due to inflammation and autoimmunity, but the other mechanisms underlying the high CV risk of SAD patients have not yet been fully clarified. The aim of this review article is to discuss some of the specific factors associated with the accelerated atherosclerosis (ATS) characterising SADs (female sex, the microcirculation and the endothelium) in order to highlight the importance of an early diagnosis and the prompt implementation of preventive measures, as well as the possible role of new therapeutic strategies such as vaccine immunomodulation. Finally, as the natural history of ATS begins with endothelial injury (a potentially reversible process that is influenced by various factors) and microvascular damage plays a central role in the etiopathogenesis of SADs, it underlines the crucial need for the development of reliable means of detecting sub-clinical abnormalities in the microcirculation, particularly coronary microcirculation dysfunction.

  7. Protection of the vascular endothelium in experimental situations



    One of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) ...


    Institute of Scientific and Technical Information of China (English)


    The cell morphology of corneal endothelium in 84 mice with experimental traumatic cataract was investigated with stained corneal buttons. In the experimental group, the boundaries between adjacent corneal endothelial cells were significantly distorted, some cell boundaries manifested degenerative changes that led to coalescence of the cells. The mean density and mean area of endothelial cells of the controls showed significant difference from those of the experimental group during the 12 weeks of observ...

  9. Prominin 1/CD133 endothelium sustains growth of proneural glioma.

    Directory of Open Access Journals (Sweden)

    Bi-Sen Ding

    Full Text Available In glioblastoma high expression of the CD133 gene, also called Prominin1, is associated with poor prognosis. The PDGF-driven proneural group represents a subset of glioblastoma in which CD133 is not overexpressed. Interestingly, this particular subset shows a relatively good prognosis. As with many other tumors, gliobastoma is believed to arise and be maintained by a restricted population of stem-like cancer cells that express the CD133 transmembrane protein. The significance of CD133(+ cells for gliomagenesis is controversial because of conflicting supporting evidence. Contributing to this inconsistency is the fact that the isolation of CD133(+ cells has largely relied on the use of antibodies against ill-defined glycosylated epitopes of CD133. To overcome this problem, we used a knock-in lacZ reporter mouse, Prom1(lacZ/+ , to track Prom1(+ cells in the brain. We found that Prom1 (prominin1, murine CD133 homologue is expressed by cells that express markers characteristic of the neuronal, glial or vascular lineages. In proneural tumors derived from injection of RCAS-PDGF into the brains of tv-a;Ink4a-Arf(-/- Prom1(lacZ/+ mice, Prom1(+ cells expressed markers for astrocytes or endothelial cells. Mice co-transplanted with proneural tumor sphere cells and Prom1(+ endothelium had a significantly increased tumor burden and more vascular proliferation (angiogenesis than those co-transplanted with Prom1(- endothelium. We also identified specific genes in Prom1(+ endothelium that code for endothelial signaling modulators that were not overexpressed in Prom1(- endothelium. These factors may support proneural tumor progression and could be potential targets for anti-angiogenic therapy.

  10. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. (United States)

    Serrato, M; Marian, A J


    Coronary artery disease (CAD) is a complex trait caused by a number of genetic and environmental factors. Recently, paraoxonase/arylesterase (PONA) enzyme has been implicated in the pathogenesis of atherosclerosis. There is a 10-40-fold variability in the activity of this enzyme among individuals. This variability is due to the presence of an A/G polymorphism in the coding region of the gene (HUMPONA). The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with A genotype have a lower enzymatic activity than those with B genotype. We determined the HUMPONA genotypes and alleles in 223 patients with angiographically documented CAD and in 247 individuals in the general population. The distribution of genotypes were in Hardy-Weinberg equilibrium in patients and in controls. Genotypes A and B were present in 120 (49%) and 28 (11%) individuals in controls and in 68 (30%) and 40 (18%) patients with CAD, respectively (chi squared= 16.5, P= 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (OR= 1.7, P= 0.0001). There were no differences in the distribution of HUMPONA genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for CAD as compared with corresponding subgroups. In summary, variants of the HUMPONA gene are involved in predisposition to coronary atherosclerosis.

  11. P2X1 receptors and the endothelium

    Directory of Open Access Journals (Sweden)

    LS Harrington


    Full Text Available Adenosine triphosphate (ATP is now established as a principle vaso-active mediator in the vasculature. Its actions on arteries are complex, and are mediated by the P2X and P2Y receptor families. It is generally accepted that ATP induces a bi-phasic response in arteries, inducing contraction via the P2X and P2Y receptors on the smooth muscle cells, and vasodilation via the actions of P2Y receptors located on the endothelium. However, a number of recent studies have placed P2X1 receptors on the endothelium of some arteries. The use of a specific P2X1 receptor ligand, a, b methylene ATP has demonstrated that P2X1 receptors also have a bi-functional role. The actions of ATP on P2X1 receptors is therefore dependant on its location, inducing contraction when located on the smooth muscle cells, and dilation when expressed on the endothelium, comparable to that of P2Y receptors.

  12. Insulin action and insulin resistance in vascular endothelium. (United States)

    Muniyappa, Ranganath; Quon, Michael J


    Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase dependent insulin signaling pathways in endothelium, which stimulate production of nitric oxide. Insulin-stimulated nitric oxide mediates capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in skeletal muscle. Distinct mitogen-activated protein kinase dependent insulin signaling pathways regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These vascular actions of insulin contribute to the coupling of metabolic and hemodynamic homeostasis that occurs under healthy conditions. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase dependent signaling in both metabolic and vascular insulin target tissues. Here we discuss consequences of pathway-specific insulin resistance in endothelium and therapeutic interventions targeting this selective impairment. Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation selectively impair phosphatidylinositol 3-kinase dependent insulin signaling pathways, creating reciprocal relationships between insulin resistance and endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously modulate phosphatidylinositol 3-kinase and mitogen-activated protein kinase dependent pathways, improving metabolic and vascular actions of insulin. Pathway-specific impairment in insulin action contributes to reciprocal relationships between endothelial dysfunction and insulin resistance, fostering clustering of metabolic and cardiovascular diseases in insulin-resistant states. Therapeutic interventions that target this selective impairment often simultaneously improve both metabolic and vascular function.

  13. Smooth muscle cells largely develop independently of functional hemogenic endothelium

    Directory of Open Access Journals (Sweden)

    Monika Stefanska


    Full Text Available Vascular smooth muscle cells represent a major component of the cardiovascular system. In vitro studies have shown that FLK1+ cells derived from embryonic stem (ES cells can differentiate into both endothelial and smooth muscle cells. These FLK1+ cells also contain a mesodermal precursor, the hemangioblast, able to produce endothelial, blood and smooth muscle cells. The generation of blood precursors from the hemangioblast was recently shown to occur through a transient cell population of specialised endothelium, a hemogenic endothelium. To date, the lineage relationship between this cell population and smooth muscle cell progenitors has not been investigated. In this study, we generated a reporter ES cell line in which expression of the fluorescent protein H2B-VENUS is driven by the α-smooth muscle actin (α-SMA regulatory sequences. We demonstrated that this reporter cell line efficiently trace smooth muscle development during ES cell differentiation. Although some smooth muscle cells are associated with broad endothelial development, we established that smooth muscle cells are mostly generated independently from a specialised functional hemogenic endothelium. This study provides new and important insights into hematopoietic and vascular development, which may help in driving further progress towards the development of bioengineered vascular grafts for regenerative medicine.

  14. Evolutionary origins of the blood vascular system and endothelium (United States)

    Monahan-Earley, Rita; Dvorak, Ann M.; Aird, William C.


    Every biological trait requires both a proximate and evolutionary explanation. The field of vascular biology is focused primarily on proximate mechanisms in health and disease. Comparatively little attention has been given to the evolutionary basis of the cardiovascular system. Here, we employ a comparative approach to review the phylogenetic history of the blood vascular system and endothelium. In addition to drawing on the published literature, we provide primary ultrastructural data related to the lobster, earthworm, amphioxus and hagfish. Existing evidence suggests that the blood vascular system first appeared in an ancestor of the triploblasts over 600 million years ago, as a means to overcome the time-distance constraints of diffusion. The endothelium evolved in an ancestral vertebrate some 540–510 million years ago to optimize flow dynamics and barrier function, and/or to localize immune and coagulation functions. Finally, we emphasize that endothelial heterogeneity evolved as a core feature of the endothelium from the outset, reflecting its role in meeting the diverse needs of body tissues. PMID:23809110

  15. Xanthorrhizol induces endothelium-independent relaxation of rat thoracic aorta. (United States)

    Campos, M G; Oropeza, M V; Villanueva, T; Aguilar, M I; Delgado, G; Ponce, H A


    Xanthorrhizol, a bisabolene isolated from the medicinal plant Iostephane heterophylla, was assayed on rat thoracic aorta rings to elucidate its effect and likely mechanism of action, by measuring changes of isometric tension. Xanthorrhizol (1, 3, 10, 30 and 100 microg/mL) significantly inhibited precontractions induced by KCI-; (60mM), noradrenaline (10(-6) M) or CaCl2 (1.0 mM). Increasing concentrations of external calcium antagonized the inhibitory effect on KCl-induced contractions. The vasorelaxing effect of xanthorrhizol was not affected by indomethacin (10 microM) or L-NAME (100 microM) in intact rat thoracic aorta rings precontracted by noradrenaline, which suggested that the effect was not mediated through either endothelium-derived prostacyclin (PGI2) or nitric oxide release from endothelial cells. Endothelium removal did not affect the relaxation induced by xanthorrhizol on rat thoracic aorta rings, discarding the participation of any substance released by the endothelium. Xanthorrhizol inhibitory effect was greater on KCI- and CaCl2-induced contractions than on those induced by noradrenaline. Xanthorrhizol inhibitory effect in rat thoracic aorta is likely explained for interference with calcium availability by inhibiting calcium influx through both voltage- and receptor-operated channels.

  16. Evaluation of combined near-IR spectroscopic (NIRS)-IVUS imaging as a means to detect lipid-rich plaque burden in human coronary autopsy specimens (United States)

    Su, Jimmy L.; Grainger, Stephanie J.; Greiner, Cherry A.; Hendricks, Michael J.; Goode, Meghan M.; Saybolt, Matthew D.; Wilensky, Robert L.; Madden, Sean P.; Muller, James E.


    Intracoronary near-infrared spectroscopy (NIRS) can identify lipid in the coronary arteries, but lacks depth resolution. A novel catheter is currently in clinical use that combines NIRS with intravascular ultrasound (IVUS), which provides depth-resolved structural information via the IVUS modality. A measure designated as lipid-rich plaque burden (LRPB) has been proposed as a means to interpret the combined acoustic and optical information of NIRS-IVUS. LRPB is defined as the area created by the intersection of the NIRS lipid-rich arc with the corresponding IVUS-measured plaque burden. We determined the correlation in human coronary autopsy specimens between LRPB, a measure of lipid presence and extent available via intravascular imaging in patients, and the area of lipid-rich plaque as determined by the gold-standard of histology. Fifteen artery segments from 8 human autopsy hearts were imaged with the NIRS-IVUS system (TVC Imaging System, Infraredx Inc., Burlington, MA). Arteries were imaged in a specialty fixture that assured accurate co-registration between imaging and histology. The arteries were then fixed and divided into 2 mm blocks for histological staining. Pathological contouring of lipid-rich areas was performed on the stained thin sections for 54 lipid-rich blocks. Computation of LRPB was performed on transverse NIRS-IVUS frames corresponding to the histologic sections. The quantified LRPB was frequently higher than the lipid-rich plaque area determined by histology, because the region denoted by the EEL and lumen within the NIRS lipid-rich arc is not entirely comprised of lipid. Overall, a moderate to strong correlation (R = 0.73) was found between LRPB determined by NIRS-IVUS imaging and the lipid-rich plaque area determined by histology. LRPB, which can be measured in patients with NIRS-IVUS imaging, corresponds to the amount of lipid-rich plaque in a coronary artery. LRPB should be evaluated in prospective clinical trials for its ability to

  17. 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. (United States)

    Shimokawa, Hiroaki


    Coronary vasomotion abnormalities play important roles in the pathogenesis of ischaemic heart disease, in which endothelial dysfunction and coronary artery spasm are substantially involved. Endothelial vasodilator functions are heterogeneous depending on the vessel size, with relatively greater role of nitric oxide (NO) in conduit arteries and predominant role of endothelium-derived hyperpolarizing factor (EDHF) in resistance arteries, where endothelium-derived hydrogen peroxide serves as an important EDHF. The functions of NO synthases in the endothelium are also heterogeneous with multiple mechanisms involved, accounting for the diverse functions of the endothelium in vasomotor as well as metabolic modulations. Cardiovascular abnormalities and metabolic phenotypes become evident when all three NO synthases are deleted, suggesting the importance of both NO and EDHF. Coronary artery spasm plays important roles in the pathogenesis of a wide range of ischaemic heart disease. The central mechanism of the spasm is hypercontraction of vascular smooth muscle cells (VSMCs), but not endothelial dysfunction, where activation of Rho-kinase, a molecular switch of VSMC contraction, plays a major role through inhibition of myosin light-chain phosphatase. The Rho-kinase pathway is also involved in the pathogenesis of a wide range of cardiovascular diseases and new Rho-kinase inhibitors are under development for various indications. The registry study by the Japanese Coronary Spasm Association has demonstrated many important aspects of vasospastic angina. The ongoing international registry study of vasospastic angina in six nations should elucidate the unknown aspects of the disorder. Coronary vasomotion abnormalities appear to be an important therapeutic target in cardiovascular medicine.


    Institute of Scientific and Technical Information of China (English)

    张延斌; 黄宗明; 吴兰芬; 陈清枝


    Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease and is considered as an early manifestation of atherosclerosis. In the conduit arteries, a vasodilator response

  19. Non-endothelial endothelin counteracts hypoxic vasodilation in porcine large coronary arteries

    DEFF Research Database (Denmark)

    Hedegaard, Elise Røge; Stankevicius, Edgaras; Simonsen, Ulf


    of large coronary arteries. RESULTS: In prostaglandin F2α (PGF2α, 10 μM)-contracted segments with endothelium, gradual lowering of oxygen tension from 95 to 1% O2 resulted in vasodilation. The vasodilation to O2 lowering was rightward shifted in segments without endothelium at all O2 concentrations except...... at 1% O2. The endothelin receptor antagonist SB217242 (10 μM) markedly increased hypoxic dilation despite the free tissue ET-1 concentration in the arterial wall was unchanged in 1% O2 versus 95% O2. Exogenous ET-1 reversed hypoxic dilation in segments with and without endothelium, and the hypoxic...... arteries showed an increased sensitivity towards ET-1 compared to the normoxic controls. Without affecting basal NO, hypoxia increased NO concentration in PGF2α-contracted arteries, and an NO synthase inhibitor, L-NOARG,(300 μM, NG-nitro-L-Arginine) reduced hypoxic vasodilation. NO-induced vasodilation...

  20. HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. (United States)

    Yasunari, K; Maeda, K; Minami, M; Yoshikawa, J


    In vitro and in vivo evidence of a decrease in vascular smooth muscle cell (SMC) migration induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been reported. When added to SMC cultures for 6 hours, the HMG-CoA reductase inhibitors fluvastatin, simvastatin, and pravastatin at 1 micromol/L resulted in a 48%, 50%, and 16% suppression, respectively, of human coronary SMC migration; these reductions mirrored the suppression in oxidative stress induced by 1 micromol/L lysophosphatidylcholine (lyso-PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluvastatin, M(2) and M(3), at 1 micromol/L also suppressed the enhancement of SMC migration by 58% and 45% and the increase in oxidative stress induced by lyso-PC of 58% and 49%, respectively. Lyso-PC activated phospholipase D and protein kinase C (PKC), and this activation was also suppressed by HMG-CoA reductase inhibitors. The inhibition of phospholipase D and PKC was reversed by 100 micromol/L mevalonate, its isoprenoid derivative, farnesol, and geranylgeraniol but not by 10 micromol/L squalene. Antisense oligodeoxynucleotides at 5 micromol/L to PKC-alpha, but not those to the PKC-beta isoform, suppressed the lyso-PC-mediated increases in SMC migration and oxidative stress. These findings suggest that HMG-CoA reductase inhibitors have direct antimigratory effects on the vascular wall beyond their effects on plasma lipids and that they might exert such antimigratory effects via suppression of the phospholipase D- and PKC (possibly PKC-alpha)-induced increase in oxidative stress, which might in turn prevent significant coronary artery disease.

  1. Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose. (United States)

    Yasunari, K; Kohno, M; Kano, H; Minami, M; Yoshikawa, J


    We examined involvement of the polyol pathway in high glucose-induced human coronary artery smooth muscle cell (SMC) migration using Boyden's chamber method. Chronic glucose treatment for 72 hours potentiated, in a concentration-dependent manner (5.6 to 22.2 mol/L), platelet-derived growth factor (PDGF) BB-mediated SMC migration. This potentiation was accompanied by an increase in PDGF BB binding, because of an increased number of PDGF-beta receptors, and this potentiation was blocked by the aldose reductase inhibitor epalrestat. Epalrestat at concentrations of 10 and 100 nmol/L inhibited high glucose-potentiated (22.2 mmol/L), PDGF BB-mediated migration. Epalrestat at 100 nmol/L inhibited a high glucose-induced increase in the reduced/oxidized nicotinamide adenine dinucleotide ratio and membrane-bound protein kinase C (PKC) activity in SMCs. PKC inhibitors calphostin C (100 nmol/L) and chelerythrine (1 micromol/L) each inhibited high glucose-induced, PDGF BB-mediated SMC migration. High glucose-induced suppression of insulin-mediated [(3)H]-deoxyglucose uptake, which was blocked by both calphostin C (100 nmol/L) and chelerythrine (1 micromol/L), was decreased by epalrestat (100 nmol/L). Chronic high glucose treatment for 72 hours increased intracellular oxidative stress, which was directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by epalrestat (100 nmol/L). Antisense oligonucleotide to PKC-beta isoform inhibited high glucose-mediated changes in SMC migration, insulin-mediated [(3)H]-deoxyglucose uptake, and oxidative stress. These findings suggest that high glucose concentrations potentiate SMC migration in coronary artery and that the aldose reductase inhibitor epalrestat inhibits high glucose-potentiated, PDGF BB-induced SMC migration, possibly through suppression of PKC (PKC-beta), impaired insulin-mediated glucose uptake, and oxidative stress.

  2. Cytochrome P450IA1 induction and localization in endothelium of vertebrate (teleost) heart. (United States)

    Stegeman, J J; Miller, M R; Hinton, D E


    Previous studies have shown that high levels of cytochrome P450 can occur in cardiac microsomes of vertebrates [Mol. Pharmacol. 21:517-526, (1982)]. Here we identify the dominant cardiac P450 in the marine fish scup as P450E, a teleost representative of P450IA1, and we describe its restricted cellular localization in the heart. Treatment of scup with beta-naphthoflavone produced an unusually strong (10-fold) induction of spectrally measured P450 in cardiac microsomes, with specific content reaching levels (0.5 nmol/mg) similar to those induced in scup liver. Microsomal ethoxyresorufin O-deethylase and aryl hydrocarbon hydroxylase activities, catalytic functions of scup P450E, were induced in parallel with P450 content. Similar induction was seen in both atrium and ventricle. Immunoblot analysis with monoclonal antibody 1-12-3, specific to scup P450E and other vertebrate P450IA1 proteins, showed that this hydrocarbon-inducible P450 is the dominant and possibly sole P450 form in heart microsomes of experimentally induced animals. Immunohistochemical analysis of scup heart sections (2-4-microns) with monoclonal antibody 1-12-3 revealed that P450E was detectable only in endothelial cells of the endocardium and of the coronary vasculature. A similar endothelial cell localization of the monoclonal antibody 1-12-3 epitope was observed in heart of rainbow trout, induced with beta-naphthoflavone, indicating a general nature for the endothelial localization of induced cardiac P450. Morphometric analysis showed that endothelium could constitute 8-9% of the volume of teleost heart, from which we calculate that P450IA1 could account for as much as 25% of the endothelial cell microsomal protein. Heart microsomes of untreated animals from contaminated environments also contained high levels of P450E, indicating that induction like that caused by beta-naphthoflavone could occur with chemicals in the environment. Strongly induced P450E (P450IA1) in endothelium could play a critical

  3. Cardioplegia cristalóide, barotrauma e função endotelial: considerações experimentais Crystalloid cardioplegia, barotrauma and endothelium function: experimental considerations

    Directory of Open Access Journals (Sweden)

    Paulo Roberto B Évora


    effect the endothelium function of epicardic canine coronary arteries. These experiments did not show any alterations at level of receptors (dose-response curves to ACH and ADP; signal transduction/G-proteins (dose-response curve to sodium fluoride; intracellular mechanisms of the EDRF/NO release (dose-response curves to phospholipase C and calcium ionophores A23187. The smooth muscular relaxant function (dose-response curves to sodium nitroprusside and isoproterenol and contarctions (doseresponse curves to KCI and PGF2alpha were also preserved. These experimental observations allow the following speculative considerations: a Should barotrauma be a phenomenon present only in damaged coronary circulation? b All infusion were performed in no more than two or three minutes. Is cardioplegia barotrauma a phenomenon time-dependente? c High levels of potassium could be associated with barotrauma, d Cardioplegia barotrauma is a fancy, at least in our experimental conditions? e Experiments in "organ chambers" study only epicardic arteries. Could barotrauma damage the microcirculation? f The canine coronary circulation is less affeccted by high pressure than human coronaries? These data are suggestive that crystalloid moderately hyperkalemic infusions at high pressures for two or three minutes, do not impair the endothelium release of EDRF/NO of canine epicardic coronary arteries.

  4. Acute lead-induced vasoconstriction in the vascular beds of isolated perfused rat tails is endothelium-dependent

    Directory of Open Access Journals (Sweden)

    E.A. Silveira


    Full Text Available Chronic lead exposure induces hypertension in humans and animals, affecting endothelial function. However, studies concerning acute cardiovascular effects are lacking. We investigated the effects of acute administration of a high concentration of lead acetate (100 µΜ on the pressor response to phenylephrine (PHE in the tail vascular bed of male Wistar rats. Animals were anesthetized with sodium pentobarbital and heparinized. The tail artery was dissected and cannulated for drug infusion and mean perfusion pressure measurements. Endothelium and vascular smooth muscle relaxation were tested with acetylcholine (5 µg/100 µL and sodium nitroprusside (0.1 µg/100 µL, respectively, in arteries precontracted with 0.1 µM PHE. Concentration-response curves to PHE (0.001-300 µg/100 µL were constructed before and after perfusion for 1 h with 100 µΜ lead acetate. In the presence of endothelium (E+, lead acetate increased maximal response (Emax (control: 364.4 ± 36, Pb2+: 480.0 ± 27 mmHg; P < 0.05 and the sensitivity (pD2; control: 1.98 ± 0.07, 2.38 ± 0.14 log mM to PHE. In the absence of endothelium (E- lead had no effect but increased baseline perfusion pressure (E+: 79.5 ± 2.4, E-: 118 ± 2.2 mmHg; P < 0.05. To investigate the underlying mechanisms, this protocol was repeated after treatment with 100 µM L-NAME, 10 µM indomethacin and 1 µM tempol in the presence of lead. Lead actions on Emax and pD2 were abolished in the presence of indomethacin, and partially abolished with L-NAME and tempol. Results suggest that acute lead administration affects the endothelium, releasing cyclooxygenase-derived vasoconstrictors and involving reactive oxygen species.

  5. Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway

    Directory of Open Access Journals (Sweden)

    Yeh Siang Lau


    Full Text Available Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE, also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma “antihypertensive tea” is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs. Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase, wortmannin (30 nM and LY294002 (20 µM; PI3 (phosphatidylinositol3-Kinase inhibitor, NG-nitro-l-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS and ODQ (1 µM; soluble guanylyl cyclase inhibitor. Total nitrite and nitrate (NOx level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.

  6. Upregulation of SK3 and IK1 channels contributes to the enhanced endothelial calcium signaling and the preserved coronary relaxation in obese Zucker rats.

    Directory of Open Access Journals (Sweden)

    Belén Climent

    Full Text Available BACKGROUND AND AIMS: Endothelial small- and intermediate-conductance KCa channels, SK3 and IK1, are key mediators in the endothelium-derived hyperpolarization and relaxation of vascular smooth muscle and also in the modulation of endothelial Ca2+ signaling and nitric oxide (NO release. Obesity is associated with endothelial dysfunction and impaired relaxation, although how obesity influences endothelial SK3/IK1 function is unclear. Therefore we assessed whether the role of these channels in the coronary circulation is altered in obese animals. METHODS AND RESULTS: In coronary arteries mounted in microvascular myographs, selective blockade of SK3/IK1 channels unmasked an increased contribution of these channels to the ACh- and to the exogenous NO- induced relaxations in arteries of Obese Zucker Rats (OZR compared to Lean Zucker Rats (LZR. Relaxant responses induced by the SK3/IK1 channel activator NS309 were enhanced in OZR and NO- endothelium-dependent in LZR, whereas an additional endothelium-independent relaxant component was found in OZR. Fura2-AM fluorescence revealed a larger ACh-induced intracellular Ca2+ mobilization in the endothelium of coronary arteries from OZR, which was inhibited by blockade of SK3/IK1 channels in both LZR and OZR. Western blot analysis showed an increased expression of SK3/IK1 channels in coronary arteries of OZR and immunohistochemistry suggested that it takes place predominantly in the endothelial layer. CONCLUSIONS: Obesity may induce activation of adaptive vascular mechanisms to preserve the dilator function in coronary arteries. Increased function and expression of SK3/IK1 channels by influencing endothelial Ca2+ dynamics might contribute to the unaltered endothelium-dependent coronary relaxation in the early stages of obesity.

  7. Dynamic, nondestructive imaging of a bioengineered vascular graft endothelium.

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    Bryce M Whited

    Full Text Available Bioengineering of vascular grafts holds great potential to address the shortcomings associated with autologous and conventional synthetic vascular grafts used for small diameter grafting procedures. Lumen endothelialization of bioengineered vascular grafts is essential to provide an antithrombogenic graft surface to ensure long-term patency after implantation. Conventional methods used to assess endothelialization in vitro typically involve periodic harvesting of the graft for histological sectioning and staining of the lumen. Endpoint testing methods such as these are effective but do not provide real-time information of endothelial cells in their intact microenvironment, rather only a single time point measurement of endothelium development. Therefore, nondestructive methods are needed to provide dynamic information of graft endothelialization and endothelium maturation in vitro. To address this need, we have developed a nondestructive fiber optic based (FOB imaging method that is capable of dynamic assessment of graft endothelialization without disturbing the graft housed in a bioreactor. In this study we demonstrate the capability of the FOB imaging method to quantify electrospun vascular graft endothelialization, EC detachment, and apoptosis in a nondestructive manner. The electrospun scaffold fiber diameter of the graft lumen was systematically varied and the FOB imaging system was used to noninvasively quantify the affect of topography on graft endothelialization over a 7-day period. Additionally, results demonstrated that the FOB imaging method had a greater imaging penetration depth than that of two-photon microscopy. This imaging method is a powerful tool to optimize vascular grafts and bioreactor conditions in vitro, and can be further adapted to monitor endothelium maturation and response to fluid flow bioreactor preconditioning.

  8. Response of the xenograft endothelium in the concordant xenotransplantation

    Institute of Scientific and Technical Information of China (English)

    Bo Wang; Yi Lu; Cheng'en Pan; Xiaogang Zhang; Hui Li; Kewei Meng; Zheng Wu


    Objective: To investigate the response of the xenograft endothelium in the concordant hamster to rat cardiac xenotransplantation and the mechanism of acute vascular rejection. Methods: The animals were divided into 5 groups randomly: control group,CsA group, splenectomy group, D0 splenectomy+CsA group and D3 splenectomy+CsA group. Hamster heart was heterotopicaly transplanted to rat abdominal cavity. The graft survival was monitored by palpation of the rat abdominal wall. The histological and ultrastructural changes of the xenogafts were investigated. NF-κB and P-selectin expression in the xenograft were detected. Hene Oxigenase-1 and Bcl-2 expression were also detected in the xenografts of different groups. Results: The mean survival time of the xenografts in control group, CsA group, splenectomy group, D0 splenectomy+CsA group and D3 splenectomy+CsA group was 3.4±0.55, 3.8±0.45, 6.4±1.52, 30 and 7.4±1.14 days. The rejected graft showed typical acute vascular rejection in control group, CsA group,splenectomy group and D3 splenectomy+CsA group. Endothelial cells of the rejected xenograft showed dramatic assembly of ribosomes and expansion of the rough endoplasmic reticulum. However, the endothelium of the long-term survived grafts in D0 splenectomy+CsA group showed normal architecture. NF-κB and P-selectin expression were detected in the rejected xenografts. HO-1 expression was observed in the long-term survived xenografts in D0 splenectomy+CsA group. Conclusion: The endothelial cells of the xenograft might be activated during the acute vascular rejection. Expression of HO-1 might inhibit the upregulation of NF-κB and adhesion molecular which decreases the activation of the endothelium of the graft.

  9. Effects of intravenous anesthetic agents on vascular endothelium


    Alp Gurbet; Fatma Nur Kaya; Alper Bayraktar; İlkin Cavuşoğlu; Serap Şirvancı; Berin Özcan


    Objectives: The objective of this study was to comparethe effects of Propofol 1%, Propofol 2%, Ketamine, Pentothal,Etomidate and Etomidate-lipuro on venous endothelium.Materials and methods: The study was done fromAugust 2007 to May 2008 after approval of Faculty’sEthic Committee. Forty rabbits were obtained. Propofol1% (n=6), Propofol 2% (n=6), Ketamin (n=6), Penthotal(n=6), Etomidate (n=6), Etomidate lipuro (n=6) and normalsaline (Control Group, n=4) was given 1 cc via externaljugular vein....

  10. Protection of Coronary Endothelial Function during Cardiac Surgery: Potential of Targeting Endothelial Ion Channels in Cardioprotection

    Directory of Open Access Journals (Sweden)

    Qin Yang


    Full Text Available Vascular endothelium plays a critical role in the control of blood flow by producing vasoactive factors to regulate vascular tone. Ion channels, in particular, K+ channels and Ca2+-permeable channels in endothelial cells, are essential to the production and function of endothelium-derived vasoactive factors. Impairment of coronary endothelial function occurs in open heart surgery that may result in reduction of coronary blood flow and thus in an inadequate myocardial perfusion. Hyperkalemic exposure and concurrent ischemia-reperfusion during cardioplegic intervention compromise NO and EDHF-mediated function and the impairment involves alterations of K+ channels, that is, KATP and KCa, and Ca2+-permeable TRP channels in endothelial cells. Pharmacological modulation of these channels during ischemia-reperfusion and hyperkalemic exposure show promising results on the preservation of NO and EDHF-mediated endothelial function, which suggests the potential of targeting endothelial K+ and TRP channels for myocardial protection during cardiac surgery.

  11. Series "Cardiovascular System" (4) : Endothelium-derived Vasoactive Hormones and Diseases


    平田, 結喜緒; HIRATA, Yukio


    Vascular endothelium synthesize and secrete a variety of bioactive substances. Among them, endothelium-derived vasoactive hormones function to regulate not only tonus of the neighboring vascular smooth muscle, but vascular remodeling as well. Therefore, endothelial dysfunction eventually leads to blood pressure abnormality as well as vascular lesions. By focusing on several novel endothelium-derived vasoconstrictors (endothelin, urotensin II) and vasodilators (nitric oxide, adrenomedullin), t...

  12. Activation of group IVC phospholipase A{sub 2} by polycyclic aromatic hydrocarbons induces apoptosis of human coronary artery endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Tithof, Patricia K. [University of Tennessee, Department of Pathobiology, College of Veterinary Medicine, Knoxville, TN (United States); University of Tennessee, Center for Environmental Biotechnology, Knoxville, TN (United States); Richards, Sean M. [University of Tennessee, Department of Biological and Environmental Sciences, Chattanooga, TN (United States); Elgayyar, Mona A. [University of Tennessee, Department of Pathobiology, College of Veterinary Medicine, Knoxville, TN (United States); Menn, Fu-Minn; Vulava, Vijay M.; McKay, Larry; Sanseverino, John; Sayler, Gary [University of Tennessee, Center for Environmental Biotechnology, Knoxville, TN (United States); Tucker, Dawn E.; Leslie, Christina C. [National Jewish Medical and Research Center, Department of Pediatrics, Denver, CO (United States); Lu, Kim P. [Texas A and M University, Department of Biology, College Station, TX (United States); Ramos, Kenneth S. [University of Louisville, Department of Biochemistry and Molecular Biology, Louisville, KY (United States)


    Exposure to environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs) found in coal tar mixtures and tobacco sources, is considered a significant risk factor for the development of heart disease in humans. The goal of this study was to determine the influence of PAHs present at a Superfund site on human coronary artery endothelial cell (HCAEC) phospholipase A{sub 2} (PLA{sub 2}) activity and apoptosis. Extremely high levels of 12 out of 15 EPA high-priority PAHs were present in both the streambed and floodplain sediments at a site where an urban creek and its adjacent floodplain were extensively contaminated by PAHs and other coal tar compounds. Nine of the 12 compounds and a coal tar mixture (SRM 1597A) activated group IVC PLA{sub 2} in HCAECs, and activation of this enzyme was associated with histone fragmentation and poly (ADP) ribose polymerase (PARP) cleavage. Genetic silencing of group IVC PLA{sub 2} inhibited both {sup 3}H-fatty acid release and histone fragmentation by PAHs and SRM 1597A, indicating that individual PAHs and a coal tar mixture induce apoptosis of HCAECs via a mechanism that involves group IVC PLA{sub 2}. Western blot analysis of aortas isolated from feral mice (Peromyscus leucopus) inhabiting the Superfund site showed increased PARP and caspase-3 cleavage when compared to reference mice. These data suggest that PAHs induce apoptosis of HCAECs via activation of group IVC PLA{sub 2}. (orig.)

  13. Effect of coronary occlusion during percutaneous transluminal angioplasty in humans on left ventricular chamber stiffness and regional diastolic pressure-radius relations

    NARCIS (Netherlands)

    W. Wijns (William); P.W.J.C. Serruys (Patrick); C.J. Slager (Cornelis); J. Grimm; H.P. Krayenbuehl; P.G. Hugenholtz (Paul); O.M. Hess (Otto)


    textabstractThe effect of repeated (3 to 10 second) and transient (15 to 75 second) abrupt coronary occlusion on the global and regional chamber stiffness was studied in nine patients undergoing angioplasty of a single proximal left anterior descending coronary artery stenosis. The left ventricular

  14. GM-CSF Differentially Regulates Eosinophil and Neutrophil Adhesive Interactions with Vascular Endothelium in Vivo

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    Nooshin Sheikh Bahaie


    Full Text Available Allergic airway inflammation is characterized by elaboration of cytokines and chemokines leading to recruitment of inflammatory leukocytes, predominantly eosinophils, to the airways. Granulocyte macrophage colony stimulating factor (GM-CSF is generated in the lungs of human subjects with asthma in response to allergen challenge and is necessary for the development of allergen-induced bronchial eosinophilia in mice. The effect of GM-CSF on human eosinophil and neutrophil interactions with the vascular endothelium under conditions of blood flow was investigated in post-capillary venules of the rabbit mesentery by intravital microscopy.While GM-CSF significantly reduced the rolling fraction of neutrophils in vivo and induced consistent shedding of neutrophil L-selectin in vitro, its effect on eosinophil rolling was variable. Eosinophils from 57% of the donors demonstrated inhibition of rolling, while eosinophils from the remaining 43% of donors demonstrated no inhibition or increased rolling. The variable effect of GM-CSF on inhibition of eosinophil rolling was associated with variable shedding of L-selectin in vitro. In contrast to the differential effect of GM-CSF on neutrophils versus eosinophils, stimulation with phorbol myristate acetate demonstrated a similar degree of inhibition of rolling and L-selectin shedding by neutrophils and eosinophils suggesting that there was no defect in L-selectin shedding in the eosinophil donors who did not respond to GM-CSF. Overall, these studies demonstrate that GM-CSF consistently inhibits interaction of neutrophils with endothelium in vivo, whereas its effect on eosinophil-endothelial interactions is variable. GM-CSF may thus be one factor accounting for the varying percentage of eosinophils and neutrophils recruited to sites of allergic inflammation in different individuals.

  15. Protective effects of simvastatin on coronary artery function in swine with acute infection

    DEFF Research Database (Denmark)

    Liuba, Petru; Pesonen, Erkki; Forslid, Anders


    BACKGROUND:: The risk for coronary events may rise during acute infection. Perturbation in coronary endothelial function emerges as one important link. We investigated whether simvastatin could protect the coronary arterial function from the adverse effects of acute infection in swine. METHODS......:: Coronary endothelium-dependent and -independent vasomotor responses were assessed by Doppler velocimetry in 12 Chlamydia pneumoniae-infected and 6 sham-infected swine 2 weeks after intratracheal inoculation. Half of animals from the infection group were pre-treated with simvastatin (80mg daily), while...... the remaining animals received placebo. The treatment was started 2 weeks prior to inoculation and continued until the end of the study. ANOVA was used for statistical calculations. Data are mean+/-S.D. RESULTS:: All animals inoculated with C. pneumoniae developed IgM antibodies against this organism...

  16. Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease. (United States)

    Beyer, Andreas M; Zinkevich, Natalya; Miller, Bradley; Liu, Yanping; Wittenburg, April L; Mitchell, Michael; Galdieri, Ralph; Sorokin, Andrey; Gutterman, David D


    In microvessels of patients with coronary artery disease (CAD), flow-mediated dilation (FMD) is largely dependent upon the endothelium-derived hyperpolarizing factor H2O2. The goal of this study is to examine the influence of age and presence or absence of disease on the mechanism of FMD. Human coronary or adipose arterioles (~150 µm diameter) were prepared for videomicroscopy. The effect of inhibiting COX [indomethacin (Indo) or NOS (L-NAME), eliminating H2O2 (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E (mtVitamin E); phenylboronic acid (mtPBA)] was determined in children aged 0-18 years; young adults 19-55 years; older adults >55 years without CAD, and similarly aged adults with CAD. Indo eliminated FMD in children and reduced FMD in younger adults. This response was mediated mainly by PGI2, as the prostacyclin-synthase-inhibitor trans-2-phenyl cyclopropylamine reduced FMD in children and young adults. L-NAME attenuated dilation in children and younger adults and eliminated FMD in older adults without CAD, but had no effect on vessels from those with CAD, where mitochondria-derived H2O2 was the primary mediator. The magnitude of dilation was reduced in older compared to younger adults independent of CAD. Exogenous treatment with a sub-dilator dose of NO blocked FMD in vessels from subjects with CAD, while prolonged inhibition of NOS in young adults resulted in a phenotype similar to that observed in disease. The mediator of coronary arteriolar FMD evolves throughout life from prostacyclin in youth, to NO in adulthood. With the onset of CAD, NO-inhibitable release of H2O2 emerges as the exclusive mediator of FMD. These findings have implications for use of pharmacological agents, such as nonsteroidal anti-inflammatory agents in children and the role of microvascular endothelium in cardiovascular health.

  17. Aspirin and pravastatin reduce lectin-like oxidized low density lipoprotein receptor-1 expression, adhesion molecules and oxidative stress in human coronary artery endothelial cells

    Institute of Scientific and Technical Information of China (English)

    CHEN Jia-wei; ZHOU Shi-bei; TAN Zhi-ming


    Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppress oxidative stress and inflammation in endothelial cells, and this concept was examined in human coronary artery endothelial cells (HCAECs).Methods Human coronary artery endothelial cells were cultured and treated with oxidized-low density iipoprotein (ox-LDL, 60 μg/ml for 24 hours) alone, or pre-treated with aspirin (1, 2 or 5 mmol/L), pravastatin (1, 5 or 10 μmol/L) or their combination (1 mmol/L aspirin and 5 μmol/L pravastatin), followed by ox-LDL treatment. After respective treatment,superoxide anion production, p38 mitogen activated protein kinase and transcription factor NF-κB activation, protein expression of lectin-like ox-LDL receptor-1 (LOX-1) and adhesion molecules, and monocyte adhesion were measured.Results Ox-LDL treatment greatly elicited its receptor LOX-1 expression, superoxide anion production and inflammatory response, which were minimally affected by low concentration of aspidn (1 mmol/L) or pravastatin (5 μmol/L), but were markedly decreased by their combination. Activation of p38 mitogen activated protein kinase and NF-κB, the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-1, which were only mildly affected by aspirin or pravastatin alone, were significantly attenuated by their combination. As a consequence, monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents. Well-known anti-oxidants α-tocopherol and γ-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin.Conclusions These studies point to a positive interaction between aspidn and pravastatin with regard to endothelial biology. Anti-oxidant and subsequent anti

  18. Intra-Section Analysis of Human Coronary Arteries Reveals a Potential Role for Micro-Calcifications in Macrophage Recruitment in the Early Stage of Atherosclerosis.

    Directory of Open Access Journals (Sweden)

    Martijn L L Chatrou

    Full Text Available Vascular calcification is associated with poor cardiovascular outcome. Histochemical analysis of calcification and the expression of proteins involved in mineralization are usually based on whole section analysis, thereby often ignoring regional differences in atherosclerotic lesions. At present, limited information is available about factors involved in the initiation and progression of atherosclerosis.This study investigates the intra-section association of micro-calcifications with markers for atherosclerosis in randomly chosen section areas of human coronary arteries. Moreover, the possible causal relationship between calcifying vascular smooth muscle cells and inflammation was explored in vitro.To gain insights into the pathogenesis of atherosclerosis, we performed analysis of the distribution of micro-calcifications using a 3-MeV proton microbeam. Additionally, we performed systematic analyses of 30 to 40 regions of 12 coronary sections obtained from 6 patients including histology and immuno-histochemistry. Section areas were classified according to CD68 positivity. In vitro experiments using human vascular smooth muscle cells (hVSMCs were performed to evaluate causal relationships between calcification and inflammation.From each section multiple areas were randomly chosen and subsequently analyzed. Depositions of calcium crystals at the micrometer scale were already observed in areas with early pre-atheroma type I lesions. Micro-calcifications were initiated at the elastica interna concomitantly with upregulation of the uncarboxylated form of matrix Gla-protein (ucMGP. Both the amount of calcium crystals and ucMGP staining increased from type I to IV atherosclerotic lesions. Osteochondrogenic markers BMP-2 and osteocalcin were only significantly increased in type IV atheroma lesions, and at this stage correlated with the degree of calcification. From atheroma area type III onwards a considerable number of CD68 positive cells were observed

  19. Vascular endothelium leaves fingerprints on the surface of erythrocytes. (United States)

    Oberleithner, Hans


    Gliding of red blood cells (RBC) through blood vessels is mediated by the negatively charged glycocalyx located on the surfaces of both RBC and endothelial cells (EC). In various vasculopathies, EC gradually lose this protective surface layer. As a consequence, RBC come into close physical contact with the vascular endothelium. It is hypothesized that the RBC glycocalyx could be adversely affected by a poor EC glycocalyx. This hypothesis was tested by evaluating the RBC and EC surface layers with atomic force microscopy techniques. In the first series of experiments, EC monolayers grown in culture were exposed to rhythmic drag forces exerted from a blood overlay (drag force treatment), and thereafter, the EC surface was investigated in terms of thickness and adhesiveness. In the second series, the glycocalyx of the EC monolayers was disturbed by enzymatic cleavage of negatively charged heparan sulfates before drag force treatment, and thereafter, the RBC surface was evaluated. In the third series, the RBC glycocalyx of the blood overlay was enzymatically disturbed before drag force treatment, and thereafter, the EC surface was evaluated. A strong positive correlation between the RBC and EC surface properties was found (r (2) = 0.95). An enzymatically affected EC glycocalyx lead to the shedding of the RBC glycocalyx and vice versa. It is concluded that there is physical interaction between the blood and endothelium. Apparently, the RBC glycocalyx reflects properties of the EC glycocalyx. This observation could have a significant impact on diagnosis and treatment of cardiovascular diseases.

  20. Testosterone Replacement Therapy Prevents Alterations of Coronary Vascular Reactivity Caused by Hormone Deficiency Induced by Castration. (United States)

    Rouver, Wender Nascimento; Delgado, Nathalie Tristão Banhos; Menezes, Jussara Bezerra; Santos, Roger Lyrio; Moyses, Margareth Ribeiro


    The present study aimed to determine the effects of chronic treatment with different doses of testosterone on endothelium-dependent coronary vascular reactivity in male rats. Adult male rats were divided into four experimental groups: control (SHAM), castrated (CAST), castrated and immediately treated subcutaneously with a physiological dose (0.5 mg/kg/day, PHYSIO group) or supraphysiological dose (2.5 mg/kg/day, SUPRA group) of testosterone for 15 days. Systolic blood pressure (SBP) was assessed at the end of treatment through tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed using the Langendorff retrograde perfusion technique. A dose-response curve for bradykinin (BK) was constructed, followed by inhibition with 100 μM L-NAME, 2.8 μM indomethacin (INDO), L-NAME + INDO, or L-NAME + INDO + 0.75 μM clotrimazole (CLOT). We observed significant endothelium-dependent, BK-induced coronary vasodilation, which was abolished in the castrated group and restored in the PHYSIO and SUPRA groups. Furthermore, castration modulated the lipid and hormonal profiles and decreased body weight, and testosterone therapy restored all of these parameters. Our results revealed an increase in SBP in the SUPRA group. In addition, our data led us to conclude that physiological concentrations of testosterone may play a beneficial role in the cardiovascular system by maintaining an environment that is favourable for the activity of an endothelium-dependent vasodilator without increasing SBP.

  1. Testosterone Replacement Therapy Prevents Alterations of Coronary Vascular Reactivity Caused by Hormone Deficiency Induced by Castration.

    Directory of Open Access Journals (Sweden)

    Wender Nascimento Rouver

    Full Text Available The present study aimed to determine the effects of chronic treatment with different doses of testosterone on endothelium-dependent coronary vascular reactivity in male rats. Adult male rats were divided into four experimental groups: control (SHAM, castrated (CAST, castrated and immediately treated subcutaneously with a physiological dose (0.5 mg/kg/day, PHYSIO group or supraphysiological dose (2.5 mg/kg/day, SUPRA group of testosterone for 15 days. Systolic blood pressure (SBP was assessed at the end of treatment through tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed using the Langendorff retrograde perfusion technique. A dose-response curve for bradykinin (BK was constructed, followed by inhibition with 100 μM L-NAME, 2.8 μM indomethacin (INDO, L-NAME + INDO, or L-NAME + INDO + 0.75 μM clotrimazole (CLOT. We observed significant endothelium-dependent, BK-induced coronary vasodilation, which was abolished in the castrated group and restored in the PHYSIO and SUPRA groups. Furthermore, castration modulated the lipid and hormonal profiles and decreased body weight, and testosterone therapy restored all of these parameters. Our results revealed an increase in SBP in the SUPRA group. In addition, our data led us to conclude that physiological concentrations of testosterone may play a beneficial role in the cardiovascular system by maintaining an environment that is favourable for the activity of an endothelium-dependent vasodilator without increasing SBP.

  2. Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise. (United States)

    Bender, Shawn B; de Beer, Vincent J; Tharp, Darla L; Bowles, Douglas K; Laughlin, M Harold; Merkus, Daphne; Duncker, Dirk J


    Accelerated development of coronary atherosclerosis is a defining characteristic of familial hypercholesterolemia (FH). However, the recent data highlight a significant cardiovascular risk prior to the development of critical coronary stenosis. We, therefore, examined the hypothesis that FH produces coronary microvascular dysfunction and impairs coronary vascular control at rest and during exercise in a swine model of FH. Coronary vascular responses to drug infusions and exercise were examined in chronically instrumented control and FH swine. FH swine exhibited ~tenfold elevation of plasma cholesterol and diffuse coronary atherosclerosis (20-60 % plaque burden). Similar to our recent findings in the systemic vasculature in FH swine, coronary smooth muscle nitric oxide sensitivity was increased in vivo and in vitro with maintained endothelium-dependent vasodilation in vivo in FH. At rest and during exercise, FH swine exhibited increased myocardial O2 extraction resulting in reduced coronary venous SO2 and PO2 versus control. During exercise in FH swine, the transmural distribution of coronary blood flow was unchanged; however, a shift toward anaerobic cardiac metabolism was revealed by increased coronary arteriovenous H(+) concentration gradient. This shift was associated with a worsening of cardiac efficiency (relationship between cardiac work and O2 consumption) in FH during exercise owing, in part, to a generalized reduction in stroke volume which was associated with increased left atrial pressure in FH. Our data highlight a critical role for coronary microvascular dysfunction as a contributor to impaired myocardial O2 balance, cardiac ischemia, and impaired cardiac function prior to the development of critical coronary stenosis in FH.

  3. [Morphofunctional correlation in congenital anomalies of the coronary arteries. I. Coronary artery fistulas]. (United States)

    Rangel-Abundis, A; Muñoz-Castellanos, L; Marín, G; Chávez Pérez, E; Badui, E


    In order to explain the congenital coronary arteries malformations, the authors review the recent concepts on the coronary artery morphogenesis, based in the findings that in the human embryo, these arteries evolve from three sources: 1) endothelial aortic buds, 2) cavitary cellular groups from pericardial origin and with angiogenic character, which migrate to the cardiac zones where the coronary arteries will be distributed, and 3) the intramyocardial sinusoids. The anatomic and histologic cardiac alterations will be reflected in modifications of the coronary artery pattern. The coronary artery fistulae are formed by the persistence of the sponge structure of the myocardial wall, present in the early ontogenic steps of the cardiac development; such fistulae alter the normal functions of the coronary vascular tree and are capable to cause angina pectoris to the patient through diverse mechanisms: absence of capillarization, steal phenomenon aggravated by the altered coronary arteries properties when aneurysm or vascular channels are developed. The authors suggest a classification of the congenital coronary arteries anomalies: I. Anomalous origin in the sinus of Valsalva (anomalous and ectopic origin), II. Malformations of the coronary branches (in number, distribution and wall anomalies) and III. Anomalous connection of the coronary arteries: fistulae and persistence of the intramyocardial sinusoids isolated or communicated to left and right ventricles. The latter are frequently associated with aortic or pulmonary valve atresia. They do not cause myocardial ischemia and are formed secondary to the intracavitary elevated pressure which maintained the persistence, dilatation and communication of the ventricular chambers with such sinusoids and coronary arteries in the case of pulmonary valve atresia and with coronary veins in the case of aortic valve atresia.

  4. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Obinata, Hideru; Kumaraswamy, Sunil B


    Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did...... not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM......(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung...

  5. Diet-induced obesity impairs endothelium-derived hyperpolarization via altered potassium channel signaling mechanisms.

    Directory of Open Access Journals (Sweden)

    Rebecca E Haddock

    Full Text Available BACKGROUND: The vascular endothelium plays a critical role in the control of blood flow. Altered endothelium-mediated vasodilator and vasoconstrictor mechanisms underlie key aspects of cardiovascular disease, including those in obesity. Whilst the mechanism of nitric oxide (NO-mediated vasodilation has been extensively studied in obesity, little is known about the impact of obesity on vasodilation to the endothelium-derived hyperpolarization (EDH mechanism; which predominates in smaller resistance vessels and is characterized in this study. METHODOLOGY/PRINCIPAL FINDINGS: Membrane potential, vessel diameter and luminal pressure were recorded in 4(th order mesenteric arteries with pressure-induced myogenic tone, in control and diet-induced obese rats. Obesity, reflecting that of human dietary etiology, was induced with a cafeteria-style diet (∼30 kJ, fat over 16-20 weeks. Age and sexed matched controls received standard chow (∼12 kJ, fat. Channel protein distribution, expression and vessel morphology were determined using immunohistochemistry, Western blotting and ultrastructural techniques. In control and obese rat vessels, acetylcholine-mediated EDH was abolished by small and intermediate conductance calcium-activated potassium channel (SK(Ca/IK(Ca inhibition; with such activity being impaired in obesity. SK(Ca-IK(Ca activation with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl-6-methyl-pyrimidin-4-yl]-amine (CyPPA and 1-ethyl-2-benzimidazolinone (1-EBIO, respectively, hyperpolarized and relaxed vessels from control and obese rats. IK(Ca-mediated EDH contribution was increased in obesity, and associated with altered IK(Ca distribution and elevated expression. In contrast, the SK(Ca-dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (K(ir and Na(+/K(+-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential K

  6. Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages (United States)

    Carnuta, Mihaela G.; Sanda, Gabriela M.; Stancu, Camelia S.; Popescu, Andreea C.; Popescu, Mihaela R.; Vlad, Adelina; Dimulescu, Doina R.; Simionescu, Maya; Sima, Anca V.


    We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera. MiR-223 and miR-486 prevailed in HDL2, while miR-92a predominated in HDL3, all three miRNAs discriminating between ACS and SA patients; their levels were increased in HDL from hyperglycemic ACS patients versus normoglycemic ones. The incubation of human macrophages with sera from ACS and SA patients showed that all patients’ sera induced an increase of Drosha, DGCR8 and Dicer expressions and of selected miRNAs levels compared to control sera, the effect being higher in the case of hyperglycemic versus normoglycemic ACS sera. The addition of glucose to SA and ACS sera increased Drosha, DGCR8 and Dicer expression and miRNAs levels in the exposed macrophages. In conclusion, hyperglycemia is associated with increased miR-223, miR-92a, miR-486 levels in HDL, which discriminate between ACS and SA patients. Exposure of human macrophages to ACS compared to SA sera determines the upregulation of Drosha, DGCR8 and Dicer expression and the increase of selected miRNAs production, the effect being augmented by an increased glucose concentration. PMID:27519051

  7. Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts (United States)

    Fedorov, Vadim V.; Glukhov, Alexey V.; Ambrosi, Christina M.; Kostecki, Geran; Chang, Roger; Janks, Deborah; Schuessler, Richard B.; Moazami, Nader; Nichols, Colin G.; Efimov, Igor R.


    INTRODUCTION This study compared the effects of ATP-regulated potassium channel (KATP) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. METHODS We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the KATP targets Kir6.1, Kir6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts. RESULTS In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by −21±3% and −27±13%, p<0.01) and ventricles (by −28±7% and −28±4%, p<0.01). Diazoxide did not change APD (0±5%) in NF atria. Pinacidil significantly decreased APDs in both atria (−46 to - 80%, p<0.01) and ventricles (−65 to −93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4±6.1 Hz and 17.5 ±5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of KATP targets were correlated to functional observations. CONCLUSION Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular KATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts. PMID:21586291


    Institute of Scientific and Technical Information of China (English)

    孙寅光; 沈卫峰; 施仲伟; 张大东


    Objective To determine the relations between endothelium dependent vasodilator function and blood flow in the brachial and coronary arteries in patients with suspected coronary artery disease.MethodsTwenty eight patients with suspected coronary artery disease underwent brachial artery endothelial function test by using high resolution B mode ultrasound before coronary angiography (CAG) and coronary flow reserve (CFR) test by using intracoronary Doppler technique. The correlation of coronary artery dilatation induced by an increase in blood flow after intracoronary adenosine infusion and brachial artery flow mediated dilatation (FMD) following reactive hyperemia was evaluated. The relation between the change of brachial artery blood flow and CFR was also studied.ResultsThere was a positive correlation between brachial FMD and percent change of coronary diameter after adenosine infusion (12.50%±9.35% vs 11.38%±7.55%, r=0.425,P=0.02). There was also a weak negative relation between brachial flow change following reactive hyperemia and CFR (r=0.397, P=0.04).ConclusionThere is a correlation between the coronary endothelial function and the CFR by ultrasonic determination of brachial flow changes following reactive hyperemia.

  9. Coronary CT angiography in coronary artery disease: Opportunities and challenges

    Directory of Open Access Journals (Sweden)

    Zhonghua Sun


    Full Text Available Coronary CT angiography is widely recognised as a reliable imaging modality for the diagnosis of coronary artery disease. Coronary CT angiography not only provides excellent visualisation of anatomical changes in the coronary artery with high diagnostic value in the detection of lumen stenosis or occlusion, but also offers quantitative characterisation of coronary plaque components. Furthermore, coronary CT angiography allows myocardial perfusion imaging with diagnostic value comparable to the reference standard method. Coronary CT angiography-derived haemodynamic analysis has the potential to evaluate functional significance of coronary lesions. This review article aims to provide an overview of clinical applications of coronary CT angiography in coronary artery disease.

  10. Role of RNA splicing in mediating lineage-specific expression of the von Willebrand factor gene in the endothelium. (United States)

    Yuan, Lei; Janes, Lauren; Beeler, David; Spokes, Katherine C; Smith, Joshua; Li, Dan; Jaminet, Shou-Ching; Oettgen, Peter; Aird, William C


    We previously demonstrated that the first intron of the human von Willebrand factor (vWF) is required for gene expression in the endothelium of transgenic mice. Based on this finding, we hypothesized that RNA splicing plays a role in mediating vWF expression in the vasculature. To address this question, we used transient transfection assays in human endothelial cells and megakaryocytes with intron-containing and intronless human vWF promoter-luciferase constructs. Next, we generated knockin mice in which LacZ was targeted to the endogenous mouse vWF locus in the absence or presence of the native first intron or heterologous introns from the human β-globin, mouse Down syndrome critical region 1, or hagfish coagulation factor X genes. In both the in vitro assays and the knockin mice, the loss of the first intron of vWF resulted in a significant reduction of reporter gene expression in endothelial cells but not megakaryocytes. This effect was rescued to varying degrees by the introduction of a heterologous intron. Intron-mediated enhancement of expression was mediated at a posttranscriptional level. Together, these findings implicate a role for intronic splicing in mediating lineage-specific expression of vWF in the endothelium.

  11. Coronary heart disease (United States)

    Heart disease, Coronary heart disease, Coronary artery disease; Arteriosclerotic heart disease; CHD; CAD ... slow down or stop. A risk factor for heart disease is something that increases your chance of getting ...

  12. Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells (United States)

    Chua, Su-Kiat; Shyu, Kou-Gi; Lin, Yuh-Feng; Lo, Huey-Ming; Wang, Bao-Wei


    Background Chemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia. Methods and Results Cultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects. Conclusion Hypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment. PMID:27792771

  13. The Collagen-Binding Protein Cnm Is Required for Streptococcus mutans Adherence to and Intracellular Invasion of Human Coronary Artery Endothelial Cells ▿ (United States)

    Abranches, Jacqueline; Miller, James H.; Martinez, Alaina R.; Simpson-Haidaris, Patricia J.; Burne, Robert A.; Lemos, José A.


    Streptococcus mutans is considered the primary etiologic agent of dental caries, a global health problem that affects 60 to 90% of the population, and a leading causative agent of infective endocarditis. It can be divided into four different serotypes (c, e, f, and k), with serotype c strains being the most common in the oral cavity. In this study, we demonstrate that in addition to OMZ175 and B14, three other strains (NCTC11060, LM7, and OM50E) of the less prevalent serotypes e and f are able to invade primary human coronary artery endothelial cells (HCAEC). Invasive strains were also significantly more virulent than noninvasive strains in the Galleria mellonella (greater wax worm) model of systemic disease. Interestingly, the invasive strains carried an additional gene, cnm, which was previously shown to bind to collagen and laminin in vitro. Inactivation of cnm rendered the organisms unable to invade HCAEC and attenuated their virulence in G. mellonella. Notably, the cnm knockout strains did not adhere to HCAEC as efficiently as the parental strains did, indicating that the loss of the invasion phenotype observed for the mutants was linked to an adhesion defect. Comparisons of the invasive strains and their respective cnm mutants did not support a correlation between biofilm formation and invasion. Thus, Cnm is required for S. mutans invasion of endothelial cells and possibly represents an important virulence factor of S. mutans that may contribute to cardiovascular infections and pathologies. PMID:21422186

  14. The collagen-binding protein Cnm is required for Streptococcus mutans adherence to and intracellular invasion of human coronary artery endothelial cells. (United States)

    Abranches, Jacqueline; Miller, James H; Martinez, Alaina R; Simpson-Haidaris, Patricia J; Burne, Robert A; Lemos, José A


    Streptococcus mutans is considered the primary etiologic agent of dental caries, a global health problem that affects 60 to 90% of the population, and a leading causative agent of infective endocarditis. It can be divided into four different serotypes (c, e, f, and k), with serotype c strains being the most common in the oral cavity. In this study, we demonstrate that in addition to OMZ175 and B14, three other strains (NCTC11060, LM7, and OM50E) of the less prevalent serotypes e and f are able to invade primary human coronary artery endothelial cells (HCAEC). Invasive strains were also significantly more virulent than noninvasive strains in the Galleria mellonella (greater wax worm) model of systemic disease. Interestingly, the invasive strains carried an additional gene, cnm, which was previously shown to bind to collagen and laminin in vitro. Inactivation of cnm rendered the organisms unable to invade HCAEC and attenuated their virulence in G. mellonella. Notably, the cnm knockout strains did not adhere to HCAEC as efficiently as the parental strains did, indicating that the loss of the invasion phenotype observed for the mutants was linked to an adhesion defect. Comparisons of the invasive strains and their respective cnm mutants did not support a correlation between biofilm formation and invasion. Thus, Cnm is required for S. mutans invasion of endothelial cells and possibly represents an important virulence factor of S. mutans that may contribute to cardiovascular infections and pathologies.

  15. Inhibitory Effect of a French Maritime Pine Bark Extract-Based Nutritional Supplement on TNF-α-Induced Inflammation and Oxidative Stress in Human Coronary Artery Endothelial Cells (United States)

    McGrath, Kristine C. Y.; Li, Xiao-Hong; McRobb, Lucinda S.; Heather, Alison K.


    Oxidative stress and inflammation, leading to endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. The popularity of natural product supplements has increased in recent years, especially those with purported anti-inflammatory and/or antioxidant effects. The efficacy and mechanism of many of these products are not yet well understood. In this study, we tested the antioxidant and anti-inflammatory effects of a supplement, HIPER Health Supplement (HIPER), on cytokine-induced inflammation and oxidative stress in human coronary artery endothelial cells (HCAECs). HIPER is a mixture of French maritime pine bark extract (PBE), honey, aloe vera, and papaya extract. Treatment for 24 hours with HIPER reduced TNF-α-induced reactive oxygen species (ROS) generation that was associated with decreased NADPH oxidase 4 and increased superoxide dismutase-1 expression. HIPER inhibited TNF-α induced monocyte adhesion to HCAECs that was in keeping with decreased expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1 and decreased nuclear factor-kappa B (NF-κB) activation. Further investigation of mechanism showed HIPER reduced TNF-α induced IκBα and p38 and MEK1/2 MAP kinases phosphorylation. Our findings show that HIPER has potent inhibitory effects on HCAECs inflammatory and oxidative stress responses that may protect against endothelial dysfunction that underlies early atherosclerotic lesion formation. PMID:26664450

  16. Heart-type fatty-acid-binding protein (FABP3 is a lysophosphatidic acid-binding protein in human coronary artery endothelial cells

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    Ryoko Tsukahara


    Full Text Available Fatty-acid-binding protein 3, muscle and heart (FABP3, also known as heart-type FABP, is a member of the family of intracellular lipid-binding proteins. It is a small cytoplasmic protein with a molecular mass of about 15 kDa. FABPs are known to be carrier proteins for transporting fatty acids and other lipophilic substances from the cytoplasm to the nucleus, where these lipids are released to a group of nuclear receptors such as peroxisome proliferator-activated receptors (PPARs. In this study, using lysophosphatidic acid (LPA-coated agarose beads, we have identified FABP3 as an LPA carrier protein in human coronary artery endothelial cells (HCAECs. Administration of LPA to HCAECs resulted in a dose-dependent increase in PPARγ activation. Furthermore, the LPA-induced PPARγ activation was abolished when the FABP3 expression was reduced using small interfering RNA (siRNA. We further show that the nuclear fraction of control HCAECs contained a significant amount of exogenously added LPA, whereas FABP3 siRNA-transfected HCAECs had a decreased level of LPA in the nucleus. Taken together, these results suggest that FABP3 governs the transcriptional activities of LPA by targeting them to cognate PPARγ in the nucleus.

  17. Deficiency of sex hormones does not affect 17-ß-estradiol-induced coronary vasodilation in the isolated rat heart

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    R.L. Santos


    Full Text Available The relaxation of coronary arteries by estrogens in the coronary vascular beds of naive and hypertensive rats has been well described. However, little is known about this action in gonadectomized rats. We investigated the effect of 17-ß-estradiol (E2 in coronary arteries from gonadectomized rats, as well as the contributions of endothelium-derived factors and potassium channels. Eight-week-old female and male Wistar rats weighing 220-300 g were divided into sham-operated and gonadectomized groups (n=9−12 animals per group. The baseline coronary perfusion pressure (CPP was determined, and the vasoactive effects of 10 μM E2 were assessed by bolus administration before and after endothelium denudation or by perfusion with NG-nitro-L-arginine methyl ester (L-NAME, indomethacin, clotrimazole, L-NAME plus indomethacin, L-NAME plus clotrimazole or tetraethylammonium (TEA. The CPP differed significantly between the female and sham-operated male animals. Gonadectomy reduced the CPP only in female rats. Differences in E2-induced relaxation were observed between the female and male animals, but male castration did not alter this response. For both sexes, the relaxation response to E2 was, at least partly, endothelium-dependent. The response to E2 was reduced only in the sham-operated female rats treated with L-NAME. However, in the presence of indomethacin, clotrimazole, L-NAME plus indomethacin or L-NAME plus clotrimazole, or TEA, the E2 response was significantly reduced in all groups. These results highlight the importance of prostacyclin, endothelium-derived hyperpolarizing factor, and potassium channels in the relaxation response of coronary arteries to E2 in all groups, whereas nitric oxide may have had an important role only in the sham-operated female group.

  18. Coronary heart disease

    Institute of Scientific and Technical Information of China (English)


    2008417 Efficacy comparison with low and high dose natroparin for patients with acute coronary syndrome underwent percutancous coronary intervention. SUN Chaoyu(孙超宇), et al. Dept Cardiol, 4th Affili Hosp, Harbin Med Univ, Harbin 150001. Chin J Cardiol 2008;36(6):493-496. Objective To evaluate the safety and optimal piror percutaneous coronary intervention (PCI) natroparin dose in patients with acute coronary syndrome (ACS).

  19. Cocaine toxic effect on endothelium-dependent vasorelaxation: an in vitro study on rabbit aorta. (United States)

    Togna, G I; Graziani, M; Russo, P; Caprino, L


    Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert-butylhydroquinone, a sarcoplasmic Ca2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca2+-ATPase pump.

  20. [Protection of corneal endothelium from apoptosis by gene and cell therapy]. (United States)

    Fuchsluger, T A


    Protection of corneal endothelium from apoptosis using gene and cell therapy is in a translational phase. This approach offers advantages for eye banking and after transplantation. Safe vehicles for gene or cell therapeutic transduction of corneal endothelium with nucleic acids are available. This strategy will be further developed in consultation with the Paul Ehrlich Institute and European regulatory authorities.

  1. (-)Epicatechin induces and modulates endothelium-dependent relaxation in isolated rat mesenteric artery rings

    Institute of Scientific and Technical Information of China (English)

    YAO Xiao-Qiang; CHAN Franky Leung; LAU Chi-Wai; HUANG Yu


    AIM: The present study was aimed to examine the role of endothelial nitric oxide in the relaxant response to green tea (-)epicatechin and its modulation of endothelium-mediated relaxation in the isolated rat mesenteric artery rings.METHODS: Changes in the isometric tension were measured with Grass force-displacement transducers. RESULTS:The (-)epicatechin-induced relaxation was largely dependent on the presence of intact endothelium and was reversed by NG-nitro-L-arginine methyl ester 10 μmol/L or methylene blue 10 μmol/L, the inhibitors of nitric oxidemediated relaxation. L-Arginine at 1 mmol/L antagonized the effect of L-NAME or methylene blue. Pretreatment of endothelium-intact rings with (-)epicatechin 10 μmol/L enhanced the relaxation induced by endothelium-dependent vasodilator, acetylcholine, while this concentration did not influence the endothelium-independent relaxation induced by sodium nitroprusside in the endothelium-denuded artery rings. CONCLUSION: The results indicate that the endothelium-dependent vasodilation by (-)epicatechin is mainly mediated through nitric oxide and low concentration of (-)epicatechin augments endothelium-dependent vasorelaxation in the rat mesenteric arteries.

  2. Inside-Out Regulation of ICAM-1 Dynamics in TNF-alpha-Activated Endothelium

    NARCIS (Netherlands)

    van Buul, J.D.; van Rijssel, J.; van Alphen, F.P.J.; Hoogenboezem, M.; Tol, S.; Hoeben, K.A.; van Marle, J.; Mul, E.P.J.; Hordijk, P.L.


    Background: During transendothelial migration, leukocytes use adhesion molecules, such as ICAM-1, to adhere to the endothelium. ICAM-1 is a dynamic molecule that is localized in the apical membrane of the endothelium and clusters upon binding to leukocytes. However, not much is known about the regul

  3. Physical (in)activity and endothelium-derived constricting factors: overlooked adaptations.

    NARCIS (Netherlands)

    Thijssen, D.H.J.; Rongen, G.A.P.J.M.; Smits, P.; Hopman, M.T.E.


    The inner surrounding of arterial vessels, the endothelium, is optimally located to detect changes in blood characteristics or blood flow that may result from changes in physical activity or from diseases. In response to physical stimuli, the endothelium varies its release of circulating vasoactive

  4. Coronary CTA assessment of coronary anomalies.

    NARCIS (Netherlands)

    Pursnani, A.; Jacobs, J.E.; Saremi, F.; Levisman, J.; Makaryus, A.N.; Capunay, C.; Rogers, I.S.; Wald, C.; Azmoon, S.; Stathopoulos, I.A.; Srichai, M.B.


    Coronary anomalies occur in <1% of the general population and can range from a benign incidental finding to the cause of sudden cardiac death. The coronary anomalies are classified here according to the traditional grouping into those of origin and course, intrinsic arterial anatomy, and

  5. Coronary CTA assessment of coronary anomalies.

    NARCIS (Netherlands)

    Pursnani, A.; Jacobs, J.E.; Saremi, F.; Levisman, J.; Makaryus, A.N.; Capunay, C.; Rogers, I.S.; Wald, C.; Azmoon, S.; Stathopoulos, I.A.; Srichai, M.B.


    Coronary anomalies occur in <1% of the general population and can range from a benign incidental finding to the cause of sudden cardiac death. The coronary anomalies are classified here according to the traditional grouping into those of origin and course, intrinsic arterial anatomy, and terminat

  6. Vascular hyperpolarization in human physiology and cardiovascular risk conditions and disease. (United States)

    Schinzari, F; Tesauro, M; Cardillo, C


    Hyperpolarization causing smooth muscle relaxation contributes to the maintenance of vascular homeostasis, particularly in small-calibre arteries and arterioles. It may also become a compensatory vasodilator mechanism upregulated in states with impaired nitric oxide (NO) availability. Bioassay of vascular hyperpolarization in the human circulation has been hampered by the complexity of mechanisms involved and the limited availability of investigational tools. Firm evidence, however, supports the notion that hyperpolarization participates in the regulation of resting vasodilator tone and vascular reactivity in healthy subjects. In addition, an enhanced endothelium-derived hyperpolarization contributes to both resting and agonist-stimulated vasodilation in a variety of cardiovascular risk conditions and disease. Thus, hyperpolarization mediated by epoxyeicosatrienoic acids (EETs) and H2 O2 has been observed in coronary arterioles of patients with coronary artery disease. Similarly, ouabain-sensitive and EETs-mediated hyperpolarization has been observed to compensate for NO deficiency in patients with essential hypertension. Moreover, in non-hypertensive patients with multiple cardiovascular risk factors and in hypercholesterolaemia, KCa channel-mediated vasodilation appears to be activated. A novel paradigm establishes that perivascular adipose tissue (PVAT) is an additional regulator of vascular tone/function and endothelium is not the only agent in vascular hyperpolarization. Indeed, some PVAT-derived relaxing substances, such as adiponectin and angiotensin 1-7, may exert anticontractile and vasodilator actions by the opening of KCa channels in smooth muscle cells. Conversely, PVAT-derived factors impair coronary vasodilation via differential inhibition of some K(+) channels. In view of adipose tissue abnormalities occurring in human obesity, changes in PVAT-dependent hyperpolarization may be relevant for vascular dysfunction also in this condition.

  7. The feto-placental endothelium in pregnancy pathologies. (United States)

    Wadsack, Christian; Desoye, Gernot; Hiden, Ursula


    This review aims to provide a comprehensive summary of the aspects of endothelial and vascular dysfunction in the feto-placental vasculature occurring in pregnancy pathologies. This endothelium is continuous with the fetal circulation. Its function and potential dysfunction in pathologies will have a profound impact on fetal development. Gestational diabetes mellitus represents one of these pathologies, in which its associated metabolic derangements will alter feto-placental endothelial functions. These, in turn, may result in functional changes of the placenta, which may entail impaired fetal development. By contrast, changes in the feto-placental vasculature observed in cases of fetal growth restriction and preeclampsia may be causative (fetal growth restriction) or secondary (preeclampsia) for the pathology.

  8. Phototoxic effects of 8-methoxypsoralen on rabbit corneal endothelium

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    Menon, I.A.; Basu, P.K.; Hasany, S.M.; Persad, S.D. (Univ. of Toronto, Ontario (Canada))


    The phototoxic effects of 8-methoxypsoralen (8-MOP) were investigated using the rabbit corneal endothelium in organ culture. The corneas were divided into four groups: (a) irradiated with a mercury vapor lamp (emitting UVA and visible radiation) in the presence of 8-MOP (experimental), (b) irradiated without 8-MOP (control A), (c) incubated with 8-MOP (control B) and (d) incubated without 8-MOP (control C). Specular and light microscopic examination showed that the experimental corneas had greater cellular damage compared to the control corneas. The effects of 8-MOP were restricted to certain localized areas of the cornea. However there was no significant difference in the amounts of 51Cr released from the labelled experimental and control corneas. These results show phototoxic damage of the corneal endothelial cells.

  9. Benzalkonium chloride suppresses rabbit corneal endothelium intercellular gap junction communication.

    Directory of Open Access Journals (Sweden)

    Zhenhao Zhang

    Full Text Available Gap junction intercellular communication (GJIC plays a critical role in the maintenance of corneal endothelium homeostasis. We determined if benzalkonium chloride (BAK alters GJIC activity in the rabbit corneal endothelium since it is commonly used as a drug preservative in ocular eyedrop preparations even though it can have cytotoxic effects.Thirty-six adult New Zealand albino rabbits were randomly divided into three groups. BAK at 0.01%, 0.05%, and 0.1% was applied twice daily to one eye of each of the rabbits in one of the three groups for seven days. The contralateral untreated eyes were used as controls. Corneal endothelial morphological features were observed by in vivo confocal microscopy (IVCM. Immunofluorescent staining resolved changes in gap junction integrity and localization. Western blot analysis and RT-PCR evaluated changes in levels of connexin43 (Cx43 and tight junction zonula occludens-1 (ZO-1 gene and protein expression, respectively. Cx43 and ZO-1 physical interaction was detected by immunoprecipitation (IP. Primary rabbit corneal endothelial cells were cultured in Dulbecco's Modified Eagle Medium (DMEM containing BAK for 24 hours. The scrape-loading dye transfer technique (SLDT was used to assess GJIC activity.Topical administration of BAK (0.05%, 0.1% dose dependently disrupted corneal endothelial cell morphology, altered Cx43 and ZO-1 distribution and reduced Cx43 expression. BAK also markedly induced increases in Cx43 phosphorylation status concomitant with decreases in the Cx43-ZO-1 protein-protein interaction. These changes were associated with marked declines in GJIC activity.The dose dependent declines in rabbit corneal endothelial GJIC activity induced by BAK are associated with less Cx43-ZO-1 interaction possibly arising from increases in Cx43 phosphorylation and declines in its protein expression. These novel changes provide additional evidence that BAK containing eyedrop preparations should be used with caution to

  10. Combined optical coherence tomography and intravascular ultrasound radio frequency data analysis for plaque characterization. Classification accuracy of human coronary plaques in vitro

    NARCIS (Netherlands)

    T.P.M. Goderie; G. van Soest (Gijs); H.M. Garcia-Garcia (Hector); N. Gonzalo (Nieves); S. Koljenovic (Senada); G.J.H.L. Leenders (Geert); F. Mastik (Frits); E.S. Regar (Eveline); J.W. Oosterhuis (Wolter); P.W.J.C. Serruys (Patrick); A.F.W. van der Steen (Ton)


    textabstractThis study was performed to characterize coronary plaque types by optical coherence tomography (OCT) and intravascular ultrasound (IVUS) radiofrequency (RF) data analysis, and to investigate the possibility of error reduction by combining these techniques. Intracoronary imaging methods h

  11. Gross anatomical study on the human myocardial bridges with special reference to the spatial relationship among coronary arteries, cardiac veins, and autonomic nerves. (United States)

    Watanabe, Yuko; Arakawa, Takamitsu; Kageyama, Ikuo; Aizawa, Yukio; Kumaki, Katsuji; Miki, Akinori; Terashima, Toshio


    Coronary arteries are frequently covered by cardiac muscles. This arrangement is termed a myocardial bridge. Previous studies have shown that myocardial bridges can cause myocardial ischemic diseases or cardiac arrhythmia, but the relevant pathogenic mechanisms remain unknown. We examined 60 hearts from Japanese cadavers macroscopically to clarify the spatial relationships among coronary arteries, cardiac veins and autonomic nerves. We found 86 myocardial bridges in 47 hearts from the 60 cadavers examined (78.3%). Next, we dissected out nine hearts with myocardial bridges in detail under the operating microscope. We found no additional branches of coronary arteries on the myocardial bridge surfaces. However, the cardiac veins, which usually accompany the coronary arteries, ran independently on the myocardial bridge surfaces in the same region. Cardiac autonomic nerves comprised two rami: one was associated with the coronary artery under the myocardial bridge and the other ran on the surface of the bridge. Such spatial relationships among the coronary arteries, cardiac veins and cardiac autonomic nerves at the myocardial bridges are quite similar to those in mouse embryo hearts.

  12. Selective venous vasodilator properties of the analgesic metamizole (dipyrone) in a human ex vivo model-implications for postoperative pain management. (United States)

    Hoenicka, Markus; Gorki, Hagen; Traeger, Karl; Liebold, Andreas


    Metamizole (dipyrone) is a first-line, non-opioid analgesic used for postoperative pain management. Clinical data and animal experiments indicate a possible vasodilator action of this drug. We investigated the effects of metamizole on human artery and vein tone in an ex vivo model to assess potential contributions to venous pooling. Excess segments of bypass grafts were harvested during coronary artery bypass grafting procedures. Tensions were measured in an organ bath for 120 min after adding metamizole to the preconstricted vessels. Contribution of endothelium was assessed in endothelium-denuded vessels, and indometacin was used to identify cyclooxygenase-mediated effects. Internal mammary arteries (n = 6) constricted after addition of 1, 3, and 10 μM metamizole and remained constricted at the lower doses. Transient constrictions also occurred in saphenous veins (n = 20), but veins relaxed below solvent controls after 20 min at all concentrations. Endothelium removal (n = 12) and cyclooxygenase inhibition (n = 12) suppressed the vasoconstrictor effect but not the vasodilator effect. Metamizole and its metabolites display counteracting effects on blood vessel tone ex vivo. The vasoconstrictor effect is mediated by cyclooxygenase-derived products. The net effect is site-specific, resulting in a selective venous vasodilator action. This may exacerbate unwanted venous pooling during postoperative pain therapy.

  13. Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. (United States)

    Brantley-Sieders, Dana M; Dunaway, Charlene M; Rao, Meghana; Short, Sarah; Hwang, Yoonha; Gao, Yandong; Li, Deyu; Jiang, Aixiang; Shyr, Yu; Wu, Jane Y; Chen, Jin


    It is well known that tumor-derived proangiogenic factors induce neovascularization to facilitate tumor growth and malignant progression. However, the concept of "angiocrine" signaling, in which signals produced by endothelial cells elicit tumor cell responses distinct from vessel function, has been proposed, yet remains underinvestigated. Here, we report that angiocrine factors secreted from endothelium regulate tumor growth and motility. We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. Slit2 activity is elevated in EphA2-deficient endothelium. Blocking Slit activity restored angiocrine-induced tumor growth/motility, whereas elevated Slit2 impaired growth/motility. To translate our findings to human cancer, we analyzed EphA2 and Slit2 expression in human cancer. EphA2 expression inversely correlated with Slit2 in the vasculature of invasive human ductal carcinoma samples. Moreover, analysis of large breast tumor data sets revealed that Slit2 correlated positively with overall and recurrence-free survival, providing clinical validation for the tumor suppressor function for Slit2 in human breast cancer. Together, these data support a novel, clinically relevant mechanism through which EphA2 represses Slit2 expression in endothelium to facilitate angiocrine-mediated tumor growth and motility by blocking a tumor suppressive signal.

  14. Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus (United States)

    Sobrevia, Luis; Salsoso, Rocío; Fuenzalida, Bárbara; Barros, Eric; Toledo, Lilian; Silva, Luis; Pizarro, Carolina; Subiabre, Mario; Villalobos, Roberto; Araos, Joaquín; Toledo, Fernando; González, Marcelo; Gutiérrez, Jaime; Farías, Marcelo; Chiarello, Delia I.; Pardo, Fabián; Leiva, Andrea


    Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies. PMID:27065887

  15. Insulin is a key modulator of fetoplacental endothelium metabolic disturbances in gestational diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Luis eSobrevia


    Full Text Available Gestational diabetes mellitus (GDM is a disease of the mother that associates with altered fetoplacental vascular function. GDM–associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring a normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

  16. The Role of the Endothelium in HPS Pathogenesis and Potential Therapeutic Approaches

    Directory of Open Access Journals (Sweden)

    Irina Gavrilovskaya


    Full Text Available American hantaviruses cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS. Hantaviruses nonlytically infect endothelial cells and cause dramatic changes in barrier functions of the endothelium without disrupting the endothelium. Instead hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions of capillaries. The endothelium of arteries, veins, and lymphatic vessels is unique and central to the function of vast pulmonary capillary beds, which regulate pulmonary fluid accumulation. The endothelium maintains vascular barrier functions through a complex series of redundant receptors and signaling pathways that serve to both permit fluid and immune cell efflux into tissues and restrict tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to alter capillary permeability but also defines potential therapeutic targets for regulating acute pulmonary edema and HPS disease. Here we discuss interactions of HPS causing hantaviruses with the endothelium, potential endothelial cell-directed permeability mechanisms, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease.

  17. Microarray analysis of ox-LDL (oxidized low-density lipoprotein)-regulated genes in human coronary artery smooth muscle cells. (United States)

    Minta, Joe; Jungwon Yun, James; St Bernard, Rosanne


    Recent studies suggest that circulating LDL (low-density lipoproteins) play a central role in the pathogenesis of atherosclerosis, and the oxidized form (ox-LDL) is highly atherogenic. Deposits of ox-LDL have been found in atherosclerotic plaques, and ox-LDL has been shown to promote monocyte recruitment, foam cell formation and the transition of quiescent and contractile vascular SMCs (smooth muscle cells) to the migratory and proliferative phenotype. SMC phenotype transition and hyperplasia are the pivotal events in the pathogenesis of atherosclerosis. To comprehend the complex molecular mechanisms involved in ox-LDL-mediated SMC phenotype transition, we have compared the differential gene expression profiles of cultured quiescent human coronary artery SMCs with cells induced with ox-LDL for 3 and 21 h using Affymetrix HG-133UA cDNA microarray chips. Assignment of the regulated genes into functional groups indicated that several genes involved in metabolism, membrane transport, cell-cell interactions, signal transduction, transcription, translation, cell migration, proliferation and apoptosis were differentially expressed. Our data suggests that the interaction of ox-LDL with its cognate receptors on SMCs modulates the induction of several growth factors and cytokines, which activate a variety of intracellular signalling mechanisms (including PI3K, MAPK, Jak/STAT, sphingosine, Rho kinase pathways) that contribute to SMC transition from the quiescent and contractile phenotype to the proliferative and migratory phenotype. Our study has also identified several genes (including CDC27, cyclin A1, cyclin G2, glypican 1, MINOR, p15 and apolipoprotein) not previously implicated in ox-LDL-induced SMC phenotype transition and substantially extends the list of potential candidate genes involved in atherogenesis.

  18. Salvianolic Acid B Down-regulates Matrix Metalloproteinase-9 Activity and Expression in Tumor Necrosis Factor-α-induced Human Coronary Artery Endothelial Cells

    Institute of Scientific and Technical Information of China (English)

    Le Ma; Yun-Qian Guan; Zhong-Dong Du


    Background:Salvianolic acid B (Sal B) is a bioactive water-soluble compound of Salviae miltiorrhizae,a traditional herbal medicine that has been used clinically tor the treatment of cardiovascular diseases.This study sought to evaluate the effect of Sal B on matrix metalloproteinase-9 (MMP-9) and on the underlying mechanisms in tumor necrosis factor-α (TNF-α)-activated human coronary artery endothelial cells (HCAECs),a cell model of Kawasaki disease.Methods:HCAECs were pretreated with 1 l0 μmol/L of Sal B,and then stimulated by TNF-α at different time points.The protein expression and activity of MMP-9 were determined by Western blot assay and gelatin zymogram assay,respectively.Nuclear factor-κB (NF-κB) activation was detected with immunofluorescence,electrophoretic mobility shift assay,and Western blot assay.Protein expression levels of mitogen-activated protein kinase (c-Jun N-terminal kinase [JNK],extra-cellular signal-regulated kinase [ERK],and p38) were determined by Western blot assay.Results:After HCAECs were exposed to TNF-α,1-10 μtmol/L Sal B significantly inhibited TNF-α-induced MMP-9 expression and activity.Furthermore,Sal B significantly decreased IκBα phosphorylation and p65 nuclear translocation in HCAECs stimulated with TNF-α for 30 min.In addition,Sal B decreased the phosphorylation of JNK and ERK1/2 proteins in cells treated with TNF-α for 10 min.Conclusions:The data suggested that Sal B suppressed TNF-α-induced MMP-9 expression and activity by blocking the activation of NF-κB,JNK,and ERK1/2 signaling pathways.

  19. The mechanism of TGF-β/miR-155/c-Ski regulates endothelial-mesenchymal transition in human coronary artery endothelial cells. (United States)

    Wang, Juan; He, Wen; Xu, Xiao; Guo, Liping; Zhang, Yin; Han, Suxia; Shen, Difei


    Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial-mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis. © 2017 The Author(s).

  20. High-fat feeding reduces endothelium-dependent vasodilation in rats: differential mechanisms for saturated and unsaturated fatty acids? (United States)

    Song, Guang-Yao; Gao, Yu; Di, Yu-Wei; Pan, Li-Li; Zhou, Yu; Ye, Ji-Ming


    1. Chronic feeding with a high-fat diet can cause metabolic syndrome in rodents similar to humans, but the role of saturated versus unsaturated fats in vascular tension remains unclear. 2. The present study shows that rats on a diet rich in either saturated or unsaturated fat had higher blood pressure compared with chow-fed rats (approximately 130 vs 100 mmHg, respectively), along with hyperlipidaemia and insulin resistance. Compared with responses of phenylephrine-preconstricted artery segments from chow-fed rats, vasorelaxation of isolated renal arteries from high-fat fed rats was reduced substantially (> 50%) in response to acetylcholine (0.01-10 micromol/L) and moderately to nitroprusside (>or=1 micromol/L) at low concentrations. Acetylcholine-induced vasorelaxation of arteries from high-fat fed rats was also more sensitive to inhibition by the nitric oxide (NO) synthase inhibitors NG-nitro-L-arginine and methylene blue. 3. In human umbilical vein endothelial cells, the production of NO and endothelin-1 was significantly inhibited by unsaturated fatty acids. In comparison, saturated fatty acids stimulated endothelin-1 production without altering NO production. 4. The data indicate that both saturated and unsaturated high-fat feeding may result in an increase in blood pressure owing to reduced endothelium-dependent vasorelaxation in the arterial system. The impaired endothelium-dependent vasorelaxation induced by saturated and unsaturated fatty acids may involve different mechanisms.

  1. Feasibility and safety of porcine Descemet's membrane as a carrier for generating tissue-engineered corneal endothelium. (United States)

    Diao, Yu-Mei; Hong, Jing


    The aim of this study was to evaluate the feasibility and safety of porcine Descemet's membrane (DM) as a carrier for the generation of tissue-engineered corneal endothelium by analyzing porcine endogenous retroviruses (PERVs) and the α-gal epitope. The morphology of porcine and human DM was observed by hematoxylin and eosin staining and scanning electron microscopy. Immunohistochemical staining was used to investigate the location of α-gal epitopes on porcine DM used for xenotransplantation. The porcine DM was treated with ethylene glycol diglycidyl ether (EDGE) for 2 weeks, and then the PERV gene sequences in porcine DM and DM-EDGE were detected by polymerase chain reaction (PCR) and real-time PCR, respectively. The porcine DM had tight basement membrane morphology, which was similar to human DM in terms of thickness. No positive immunohistochemical staining of the α-gal epitope was detected in porcine DM. PERV expression of pol, gag, env-A and env-B was noted in porcine DM, but in DM-EDGE it was completely degraded. Based on structural, immunological and etiological studies, porcine DM may be an ideal and viable carrier for the generation of tissue-engineered corneal endothelium.

  2. The coronary heart team. (United States)

    Yanagawa, Bobby; Puskas, John D; Bhatt, Deepak L; Verma, Subodh


    The concept of a Coronary Heart Team has generated increased interest, including support from major practice guidelines. Here, we review the rationale and the published experience of Coronary Heart Teams. A Coronary Heart Team should be led by both cardiology and cardiac surgery with a shared decision-making approach. The team should incorporate data from anatomic and clinical risk prediction models to offer individualized care. Most teams focus on management of complex patients and those with indications for both coronary artery bypass graft and percutaneous coronary intervention. The potential benefits of a Coronary Heart Team include balanced decision-making, greater adherence to evidence-based practice guidelines, as well as promoting greater collegiality and exchange of knowledge between specialties. Single-center series have demonstrated consistency in decision-making by Coronary Heart Teams but prospective data demonstrating improved patient outcomes and/or cost effectiveness are necessary. The concept of a Coronary Heart Team is gaining traction for patients with complex coronary artery disease. There is a growing literature in support of Coronary Heart Teams but comparative and prospective data demonstrating improved patient outcomes are needed.

  3. Vascular endothelium-leukocyte interaction; sticking shear force in venules. (United States)

    Schmid-Schoenbein, G W; Fung, Y C; Zweifach, B W


    To determine the shear force acting on a white blood cell sticking to the endothelium of a blood vessel, the flow field about a single white blood cell in a venule was determined by hign-speed motion picture photomicrography. The force acting on the white blood cell was then calculated according to the principles of fluid mechanics. In this paper, the calculation was made using an experimentally determined dimensionless shear force coefficient obtained from a kinematically and dynamically similar model. The large physical model of the hemodynamic system could be easily instrumented, and the shear force acting on the model cell and the flow field around it were measured. The data were then used to calculate a shear force coefficient. On the basis of dynamic similarity, this shear force coefficient was applied to the white blood cell in the venule. The shear force coefficient was strongly influenced by the hematocrit, so in vivo hematocrits were measured from electron micrographs. It was found that in the venules of the rabbit omentum a white blood cell sticking to the endothelial wall was subjected to a shear force in the range of 4 times 10--5 dynes to 234 times 10--5 dynes; the exact value depended on the size and motion of the white blood cell, the size of the blood vessel, the velocity of the blood flow, and the local hematocrit, which varied between 20% and 40% in venules of about 40 mum in diameter. The contact area between the white blood cell and the endothelial cell was estimated, and the shear stress was found to range between 50 dynes/cm-2 and 1060 dynes/cm-2. The normal stress of interaction between the white blood cell and the endothelium had a maximum value that was of the same order of magnitude as the shear stress. The accumulated relative error of the experimental procedure was about 49%. The instantaneous shear force was a random function of time because of random fluctuations of the hematocrit.

  4. Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells: NEW AP-1 TRANSCRIPTION FACTOR SITE AND NEGATIVE REGULATOR. (United States)

    Liu, Yiwei; Zhang, Lingxin; Wang, Chuan; Roy, Shama; Shen, Jianzhong


    We recently reported that the P2Y2 receptor (P2Y2R) is the predominant nucleotide receptor expressed in human coronary artery endothelial cells (HCAEC) and that P2Y2R activation by ATP or UTP induces dramatic up-regulation of tissue factor (TF), a key initiator of the coagulation cascade. However, the molecular mechanism of this P2Y2R-TF axis remains unclear. Here, we report the role of a newly identified AP-1 consensus sequence in the TF gene promoter and its original binding components in P2Y2R regulation of TF transcription. Using bioinformatics tools, we found that a novel AP-1 site at -1363 bp of the human TF promoter region is highly conserved across multiple species. Activation of P2Y2R increased TF promoter activity and mRNA expression in HCAEC. Truncation, deletion, and mutation of this distal AP-1 site all significantly suppressed TF promoter activity in response to P2Y2R activation. EMSA and ChIP assays further confirmed that upon P2Y2R activation, c-Jun, ATF-2, and Fra-1, but not the typical c-Fos, bound to the new AP-1 site. In addition, loss-of-function studies using siRNAs confirmed a positive transactivation role of c-Jun and ATF-2 but unexpectedly revealed a strong negative role of Fra-1 in P2Y2R-induced TF up-regulation. Furthermore, we found that P2Y2R activation promoted ERK1/2 phosphorylation through Src, leading to Fra-1 activation, whereas Rho/JNK mediated P2Y2R-induced activation of c-Jun and ATF-2. These findings reveal the molecular basis for P2Y G protein-coupled receptor control of endothelial TF expression and indicate that targeting the P2Y2R-Fra-1-TF pathway may be an attractive new strategy for controlling vascular inflammation and thrombogenicity associated with endothelial dysfunction.

  5. Coronary Artery Disease

    DEFF Research Database (Denmark)

    Christiansen, Morten Krogh


    A family history of coronary artery disease (CAD) is an important risk factor for adverse coronary events, in particular if the disease has an early onset. The risk of CAD is influenced by genetic and environmental factors with a greater genetic contribution earlier in life. Through recent years...... Registry and risk factor control was evaluated. The study revealed that risk factors are common in early-onset CAD and that a large room for risk factor improvement remains. In study II, we used coronary computed tomography angiography to compare the coronary plaque burden and characteristics between 88...... first-degree relatives of patients with early-onset CAD and 88 controls with no familial predisposition. Relatives had a significantly increased coronary plaque burden, which displayed characteristics associated with myocardial ischemia and adverse coronary events. In study III, 134 patients with early...

  6. Decoding Dynamic Ca2+ Signaling in the Vascular Endothelium

    Directory of Open Access Journals (Sweden)

    Mark Stephen Taylor


    Full Text Available Although acute and chronic vasoregulation is inherently driven by endothelial Ca2+, control and targeting of Ca2+-dependent signals are poorly understood. Recent studies have revealed localized and dynamic endothelial Ca2+ events comprising an intricate signaling network along the vascular intima. Discrete Ca2+ transients emerging from both internal stores and plasmalemmal cation channels couple to specific membrane K+ channels, promoting endothelial hyperpolarization and vasodilation. The spatiotemporal tuning of these signals, rather than global Ca2+ elevation, appear to direct endothelial functions under physiologic conditions. In fact, altered patterns of dynamic Ca2+ signaling may underlie essential endothelial dysfunction in a variety of cardiovascular diseases. Advances in imaging approaches and analyses in recent years have allowed for detailed detection, quantification, and evaluation of Ca2+ dynamics in intact endothelium. Here, we discuss recent insights into these signals, including their sources of origination and their functional encoding. We also address key aspects of data acquisition and interpretation, including broad applications of automated high-content analysis.

  7. Effects of intravenous anesthetic agents on vascular endothelium

    Directory of Open Access Journals (Sweden)

    Alp Gurbet


    Full Text Available Objectives: The objective of this study was to comparethe effects of Propofol 1%, Propofol 2%, Ketamine, Pentothal,Etomidate and Etomidate-lipuro on venous endothelium.Materials and methods: The study was done fromAugust 2007 to May 2008 after approval of Faculty’sEthic Committee. Forty rabbits were obtained. Propofol1% (n=6, Propofol 2% (n=6, Ketamin (n=6, Penthotal(n=6, Etomidate (n=6, Etomidate lipuro (n=6 and normalsaline (Control Group, n=4 was given 1 cc via externaljugular vein. After 5 minutes from the injenction 6species 2 mm in length segments were taken from theinjencted veins. Species were fixed in 4˚C gluteraldehydethan postfixed in 4°C osmium tetroxide. Visualisation wasperformed with scanning electron microscope.Results: In Propofol 1 %, Propofol 2% and Penthotalgroups normal endothelial structures were observed. InEtomidate group damage of the endothelial cells were observedsignificantly compared with control. In Etomidatelipuro group minimal deformation was observed comparedto control.Conclusion: Etomidat causes significant endothelial deformation,moreover lipuro minimalises these effects. Inorder to need to use etomidate for general anesthesia,for less pain during injection depending on vascular injurylipuro form would be more appropriate. However, furtherstudy is required. J Clin Exp Invest 2011; 3(2: 164-167

  8. [Molecular basis of red blood cell adhesion to endothelium]. (United States)

    Wautier, J-L; Wautier, M-P


    The extent of red blood cell adhesion is correlated with the incidence of vascular complications and the severity of the disease. Patients with sickle cell anemia (HbSS) experience vasoocclusive episodes. The adhesion of RBCs from HbSS patients is increased and related to VLA-4 exposure, which binds to vascular cell adhesion molecule (VCAM-1). Inter Cellular Adhesion Molecule (ICAM-1), CD31, CD36 and glycans are potential receptors for PfEMP1 of RBCs parasited by plasmodium falciparum. The incidence of vascular complications is very high in patients with diabetes mellitus. RBC adhesion is increased and statistically correlated with the severity of the angiopathy. Glycation of RBC membrane proteins is responsible for binding to the receptor for advanced glycation end products (RAGE). Polycythemia Vera (PV) is the most frequent myeloproliferative disorder and characterized by a high occurrence of thrombosis of mesenteric and cerebral vessels. PV is due to a mutation of the Janus kinase 2 (JAK2 V617F). This mutation stimulates erythropoiesis and is the cause of Lu/BCAM (CD239) phosphorylation, which potentiated the interaction with laminin alpha 5. The couple laminin alpha 5 endothelial and phosphorylated Lu/BCAM explained the increased adhesion of RBCs from patients PV to endothelium.

  9. Effects of iodinated contrast media on blood and endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Aspelin, Peter [Karolinska Institute/Huddinge University Hospital, Division of Radiology, Centre for Surgical Sciences, Stockholm (Sweden); Stacul, Fulvio [Institute of Radiology, Trieste (Italy); Thomsen, Henrik S. [Copenhagen University Hospital at Herlev, Department of Diagnostic Radiology 54E2, Herlev (Denmark); Morcos, Sameh K. [Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Northern General Hospital, Sheffield (United Kingdom); Molen, Aart J. van der [Leiden University Medical Centre, Department of Radiology, Leiden (Netherlands)


    The aim of the study was to assess the effects of iodinated contrast media on blood components and endothelium based on experimental and clinical studies and to produce clinically relevant guidelines for reducing thrombotic and hematologic complications following the intravascular use of contrast media. A report was drafted after review of the literature and discussions among the members of the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The final report was produced following discussion at the 12th European Symposium on Urogenital Radiology in Ljubljana, Slovenia (2005). Experimental data indicate that all iodinated contrast media produce an anticoagulant effect and that this effect is greater with ionic contrast media. Several of the in vitro and experimental in vivo studies on haematological effects of contrast media have not been confirmed by clinical studies. Low- or iso-osmolar contrast media should be used for diagnostic and interventional angiographic procedures, including phlebography. Meticulous angiographic technique is the most important factor for reducing the thrombotic complications associated with angiographic procedures. Drugs and interventional devices that decrease the risk of thromboembolic complications during interventional procedures minimize the importance of the effects of contrast media. (orig.)

  10. Living with Coronary Heart Disease (United States)

    ... from the NHLBI on Twitter. Living With Coronary Heart Disease Coronary heart disease (CHD) can cause serious complications. However, if you ... changes and medicines, go to "How Is Coronary Heart Disease Treated?" Work closely with your doctor to control ...

  11. Coronary artery aneurysms

    Energy Technology Data Exchange (ETDEWEB)

    Koischwitz, D.; Harder, T.; Schuppan, U.; Thurn, P.


    Seven saccular coronary artery aneurysms have been demonstrated in the course of 1452 selective coronary artery angiograms. In six patients they were arterio-sclerotic; in one patient the aneurysm must have been congenital or of mycotic-embolic origin. The differential diagnosis between true aneurysms and other causes of vascular dilatation is discussed. Coronary artery aneurysms have a poor prognosis because of the possibility of rupture with resultant cardiac tamponade, or the development of thrombo-embolic myocardial infarction. These aneurysms can only be diagnosed by means of coronary angiography and require appropriate treatment.

  12. Selective Coronary Arteriography (United States)

    Parker, John O.; Challis, Thomas W.; West, Roxroy O.


    The technique of selective coronary arteriography, as described originally by Sones, was employed in 255 patients. Successful catheterization of both coronary arteries was carried out in 88% of these patients, and in the last 100 examinations both coronary arteries were entered in 95 patients. Selective coronary arteriography is a useful diagnostic tool but is a potentially hazardous form of examination as we encountered four episodes of ventricular fibrillation in the present series. ImagesFig. 1Fig. 2Figs. 3A-DFig. 3EFig. 3FFig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9 PMID:5902704

  13. A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.

    Directory of Open Access Journals (Sweden)

    Timothy Gatheral

    Full Text Available Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of gram negative and some gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.

  14. A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses. (United States)

    Gatheral, Timothy; Reed, Daniel M; Moreno, Laura; Gough, Peter J; Votta, Bart J; Sehon, Clark A; Rickard, David J; Bertin, John; Lim, Eric; Nicholson, Andrew G; Mitchell, Jane A


    Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of gram negative and some gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.

  15. Associations of C1q/TNF-Related Protein-9 Levels in Serum and Epicardial Adipose Tissue with Coronary Atherosclerosis in Humans

    Directory of Open Access Journals (Sweden)

    Jing Wang


    Full Text Available Objective. To investigate the correlation of CTRP9 with coronary atherosclerosis. Methods. Coronary angiography confirmed CAD in 241 patients (62 received CABG and non-CAD in 121 (55 received valve replacement. Results. Serum levels of LDL-C, CRP, TNF-α, IL-6, and leptin in CAD patients were significantly higher than those in non-CAD patients (P<0.05, but APN and CTRP9 were lower (P<0.05. Serum levels of CTRP9 and APN were negatively related to BMI, HOMA-IR, TNF-α, IL-6, and leptin but positively to HDL-C (P<0.05 in CAD patients. After adjustment of APN, CTRP9 was still related to the above parameters. Serum CTRP9 was a protective factor of CAD (P<0.05. When compared with non-CAD patients, leptin mRNA expression increased dramatically, while CTRP9 mRNA expression reduced markedly in epicardial adipose tissue of CAD patients (P<0.05. The leptin expression and macrophage count in CAD group were significantly higher than in non-CAD group, but CAD patients had a markedly lower CTRP9 expression (P<0.05. Conclusions. Circulating and coronary CTRP9 plays an important role in the inflammation and coronary atherosclerosis of CAD patients. Serum CTRP9 is an independent protective factor of CAD.

  16. Role of endothelium/nitric oxide in vascular response to flavonoids and epicatechin

    Institute of Scientific and Technical Information of China (English)

    HUANG Yu; YAO Xiao-qiang; TSANG Suk Ying; LAU Chi-Wai; CHEN Zhen-Yu


    AIM: To examine the role of endothelium in the vascular responses to flavonoids, baicalein, baicalin, cardamonin, alpinetin, and to purified jasmine green tea (-)epicatechin in the isolated rat mesenteric artery rings. METHODS: The isometric contraction was measured by Grass force-displacement transducers. RESULTS: Both baicalein and baicalin enhanced the phenylephrine-induced contractile response in the endothelium-intact rings. This enhancement was abolished by pretreatment with the nitric oxide inhibitor NG-nitro- L-arginine or in the absence of the endothelium. Both flavonoids also inhibited the acetylcholine-induced endothelial nitric oxide-dependent relaxation. In contrast, cardamonin, alpinetin or (-)epicatechin induced both endothelium-dependent and -independent relaxation. NG-nitro-L-arginine meyhyl ester or endothelium denudation attenuated the endotheliurn-dependent relaxation to the same extent. CONCLUSION: Baicalein and baicalin enhanced the phenylephrine-induced contraction most likely through inhibiting production or/and release of endothelial nitric oxide. Whilst, cardamonin-, alpinetin- or (-)epicatechin-induced endothelium-dependent relaxation is primarily mediated through endothelial nitric oxide.

  17. Effects of catechins on vascular tone in rat thoracic aorta with endothelium. (United States)

    Sanae, Fujiko; Miyaichi, Yukinori; Kizu, Haruhisa; Hayashi, Hisao


    The effects of eight catechin derivatives on vascular tone in rat thoracic aorta were examined. Catechin derivatives (10 microM) potentiated the contractile response to phenylephrine in endothelium-intact arteries. The potentiations produced by EGCg and EGC were almost absent in endothelium-denuded arteries and abolished by N(G)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis. The catechin derivatives also inhibited endothelium-dependent relaxation in response to acetylcholine. The order of catechin derivatives ranked in terms of both increasing vascular reactivity and impairing endothelium-dependent relaxation was similar; (-)-gallocatechin (GC) >or= (-)-epigallocatechin (EGC) >or= (-)-gallocatechin gallate (GCg) >or= (-)-epigallocatechin gallate (EGCg) >or= (-)-catechin (C) >or= (-)-epicatechin (EC) >or= (-)-catechin gallate (Cg) >or= (-)-epicatechin gallate (ECg). In addition, EGC inhibited the endothelium-independent relaxation evoked by both sodium nitroprusside and NOC-7, a spontanous NO releaser, but EGCg inhibited only that by NOC-7. These findings indicate that catechin derivatives produce a potentiation of the contractile response and an inhibition of the vasorelaxant response, probably through inactivation of endothelium-derived nitric oxide (NO), and that the hydroxyl on C-5 of the B ring together with the stereoscopic structure between the C-3 group and the B ring of flavanols was of importance in mediating the above effects and that the substitution of a gallate group of C-3 attenuated the effects, probably due to a decreased response to solube guanylate cyclase in vascular smooth muscle cells.

  18. Endothelium-dependent contraction of rat thoracic aorta induced by gallic acid. (United States)

    Sanae, Fujiko; Miyaichi, Yukinori; Hayashi, Hisao


    The vascular effect of a component of hydrolysable tannins, gallic acid, was examined in isolated rat thoracic aorta. Gallic acid exerted a contractile effect on the phenylephrine- or prostaglandin F(2/alpha)-precontracted endothelium-intact arteries. In endothelium-denuded arteries, the contractile response to-gallic acid was absent. Pretreatment with N(G)-nitro-L-arginine methyl ester (30 microM) abolished the gallic acid-induced contraction. Pretreatment with indomethacin (10 microM) or BQ610 (100 nM) had no observed effect. Pretreatment with gallic acid (1-10 microM) significantly attenuated the relaxation induced by acetylcholine, and that with 10 microM gallic acid also reduced the potency of sodium nitroprusside in the relaxation, without a reduction in efficacy, in endothelium-denuded arteries. These findings indicate that gallic acid induced endothelium-dependent contraction and strongly inhibited the endothelium-dependent relaxation rather than the endothelium-independent relaxation, probably through inhibition of endothelial nitric oxide (NO) production. Since NO plays an important role in vasodilative regulation and inflammatory disorders, these findings may also indicate that gallic acid interferes with the inflammatory responses.

  19. Northern contaminant mixtures induced morphological and functional changes in human coronary artery endothelial cells under culture conditions typifying high fat/sugar diet and ethanol exposure. (United States)

    Florian, Maria; Yan, Jin; Ulhaq, Saad; Coughlan, Melanie; Laziyan, Mahemuti; Willmore, William; Jin, Xiaolei


    It has been reported that Northern populations are exposed to mixtures of various environmental contaminants unique to the Arctic (Northern contaminant mixtures - NCM) at a large range of concentrations, depending on their geological location, age, lifestyle and dietary habits. To determine if these contaminants may contribute to a cardiovascular health risk, especially when combined with a high fat and sugar diet and ethanol exposure, we treated human coronary artery endothelial cells (HCAEC) with two mixtures of 4 organic (NCM1) or 22 organic and inorganic (NCM2) chemicals detected in Northerners' blood during 2004-2005 in the presence or absence of low-density lipoprotein (1.5mg/ml), very-low-density lipoprotein (1.0mg/ml) and glucose (10mmol/L) (LVG), and in the absence or presence of 0.1% ethanol. After 24h of exposure, cell morphology and markers of cytotoxicity and endothelial function were examined. NCM1 treatment did not affect cell viability, but increased cell size, disrupted cell membrane integrity, and decreased cell density, uptake of small peptides, release of endothelin-1 (ET-1) and plasminogen activator inhibitor (PAI), while causing no changes in endothelial nitric oxide synthase (eNOS) protein expression and nitric oxide (NO) release. In contrast, NCM2 decreased cell viability, total protein yield, uptake of small peptides, eNOS protein expression, and NO release and caused membrane damage, but caused no changes in the secretion of ET-1, prostacyclin and PAI. The presence of LVG and/or alcohol did or did not influence the effects of NCM1 or NCM2 depending on the endpoint and the mixture examined. These results suggested that the effects of one or one group of contaminants may be altered by the presence of other contaminants, and that with or without the interaction of high fat and sugar diet and/or ethanol exposure, NCMs at the concentrations used caused endothelial dysfunction in vitro. It remains to be investigated if these effects of NCMs also

  20. Nitric oxide, cholesterol oxides and endothelium-dependent vasodilation in plasma of patients with essential hypertension

    Directory of Open Access Journals (Sweden)

    P. Moriel


    Full Text Available The objective of the present study was to identify disturbances of nitric oxide radical (·NO metabolism and the formation of cholesterol oxidation products in human essential hypertension. The concentrations of·NO derivatives (nitrite, nitrate, S-nitrosothiols and nitrotyrosine, water and lipid-soluble antioxidants and cholesterol oxides were measured in plasma of 11 patients with mild essential hypertension (H: 57.8 ± 9.7 years; blood pressure, 148.3 ± 24.8/90.8 ± 10.2 mmHg and in 11 healthy subjects (N: 48.4 ± 7.0 years; blood pressure, 119.4 ± 9.4/75.0 ± 8.0 mmHg.Nitrite, nitrate and S-nitrosothiols were measured by chemiluminescence and nitrotyrosine was determined by ELISA. Antioxidants were determined by reverse-phase HPLC and cholesterol oxides by gas chromatography. Hypertensive patients had reduced endothelium-dependent vasodilation in response to reactive hyperemia (H: 9.3 and N: 15.1% increase of diameter 90 s after hyperemia, and lower levels of ascorbate (H: 29.2 ± 26.0, N: 54.2 ± 24.9 µM, urate (H: 108.5 ± 18.9, N: 156.4 ± 26.3 µM, ß-carotene (H: 1.1 ± 0.8, N: 2.5 ± 1.2 nmol/mg cholesterol, and lycopene (H: 0.4 ± 0.2, N: 0.7 ± 0.2 nmol/mg cholesterol, in plasma, compared to normotensive subjects. The content of 7-ketocholesterol, 5alpha-cholestane-3ß,5,6ß-triol and 5,6alpha-epoxy-5alpha-cholestan-3alpha-ol in LDL, and the concentration of endothelin-1 (H: 0.9 ± 0.2, N: 0.7 ± 0.1 ng/ml in plasma were increased in hypertensive patients. No differences were found for ·NO derivatives between groups. These data suggest that an increase in cholesterol oxidation is associated with endothelium dysfunction in essential hypertension and oxidative stress, although ·NO metabolite levels in plasma are not modified in the presence of elevated cholesterol oxides.

  1. Myocardial serotonin exchange: negligible uptake by capillary endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Moffett, T.C.; Chan, I.S.; Bassingthwaighte, J.B.


    The extraction of serotonin from the blood during transorgan passage through the heart was studied using Langendorff-perfused rabbit hearts. Outflow dilution curves of /sup 131/I- or /sup 125/I-labeled albumin, (/sup 14/C)sucrose, and (3H)serotonin injected simultaneously into the inflow were fitted with an axially distributed blood-tissue exchange model to examine the extraction process. The model fits of the albumin and sucrose outflow dilution curves were used to define flow heterogeneity, intravascular dispersion, capillary permeability, and the volume of the interstitial space, which reduced the degrees of freedom in fitting the model to the serotonin curves. Serotonin extractions, measured against albumin, during single transcapillary passage, ranged from 24 to 64%. The ratio of the capillary permeability-surface area products for serotonin and sucrose, based on the maximum instantaneous extraction, was 1.37 +/- 0.2 (n = 18), very close to the predicted value of 1.39, the ratio of free diffusion coefficients calculated from the molecular weights. This result shows that the observed uptake of serotonin can be accounted for solely on the basis of diffusion between endothelial cells into the interstitial space. Thus it appears that the permeability of the luminal surface of the endothelial cell is negligible in comparison to diffusion through the clefts between endothelial cells. In 18 sets of dilution curves, with and without receptor and transport blockers or competitors (ketanserin, desipramine, imipramine, serotonin), the extractions and estimates of the capillary permeability-surface area product were not reduced, nor were the volumes of distribution. The apparent absence of transporters and receptors in rabbit myocardial capillary endothelium contrasts with their known abundance in the pulmonary vasculature.

  2. TSG-6 protects corneal endothelium from transcorneal cryoinjury in rabbits. (United States)

    Kim, Jeong-Ah; Ko, Jung Hwa; Ko, Ah Young; Lee, Hyun Ju; Kim, Mee Kum; Wee, Won Ryang; Lee, Ryang Hwa; Fulcher, Samuel F; Oh, Joo Youn


    To investigate the effect of an anti-inflammatory protein, TNF-α stimulated gene/protein (TSG)-6 and an antiapoptotic protein, stanniocalcin (STC)-1 on corneal endothelium in rabbits with transcorneal cryoinjury. Transcorneal freezing (-80°C) was applied to rabbit corneas for 30 seconds. Immediately post injury, either TSG-6 (10 μg/100 μL), STC-1 (10 μg/100 μL), or the same volume of balanced salt solution (BSS) was injected into the anterior chamber. Each eye was examined for corneal opacity, corneal thickness, endothelial cell density, and endothelial hexagonality every 2 to 6 hours for 48 hours post injury. The concentrations of myeloperoxidase (MPO) and IL-1β were measured in the aqueous humor every 6 hours. At 48 hours post injury, each cornea was assayed for TNF-α, IL-1β, IL-6, and MPO, and histologically evaluated with alizarin red-trypan blue staining, hematoxylin-eosin staining, and immunostaining for neutrophils. Tumor necrosis factor-α stimulated gene/protein-6 significantly decreased the development of corneal opacity and edema after cryoinjury compared with STC-1 or BSS. The corneal endothelial cell density and hexagonality were markedly preserved by TSG-6. The mRNA levels of TNF-α, IL-1β, and IL-6 in the cornea and the protein levels of MPO and IL-1β in the aqueous humor and cornea were significantly lower in TSG-6-treated eyes than BSS-treated controls. Similarly, the expression of fibroblast growth factor-2 was reduced by TSG-6 treatment. Histologic evaluation demonstrated that neutrophil infiltration of the cornea was decreased in TSG-6-treated eyes. Tumor necrosis factor-α stimulated gene/protein-6 protected corneal endothelial cells from transcorneal cryoinjury through suppression of inflammation. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  3. RO-heparin Inhibits L-Selectin-mediated Neutrophils Adhesion to Vascular Endothelium Under Flow Conditions

    Institute of Scientific and Technical Information of China (English)


    Selectins are carbohydrate-binding cell adhesion molecules that play a major role in the initiation of inflammatory responses. Accumulaed evidence has suggested that heparin's anti-inflammatory effects are mainly mediated by blocking L- or P-selectin-initiated cell adhesion. Recently, we have reported that periodate-oxidized, borohydridereduced heparin (RO-heparin) can inhibit P-selectin-mediated acute inflammation. Here we further examined the effect of RO-heparin on the adhesion of L-selectin-mediated leukocytes to vascular endothelium under flow conditions in vivo and in vitro. The results show that RO-heparin with a low anticoagulant activity can effectively reduce leucocyte rolling on thioglycollate-induced rat mesenteric venules and L-selectin-metadiated neutrophil rolling on TNF-α-induced human umbilical vein endothelial cells(HUVECs) under flow conditions. Our findings suggest that the effect of RO-heparin on inflammatory responses is mainly a result of its inhibiting the interaction between P- or L-selectin and its ligands. The findings also suggest that RO-heparin may be useful in preventing inflammation diseases.

  4. Homoharringtonine induces apoptosis of endothelium and down-regulates VEGF expression of K562 cells

    Institute of Scientific and Technical Information of China (English)

    叶琇锦; 林茂芳


    Homoharringtonine (HHT) has currently been used successfully in the treatment of acute and chronic myeloid leukemias and has been shown to induce apoptosis of different types of leukemic cells in vitro. Emerging evidence suggests that angiogenesis may play an important role in hematological malignancies, such as leukemia. However, whether HHT can relieve leukemia by anti-angiogenesis is still unknown. We investigated the anti-angiogenesis potential of HHT with the human umbilical vein endothelial cell line (ECV304) and leukemic cell line (K562) in vitro. Cellular proliferation was determined by MTT assay and apoptosis was analyzed by flow cytometry, The mRNA expression of vascular endothelial growth factor (VEGF) was assessed by RT-PCR and VEGF protein production was detected by Western blot. Inhibition of cell proliferation and induction of apoptosis by HHT were discovered in ECV304 cells, and appeared in a dose- and time-dependent manner, Also, treatment with HHT caused down-regulation of VEGF mRNA expression in K562 cells in similar dose- and time-dependent manner and inhibition of VEGF protein production in K562 cells in response to the enhancing concentration of HHT. The results demonstrated that HHT could also induce apoptosis in endothelium and down-regulate VEGF expression in K562 cells. In conclusion, we believe HHT has anti-angiogenesis potential and speculate that HHT might exert its anti-leukemia effects via reduction of angiogenesis.

  5. Coronary Artery Bypass Surgery (United States)

    In coronary artery disease (CAD), the arteries that supply blood and oxygen to your heart muscle grow hardened and narrowed. You may try ... these treatments don't help, you may need coronary artery bypass surgery. The surgery creates a new ...

  6. Exercised-Induced Coronary Spasm in Near Normal Coronary Arteries

    Directory of Open Access Journals (Sweden)

    Damian Franzen


    Full Text Available In contrast to effort-induced symptoms in obstructive coronary disease, spasm in normal coronary arteries is characterized by angina at rest. We describe a 44-year-old patient with minor coronary plaques and pure exercised-induced coronary spasm. The case questions the differential pathogenic considerations of variant of the variant as opposed to Prinzmetal's variant angina.

  7. Role of the Endothelium during Tumor Cell Metastasis: Is the Endothelium a Barrier or a Promoter for Cell Invasion and Metastasis?

    Directory of Open Access Journals (Sweden)

    Claudia Tanja Mierke


    Full Text Available The malignancy of cancer disease depends on the ability of the primary tumor to metastasize to distant organs. The process of the metastasis formation has largely been analyzed, but still main pathways regarding the extravasation step at the end of the metastasis formation process are controversially discussed. An agreement has been reached about the importance of the endothelium to promote metastasis formation either by enhancing the growth of the primary tumor or by homing (targeting the tumor cells to blood or lymph vessels. The mechanical properties of the invading tumor cells become the focus of several studies, but the endothelial cell mechanical properties are still elusive. This paper describes the different roles of the endothelium in the process of metastasis formation and focuses on a novel role of the endothelium in promoting tumor cell invasion. It discusses how novel biophysical tools and in vivo animal models help to determine the role of the endothelium in the process of tumor cell invasion. Evidence is provided that cell mechanical properties, for example, contractile force generation of tumor cells, are involved in the process of tumor cell invasion.

  8. Distinct Differences on Neointima Formation in Immunodeficient and Humanized Mice after Carotid or Femoral Arterial Injury (United States)

    Moser, Jill; van Ark, Joris; van Dijk, Marcory C.; Greiner, Dale L.; Shultz, Leonard D.; van Goor, Harry; Hillebrands, Jan-Luuk


    Percutaneous coronary intervention is widely adopted to treat patients with coronary artery disease. However, restenosis remains an unsolved clinical problem after vascular interventions. The role of the systemic and local immune response in the development of restenosis is not fully understood. Hence, the aim of the current study was to investigate the role of the human immune system on subsequent neointima formation elicited by vascular injury in a humanized mouse model. Immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl(NSG) mice were reconstituted with human (h)PBMCs immediately after both carotid wire and femoral cuff injury were induced in order to identify how differences in the severity of injury influenced endothelial regeneration, neointima formation, and homing of human inflammatory and progenitor cells. In contrast to non-reconstituted mice, hPBMC reconstitution reduced neointima formation after femoral cuff injury whereas hPBMCs promoted neointima formation after carotid wire injury 4 weeks after induction of injury. Neointimal endothelium and smooth muscle cells in the injured arteries were of mouse origin. Our results indicate that the immune system may differentially respond to arterial injury depending on the severity of injury, which may also be influenced by the intrinsic properties of the arteries themselves, resulting in either minimal or aggravated neointima formation. PMID:27759053

  9. Thoracic fat volume is independently associated with coronary vasomotion

    Energy Technology Data Exchange (ETDEWEB)

    Dunet, Vincent; Allenbach, Gilles; Prior, John O. [Lausanne University Hospital, Department of Nuclear Medicine and Molecular Imaging, Lausanne (Switzerland); Feihl, Francois; Dabiri, Amin; Waeber, Bernard [Lausanne University Hospital, Department of Clinical Physiopathology, Lausanne (Switzerland); Heinzer, Raphael [Lausanne University Hospital, Center for Investigation and Research in Sleep, Lausanne (Switzerland)


    Thoracic fat has been associated with an increased risk of coronary artery disease (CAD). As endothelium-dependent vasoreactivity is a surrogate of cardiovascular events and is impaired early in atherosclerosis, we aimed at assessing the possible relationship between thoracic fat volume (TFV) and endothelium-dependent coronary vasomotion. Fifty healthy volunteers without known CAD or major cardiovascular risk factors (CRFs) prospectively underwent a {sup 82}Rb cardiac PET/CT to quantify myocardial blood flow (MBF) at rest, and MBF response to cold pressor testing (CPT-MBF) and adenosine (i.e., stress-MBF). TFV was measured by a 2D volumetric CT method and common laboratory blood tests (glucose and insulin levels, HOMA-IR, cholesterol, triglyceride, hsCRP) were performed. Relationships between CPT-MBF, TFV and other CRFs were assessed using non-parametric Spearman rank correlation testing and multivariate linear regression analysis. All of the 50 participants (58 ± 10y) had normal stress-MBF (2.7 ± 0.6 mL/min/g; 95 % CI: 2.6-2.9) and myocardial flow reserve (2.8 ± 0.8; 95 % CI: 2.6-3.0) excluding underlying CAD. Univariate analysis revealed a significant inverse relation between absolute CPT-MBF and sex (ρ = -0.47, p = 0.0006), triglyceride (ρ = -0.32, p = 0.024) and insulin levels (ρ = -0.43, p = 0.0024), HOMA-IR (ρ = -0.39, p = 0.007), BMI (ρ = -0.51, p = 0.0002) and TFV (ρ = -0.52, p = 0.0001). MBF response to adenosine was also correlated with TFV (ρ = -0.32, p = 0.026). On multivariate analysis, TFV emerged as the only significant predictor of MBF response to CPT (p = 0.014). TFV is significantly correlated with endothelium-dependent and -independent coronary vasomotion. High TF burden might negatively influence MBF response to CPT and to adenosine stress, even in persons without CAD, suggesting a link between thoracic fat and future cardiovascular events. (orig.)

  10. Hepatitis C virus infection and risk of coronary artery disease

    DEFF Research Database (Denmark)

    Roed, Torsten; Lebech, Anne-Mette; Kjaer, Andreas


    Several chronic infections have been associated with cardiovascular diseases, including Chlamydia pneumoniae, human immunodeficiency virus and viral hepatitis. This review evaluates the literature on the association between chronic hepatitis C virus (HCV) infection and the risk of coronary artery...

  11. Oscular system changes and functional state of endothelium in systemic vasculitides

    Directory of Open Access Journals (Sweden)

    N P Shilkina


    Full Text Available Objective. To assess by noninvasive methods degree, character and relationship of structural and functional endothelium state disturbances in different regions of vascular bed in systemic vasculitides. Material and methods. 65 pts with systemic vasculitides were examined: 20 with hemorrhagic vasculitis (HV, 20 — with thromboangitis obliterans (TO, 10 — with polyarteritis nodosa (PN, 15 — with Takayasu arteritis (ТА. 30 conditionally healthy persons were included in the control group. Carotid angioscanning with intima-media complex thickness (IMT measurement and functional tests on brachial artery under sonographic control using SONOS-1500 apparatus with assessment of endothelium-dependent and endothelium- independent vasodilatation were performed. Intracutaneous blood flow was examined by laser Doppler flowmetry with functional tests using LAKK-01 apparatus. Results. Examination of common carotid arteries showed significant increase of IMP in pts with PN and ТА. Pts with HV and TO did not differ from control. Endothelium-dependent vasodilatation was decreased in all groups of pts. The most prominent changes were revealed in ТА and TO. Response to nitroglycerine was normal only in pts with TO. In other groups it was decreased. Endothelium sensitivity to reactive hyperemia was decreased. Hyperemic type of microcirculation prevailed in groups with systemic vasculitides but in HV group microcirculation was mainly normal. Capillary blood flow reserve was significantly lower in PN and TO. Correlation relationship was revealed between main IMP, brachial artery reactivity measures and skin microcirculation. Conclusion. Structural and functional endothelium state disturbances of different regions of vascular bed revealed in systemic vasculitides are interconnected what proves their participation in endothelium damage in these diseases.

  12. Ectopic Origin of Coronary Arteries Diagnozed by Coronary Angiography (United States)

    Krasniqi, Xhevdet; Gorani, Daut; Sejdiu, Basri; Citaku, Hajdin


    Introduction: Anomalous origin of coronary arteries from opposite sinus of Valsalva is rare finding. The incidence of anomalous origination of the left coronary artery from right sinus is 0.15% and the right coronary artery from the left sinus is 0.92%. The ectopic origin of left coronary artery or right coronary artery from opposite sinus depending on pathways and considering atherosclerotic changes are manifested with different clinical significance. Case report: We report two cases, the first case the coronary angiography showed the left coronary artery arising from the right coronary sinus, presenting with proximally and distally stenosed left anterior descending artery (LAD), associated with medial and distal stenosed right coronary artery (RCA). The second case the coronary angiography revealed the right coronary artery arising from the left coronary sinus, associated with tortuous medial and distal segments of left anterior descending artery (LAD), without atherosclerotic changes. The first case successfully underwent treatment procedures based on guidelines for revascularization. Conclusion: The coronary angiography of patients with coronary ischemia determines atherosclerotic disease with possibility of the presence of coronary artery anomalies that in cases with ectopic origin from opposite sinus continues to exist as a challenge during treatment in interventional cardiology. PMID:27482140

  13. Os ramos ventriculares posteriores das artérias coronárias no homem The posterior ventricular branches of the coronary arteries in the human heart

    Directory of Open Access Journals (Sweden)

    José Roberto Ortale


    Full Text Available OBJETIVO: Descrever os ramos ventriculares posteriores no tecido adiposo epicárdico e propor um novo critério de análise da distribuição desses ramos, conforme a classificação tradicional, a fim de determinar a predominância ou o equilíbrio entre as artérias coronárias no suprimento arterial do coração. MÉTODOS: Dissecados 40 corações obtidos de necroscopias de adultos, fixados em solução de formol e a face posterior de cada ventrículo dividida em oito áreas, aproximadamente iguais, para a classificação morfológica da circulação coronariana. Foram considerados os três tipos tradicionais: A dominância da direita, B tipo balanceado e C dominância da esquerda e analisados o número, o diâmetro e as áreas de terminação dos ramos ventriculares posteriores no epicárdio. RESULTADOS: Os ramos verificados e sua freqüência foram: ramo marginal esquerdo - 100%; ramos posteriores do ventrículo esquerdo: lateral - 75%, intermédio - 82,5% e medial - 87,5%; ramo interventricular posterior - 95%; ramos posteriores do ventrículo direito: medial - 40%, intermédio - 32,5% e lateral - 40%; ramo diagonal posterior do ventrículo direito - 17,5%; ramo marginal direito - 95%. Foram encontrados 62,5% de dominância da artéria coronária direita, 25% de tipo balanceado e 12,5% de dominância da coronária esquerda. CONCLUSÃO: O método adotado permitiu-nos uma classificação mais precisa dos casos analisados nos tipos de distribuição coronariana. O tipo de dominância da artéria coronária direita foi o prevalente, seguido do equilíbrio e da dominância esquerda.OBJECTIVE: To describe the trajectory of the posterior ventricular branches of the coronary arteries in the epicardial adipose tissue, and to propose a new criterion for analyzing the distribution of these branches, according to the traditional classification, to determine the predominance or balance of the coronary arteries in the arterial supply to the heart

  14. Coronary artery disease and its association with Vitamin D deficiency

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    Ramesh Aggarwal


    Full Text Available Coronary artery disease (CAD has become the latest scourge of humankind and referred to in this article as CAD, is the end result of the accumulation of atheromatous plaques within the walls of coronary arteries that supply the myocardium, a process also known as atherosclerosis and manifests mostly in the form of chronic stable angina or acute coronary syndrome. Vitamin D has attracted considerable interest recently due to its role in a number of extraskeletal disease processes including multiple sclerosis, malignancies, diabetes mellitus, and CAD. It is also known as sunshine vitamin due to its production in the body following exposure to ultraviolet rays, and it is a unique vitamin as it acts like a hormone with its receptor present in a wide range of tissues including endothelium, which is the important mediator of atherosclerosis and subsequent CAD. A large number of studies conducted in the past have provided the basic scientific framework and this article attempts to explore the role of Vitamin D deficiency in the pathogenesis of CAD and stresses the need for further research to fill up gap in our knowledge.

  15. Pyocyanin inhibits both nitric oxide-dependent and -independent relaxation in porcine coronary arteries. (United States)

    Hempenstall, Allison; Grant, Gary D; Anoopkumar-Dukie, Shailendra; Johnson, Peter J


    The effects of the Pseudomonas aeruginosa virulence factor pyocyanin (PCN) on the contractile function of porcine coronary arteries was investigated in vitro. Artery rings (5 mm) were suspended in organ baths containing Krebs' solution for the measurement of isometric tension. The effect of PCN on resting and precontracted coronary arteries was initially investigated with various agents. Arteries were precontracted with prostaglandin (PG) F2α or potassium chloride and endothelium-dependent relaxations were induced by various agents in the presence of PCN. Pyocyanin (0.1-10 μmol/L) evoked small-amplitude, dose-dependent contractions in resting porcine coronary arteries. In addition, PCN amplified the contractile response to PGF2α , but did not alter responses to carbachol. Pyocyanin (0.1-10 μmol/L) significantly inhibited endothelium-dependent relaxations evoked by neurokinin A. Pyocyanin also inhibited relaxations evoked by diethylamine nitric oxide (a nitric oxide donor), forskolin (an adenylate cyclase activator), dibuytyryl-cAMP (a cAMP analogue), 8-bromo-cGMP (a cGMP analogue) and P1075 (a KATP channel activator), but not isoprenaline (β-adrenoceceptor agonist). These results indicate that physiological concentrations of PCN interfere with multiple intracellular processes involved in vascular smooth muscle relaxation, in particular pathways downstream of nitric oxide release. Thus, PCN may alter normal vascular function in patients infected with P. aeruginosa.

  16. Coronary Artery Disease - Coronary Heart Disease (United States)

    ... result of coronary artery disease, or CAD, said Edward A. Fisher, M.D., Ph.D., M.P. ... Problems and Disease • High Blood Pressure (HBP) • Metabolic Syndrome • Pericarditis • Peripheral Artery Disease (PAD) • Stroke • Vascular Health • ...

  17. Coronary Artery Bypass

    Directory of Open Access Journals (Sweden)

    Kadri Ceberut


    Full Text Available Ancient schwannoma is a rare variant of neural tumors though rarely seen in the thorax. The combination with coronary artery diseases is also rare. Here we describe a 66 year-old male who had undergone one-stage combined surgery for thoracic ancient schwannomas removal and coronary artery disease. The masses were, respectively, 13 cm in the middle mediastinum and 5 cm in diameter originating from the intercostal nerve. The tumors were successfully removed using sternotomy, and then a coronary artery bypass grafting was performed. Here we discuss this rare tumor in relation to the relevant literature.

  18. Endothelium and the effect of activated neutrophils on arterial smooth muscle

    Directory of Open Access Journals (Sweden)

    Bauer Viktor


    Full Text Available The aim of the study was to analyze the involvement of the endothelium in the effects of neutrophils (PMNL on phenylephrine-pre-contracted isolated rings of the rat thoracic aorta and to compare their effects with those of peroxynitrite (ONOO− and hypochlorous acid (HOCl. Activated PMNL-induced contraction of the precontracted aorta was prevented by the blockade of NO-synthase and by endothelium removal. In the endothelium-free preparations, the effect of PMNL reappeared in the presence of sodium nitroprusside. The effect of ONOO− and HOCl significantly differed from that of activated PMNL both in the presence and absence of the endothelium. It is therefore likely that neither ONOO− nor HOCl generated by transformation of superoxide anion radical (O2•− produced by PMNL is involved in their action. Reduction of the relaxant effect of nitric oxide derived from the endothelium by O2•− seems to be the keystone mechanism in generation of PMNL-induced contraction.

  19. Different effects of antisense RelA p65 and NF-κB1 p50 oligonucleotides on the nuclear factor-κB mediated expression of ICAM-1 in human coronary endothelial and smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Both Anton


    Full Text Available Abstract Background Activation of nuclear factor-κB (NF-κB is one of the key events in early atherosclerosis and restenosis. We hypothesized that tumor necrosis factor-α (TNF-α induced and NF-κB mediated expression of intercellular adhesion molecule-1 (ICAM-1 can be inhibited by antisense RelA p65 and NF-κB1 p50 oligonucleotides (RelA p65 and NF-κB1 p50. Results Smooth muscle cells (SMC from human coronary plaque material (HCPSMC, plaque material of 52 patients, SMC from the human coronary media (HCMSMC, human endothelial cells (EC from umbilical veins (HUVEC, and human coronary EC (HCAEC were successfully isolated (HCPSMC, HUVEC, identified and cultured (HCPSMC, HCMSMC, HUVEC, HCAEC. 12 hrs prior to TNF-α stimulus (20 ng/mL, 6 hrs RelA p65 and NF-κB1 p50 (1, 2, 4, 10, 20, and 30 μM and controls were added for a period of 18 hrs. In HUVEC and HCAEC there was a dose dependent inhibition of ICAM-1 expression after adding of both RelA p65 and NF-κB1 p50. No inhibitory effect was seen after incubation of HCMSMC with RelA p65 and NF-κB1 p50. A moderate inhibition of ICAM-1 expression was found after simultaneous addition of RelA p65 and NF-κB1 p50 to HCPSMC, no inhibitory effect was detected after individual addition of RelA p65 and NF-κB1 p50. Conclusions The data point out that differences exist in the NF-κB mediated expression of ICAM-1 between EC and SMC. Experimental antisense strategies directed against RelA p65 and NF-κB1 p50 in early atherosclerosis and restenosis are promising in HCAEC but will be confronted with redundant pathways in HCMSMC and HCPSMC.

  20. Endothelial Nlrp3 inflammasome activation associated with lysosomal destabilization during coronary arteritis. (United States)

    Chen, Yang; Li, Xiang; Boini, Krishna M; Pitzer, Ashley L; Gulbins, Erich; Zhang, Yang; Li, Pin-Lan


    Inflammasomes play a critical role in the development of vascular diseases. However, the molecular mechanisms activating the inflammasome in endothelial cells and the relevance of this inflammasome activation is far from clear. Here, we investigated the mechanisms by which an Nlrp3 inflammasome is activated to result in endothelial dysfunction during coronary arteritis by Lactobacillus casei (L. casei) cell wall fragments (LCWE) in a mouse model for Kawasaki disease. Endothelial dysfunction associated with increased vascular cell adhesion protein 1 (VCAM-1) expression and endothelial-leukocyte adhesion was observed during coronary arteritis in mice treated with LCWE. Accompanied with these changes, the inflammasome activation was also shown in coronary arterial endothelium, which was characterized by a marked increase in caspase-1 activity and IL-1β production. In cultured endothelial cells, LCWE induced Nlrp3 inflammasome formation, caspase-1 activation and IL-1β production, which were blocked by Nlrp3 gene silencing or lysosome membrane stabilizing agents such as colchicine, dexamethasone, and ceramide. However, a potassium channel blocker glibenclamide or an oxygen free radical scavenger N-acetyl-l-cysteine had no effects on LCWE-induced inflammasome activation. LCWE also increased endothelial cell lysosomal membrane permeability and triggered lysosomal cathepsin B release into cytosol. Silencing cathepsin B blocked LCWE-induced Nlrp3 inflammasome formation and activation in endothelial cells. In vivo, treatment of mice with cathepsin B inhibitor also abolished LCWE-induced inflammasome activation in coronary arterial endothelium. It is concluded that LCWE enhanced lysosomal membrane permeabilization and consequent release of lysosomal cathepsin B, resulting in activation of the endothelial Nlrp3 inflammasome, which may contribute to the development of coronary arteritis.

  1. The effect of mepivacaine on swine lingual, pulmonary and coronary arteries. (United States)

    Satoh, Kenichi; Chikuda, Mami; Ohashi, Ayako; Kumagai, Miho; Sato, Masahito; Joh, Shigeharu


    Although mepivacaine has a known biphasic action on the aortic and coronary artery in several animal species, its effects on the lingual and pulmonary artery are not well understood and it is not yet known whether mepivacaine produces vasoconstriction in these vessels. The present study aims to investigate the direct effects of mepivacaine on swine lingual, pulmonary and coronary arterial endothelium-denuded rings. Artery rings were perfused with isotonic 40 mM KCl until a stable constricted plateau was reached. The rings were then perfused with isotonic 40 mM KCl plus a particular concentration of mepivacaine (0.4 μM, 4.0 μM, 40 μM, 0.4 mM and 4.0 mM). The isometric tension strengths in each experiment were normalized to the strength of the isometric tension immediately before mepivacaine perfusion and expressed as a percentage. Mepivacaine at 0.4 to 40 μM did not significantly alter 40 mM KCl-induced contraction in the lingual, pulmonary and coronary arterial rings. In contrast, mepivacaine at 4 mM produced attenuated vasoconstriction in the lingual, pulmonary and coronary arterial compared with isotonic 40 mM KCl. Mepivacaine produced vasoconstriction at lower concentrations, followed by attenuated vasoconstriction at higher concentrations on swine lingual, pulmonary and coronary arterial endothelium-denuded rings. Mepivacaine (4 μM) appeared to increase isotonic 40 mM KCl-induced contraction, followed by attenuated vasoconstriction at 4 mM. Dentists using 3 % mepivacaine should take into consideration that the risk of complications may be increased if more than six mepivacaine cartridges are used in dental treatment or minor surgery, or if over 15 ml of mepivacaine is administered to a patient with cardiovascular complications during general anesthesia for oral maxillofacial surgery.

  2. Pathology of Coronary Chronic Total Occlusion

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    Kenichi Sakakura


    Full Text Available There is an increasing need for percutaneous revascularization procedures of coronary Chronic Total Occlusion (CTO, because many patients with severe coronary artery disease have limited options for revascularization. Although the success rate of percutaneous revascularization of CTOs was unsatisfactory from the 1990s to the 2000s, recent technological advances in interventional strategies have improved the success rate to 85%. Detailed histological assessment of human autopsy studies of CTO has contributed significantly to the refinement in Percutaneous Coronary Intervention (PCI techniques and device development. We have recently reported the pathological findings and characteristics of CTOs that occur in different clinical scenarios. In this review, we discuss the pathology of CTOs to facilitate greater understanding of revascularization strategies for CTOs.

  3. Coronary artery spasm (United States)

    ... Saunders; 2016:chap 71. Giugliano RP, Cannon CP, Braunwald E. Non-ST elevation acute coronary syndromes In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of ...

  4. Auxetic coronary stent endoprosthesis

    DEFF Research Database (Denmark)

    Amin, Faisal; Ali, Murtaza Najabat; Ansari, Umar;


    BACKGROUND: Cardiovascular heart disease is one of the leading health issues in the present era and requires considerable health care resources to prevent it. The present study was focused on the development of a new coronary stent based on novel auxetic geometry which enables the stent to exhibit...... a negative Poisson's ratio. Commercially available coronary stents have isotropic properties, whereas the vascular system of the body shows anisotropic characteristics. This results in a mismatch between anisotropic-isotropic properties of the stent and arterial wall, and this in turn is not favorable...... for mechanical adhesion of the commercially available coronary stents with the arterial wall. It is believed that an auxetic coronary stent with inherent anisotropic mechanical properties and negative Poisson's ratio will have good mechanical adhesion with the arterial wall. METHODS: The auxetic design...

  5. Coronary Artery Disease (United States)

    Coronary artery disease (CAD) is the most common type of heart disease. It is the leading cause of death ... happens when the arteries that supply blood to heart muscle become hardened and narrowed. This is due ...

  6. Electrical coupling between smooth muscle and endothelium in arterioles of the guinea-pig small intestine (United States)

    Crane, G. J.; Kotecha, N.; Luff, S. E.; Neild, T. O.


    Equations describing the steady-state passive electrical properties of arterioles have been derived. The arteriole was modelled as having two thin layers of cells (muscle and endothelium) with strong electrical coupling between cells within a layer and variable coupling between the layers. The model indicated that spread of membrane potential changes was highly dependent on the thickness of cells within the layers. The model was also used to identify the optimal experimental strategy for detecting coupling between the two layers, and experiments were carried out on arterioles from the guinea-pig small intestine. Thickness of the endothelial layer was measured using electron microscopy and was found to be around 0.5 μm. Electrical input resistance was measured in intact arterioles and compared to input resistance of arterioles from which the endothelium had been removed. The experiments confirmed that there was a strong electrical coupling between the muscle and endothelium in these vessels.

  7. Coronary heart disease

    Institute of Scientific and Technical Information of China (English)


    2008042 Analysis of coronary artery lesion characteristics and its clinical implications in patients with acute non-ST-segment elevation myocardial infarction. BAI Taizhu(柏太柱), et al. Cardiovasc Dept, Hengyang Centr Hosp & Hengyang Cardiovasc Intervention Center, Hengyang 421001. Chin J Arterioscler 2007;15(10):780-782. Objective To investigate the coronary artery lesion characteristics and its clinical implications in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI).

  8. Coronary heart disease

    Institute of Scientific and Technical Information of China (English)


    2008277 Relationship between pulse wave velocity and the NYHA classification of coronary insufficiency.SUN Weiping(孙卫平),et al.Dept Cardiol,Tongji Hosp Tongji Univ,Shanghai 200065.Chin J Intern Med 2008;47(5):382-384.Objective To investigate the relationship between brachial-ankle pulse wave velocity(baPWV)and different stage of cardiac dysfunction.Methods 253 consecutive patients with coronary atherosclerotic heart disease

  9. Large coronary intramural hematomas

    DEFF Research Database (Denmark)

    Antonsen, Lisbeth; Thayssen, Per; Jensen, Lisette Okkels


    coronary vessel wall pathology, with poorly understood underlying pathogenic mechanisms. Affected individuals may present with a broad spectrum of symptoms ranging from acute coronary syndromes (ACS) to cardiogenic shock or even sudden cardiac death. The disease entity causes challenges in terms of both......, no randomized, controlled trials exist to guide treatment, and no consensus regarding management is available. Currently, treatment strategies are based on a case-by-case clinical assessment, and experiences described in previous, limited retrospective studies and case reports....

  10. Coronary Fistulas: A Case Series

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    Nada Fennich


    Full Text Available Coronary artery fistula is an uncommon finding during angiographic exams. We report a case series of five patients with congenital coronary fistulas. The first patient was 56 years old and had a coronary fistula associated with a partial atrio ventricular defect, the second patient was 54 years old and had two fistulas originating from the right coronary artery with a severe atherosclerotic coronary disease, the third patient was 57 years old with a fistula originating from the circumflex artery associated with a rheumatic mitral stenosis, the fourth patient was 50 years old and had a fistulous communication between the right coronary artery and the right bronchial artery, and the last patient was 12 years old who had bilateral coronary fistulas draining into the right ventricle with an aneurismal dilatation of the coronary arteries. Angiographic aspects of coronary fistulas are various; management is controversial and depends on the presence of symptoms.

  11. Biocompatibility of Coronary Stents

    Directory of Open Access Journals (Sweden)

    Thamarasee M. Jeewandara


    Full Text Available Cardiovascular disease is the dominant cause of mortality in developed countries, with coronary artery disease (CAD a predominant contributor. The development of stents to treat CAD was a significant innovation, facilitating effective percutaneous coronary revascularization. Coronary stents have evolved from bare metal compositions, to incorporate advances in pharmacological therapy in what are now known as drug eluting stents (DES. Deployment of a stent overcomes some limitations of balloon angioplasty alone, but provides an acute stimulus for thrombus formation and promotes neointimal hyperplasia. First generation DES effectively reduced in-stent restenosis, but profoundly delay healing and are susceptible to late stent thrombosis, leading to significant clinical complications in the long term. This review characterizes the development of coronary stents, detailing the incremental improvements, which aim to attenuate the major clinical complications of thrombosis and restenosis. Despite these enhancements, coronary stents remain fundamentally incompatible with the vasculature, an issue which has largely gone unaddressed. We highlight the latest modifications and research directions that promise to more holistically design coronary implants that are truly biocompatible.

  12. Role of non-nitric oxide non-prostaglandin endothelium-derived relaxing factor(s in bradykinin vasodilation

    Directory of Open Access Journals (Sweden)

    A.C. Resende


    Full Text Available The most conspicuous effect of bradykinin following its administration into the systemic circulation is a transient hypotension due to vasodilation. In the present study most of the available evidence regarding the mechanisms involved in bradykinin-induced arterial vasodilation is reviewed. It has become firmly established that in most species vasodilation in response to bradykinin is mediated by the release of endothelial relaxing factors following the activation of B2-receptors. Although in some cases the action of bradykinin is entirely mediated by the endothelial release of nitric oxide (NO and/or prostacyclin (PGI2, a large amount of evidence has been accumulated during the last 10 years indicating that a non-NO/PGI2 factor accounts for bradykinin-induced vasodilation in a wide variety of perfused vascular beds and isolated small arteries from several species including humans. Since the effect of the non-NO/PGI2 endothelium-derived relaxing factor is practically abolished by disrupting the K+ electrochemical gradient together with the fact that bradykinin causes endothelium-dependent hyperpolarization of vascular smooth muscle cells, the action of such factor has been attributed to the opening of K+ channels in these cells. The pharmacological characteristics of these channels are not uniform among the different blood vessels in which they have been examined. Although there is some evidence indicating a role for KCa or KV channels, our findings in the mesenteric bed together with other reports indicate that the K+ channels involved do not correspond exactly to any of those already described. In addition, the chemical identity of such hyperpolarizing factor is still a matter of controversy. The postulated main contenders are epoxyeicosatrienoic acids or endocannabinoid agonists for the CB1-receptors. Based on the available reports and on data from our laboratory in the rat mesenteric bed, we conclude that the NO/PGI2-independent endothelium

  13. Association of cytokines with endothelium dependent flow mediated vasodilation (FMD of systemic arteries in patients with non-ischemic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Kazak Ilkay


    Full Text Available Abstract Background Aim of this study was to elucidate the relation between localised inflammatory heart disease and endothelial dysfunction in the peripheral circulation, considering circulating cytokines as a potential link. Methods In 38 patients with non-ischemic heart disease, myocardial biopsies were examined for myocardial inflammation (immunohistology and virus persistence (PCR. Cytokines (sIL-4, IFN-g, IFN-b, IFN-a, sIL-12p7, TNF-a were measured by ELISA in venous serum. Endothelial function of the radial artery was examined by ultrasound, measuring diameter changes in response to reactive hyperemia (FMD, compared to glyceroltrinitrate (GTN-MD. Patients with EF Results Age 44 ± 14 years, 19 male, 19 female, EF 63.5[16]%. FMD 4.38 [4.82]%. 30 patients had myocardial inflammation (8 not, 23 virus persistence (15 not. FMD correlated significantly with sIL-12p7 (p = 0.024, r = -0.365, but not with other cytokines. sIL-12p7 levels were significantly higher in patients with severely impaired FMD (n = 17, compared with normal FMD (n = 21: 10.70 [10.72] vs. 4.33 [7.81] pg/ml (p = 0.002. Endothelium independent vasodilation (GTN-MD 23.67 [8.21]% was not impaired. Conclusion Endothelial dysfunction of peripheral arteries in patients with non-ischemic cardiomyopathy is associated with elevated serum concentrations of sIL-12p7, but not of other cytokines. Circulating sIL-12p7 may partly explain, that endothelial dysfunction is not restricted to the coronary circulation, but involves systemic arteries.

  14. 人胎冠状动脉原位杂交c-myc和jun原癌基因表达%Expression of proto - oncogenes c - myc and jun in human coronary artery ruring development

    Institute of Scientific and Technical Information of China (English)

    蔡维君; 陈新平; 伍校琼; 罗学港


    目的研究原癌基因c-myc和jun在人胎冠状动脉发育过程中的表达与平滑肌细胞增殖的关系.方法用原位杂交方法检测,胎龄分别为16周、22周(因治疗需要引产)的胎儿和意外死亡的足月胎儿冠状动脉前降支c-myc mRNA和jun mRNA的表达水平.杂交反应产物用图像分析仪(MIAS300)作定量分析.结果C-myc mRNA原位杂交反应产物与被测血管区域面积的百分比在16周、22周和足月胎儿分别是70、56和10;Jun mRNA的杂交信反应产物与被测血管区域面积的百分比在这三个时期分别是68、53和8.两个原癌基因在不同阶段的表达均具有显著性差异.结论本实验首次报道c-myc和jun在人胎冠状动脉发育过程中平滑肌的表达图型,c-myc和jun在胎儿冠状动脉平滑肌细胞增殖和内膜的形成过程中可能具有重要的调控作用.%Objective: To investigate the expression of protooncogenes, c - myc and jun, in human coronary artery during development. Methods: In situ hybridization was employed to detect c - myc mRNA and jun mRNA in human coronary artery from aborted fetus with embryonic ages from week 16 to 22 due to treatment requirements. In addition, 3 cases of full term human fetus died of accident were also studied. Hybridized signals were quantified with a computer - assisted image - analyzing system ( MIAS 300 ). Results: The ratio of hybridized signal of c - myc to the area of vascular wall detected were 0.7, 0.54 and 0.10 respectively corresponding to the embryonic ages, 16 weeks,22 weeks and full term. Similar results with the ratio of 0.68, 0.53 and 0.08 for jun mRNA at above embryonic ages was also found. The levels of c - myc and jun mRNA expressed at different embryonic stage showed a significant difference. Conclusions: We first reported the expression of proto - oncogenes, c - myc and jun, in human coronary artery during embryonic development. These two proto - oncogenes may play an important role in the

  15. Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat. (United States)

    Bunker, Aaron K; Arce-Esquivel, Arturo A; Rector, R Scott; Booth, Frank W; Ibdah, Jamal A; Laughlin, M Harold


    We tested the hypothesis that physical activity can attenuate the temporal decline of ACh-induced endothelium-dependent relaxation during type 2 diabetes mellitus progression in the Otsuka Long-Evans Tokushima fatty (OLETF) rat. Sedentary OLETF rats exhibited decreased ACh-induced abdominal aortic endothelium-dependent relaxation from 13 to 20 wk of age (20-35%) and from 13 to 40 wk of age (35-50%). ACh-induced endothelium-dependent relaxation was maintained in the physically active OLETF group and control sedentary Long-Evans Tokushima Otsuka (LETO) group from 13 to 40 wk of age. Aortic pretreatment with N(G)-nitro-l-arginine (l-NNA), indomethacin (Indo), and l-NNA + Indo did not alter the temporal decline in ACh-induced endothelium-dependent relaxation. Temporal changes in the protein expression of SOD isoforms in the aortic endothelium or smooth muscle did not contribute to the temporal decline in ACh-induced endothelium-dependent relaxation in sedentary OLETF rats. A significant increase in the 40-wk-old sedentary LETO and physically active OLETF rat aortic phosphorylated endothelial nitric oxide (p-eNOS)-to-eNOS ratio was observed versus 13- and 20-wk-old rats in each group that was not seen in the 40- versus 13- and 20-wk-old sedentary OLETF rats. These results suggest that temporal changes in the antioxidant system, EDHF, and cycloxygenase metabolite production in sedentary OLETF rat aortas do not contribute to the temporal decline in sedentary OLETF rat aortic ACh-induced endothelium-dependent relaxation seen with type 2 diabetes mellitus progression. We also report that physical activity in conjunction with aging in the OLETF rat results in a temporal increase in the aortic endothelial p-eNOS-to-eNOS ratio that was not seen in sedentary OLETF rats. These results suggest that the sustained aortic ACh-induced endothelium-dependent relaxation in aged physically active OLETF rats may be the result of an increase in active aortic eNOS.

  16. Coronary Artery Imaging in Children (United States)


    Coronary artery problems in children usually have a significant impact on both short-term and long-term outcomes. Early and accurate diagnosis, therefore, is crucial but technically challenging due to the small size of the coronary artery, high heart rates, and limited cooperation of children. Coronary artery visibility on CT and MRI in children is considerably improved with recent technical advancements. Consequently, CT and MRI are increasingly used for evaluating various congenital and acquired coronary artery abnormalities in children, such as coronary artery anomalies, aberrant coronary artery anatomy specific to congenital heart disease, Kawasaki disease, Williams syndrome, and cardiac allograft vasculopathy. PMID:25741188

  17. Distal coronary hemoperfusion during percutaneous transluminal coronary angioplasty

    NARCIS (Netherlands)

    deMuinck, ED; denHeijer, P; vanDijk, RB; Crijns, HJGM; Hillige, HL; Lie, KI


    Distal coronary hemoperfusion during percutaneous transluminal coronary angioplasty (PTCA)-with an autoperfusion balloon or active system-facilitates prolonged balloon inflation. Prolonged inflations may tack up intimal dissections and improve the primary angioplasty result in complex lesions. Addit

  18. Targeted Delivery of Neutralizing Anti-C5 Antibody to Renal Endothelium Prevents Complement-Dependent Tissue Damage

    Directory of Open Access Journals (Sweden)

    Paolo Durigutto


    Full Text Available Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process. To this end, we generated Ergidina, a neutralizing recombinant anti-C5 human antibody coupled with a cyclic-RGD peptide, with a distinctive homing property for ischemic endothelial cells and effective in controlling tissue damage in a rat model of renal ischemia/reperfusion injury (IRI. As a result of its preferential localization on renal endothelium, the molecule induced complete inhibition of complement activation at tissue level, and local protection from complement-mediated tissue damage without affecting circulating C5. The ex vivo binding of Ergidina to surgically removed kidney exposed to cold ischemia supports its therapeutic use to prevent posttransplant IRI leading to delay of graft function. Moreover, the finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this RGD-targeted anti-C5 antibody may represent a useful tool to treat organs prior to transplantation. Based on this evidence, we propose preliminary data showing that Ergidina is a novel targeted drug to prevent complement activation on the endothelium of ischemic kidney.

  19. Maternal smoking and impaired endothelium-dependent nitric oxide-mediated relaxation of uterine small arteries in vitro

    DEFF Research Database (Denmark)

    Andersen, Malene R; Uldbjerg, Niels; Stender, Steen;


    This study aimed to investigate the endothelium-dependent relaxation of uterine small arteries from pregnant nonsmokers, smokers, and ex-smokers who stopped smoking early in pregnancy.......This study aimed to investigate the endothelium-dependent relaxation of uterine small arteries from pregnant nonsmokers, smokers, and ex-smokers who stopped smoking early in pregnancy....

  20. Dual anterior descending coronary artery associated with coronary artery disease

    Directory of Open Access Journals (Sweden)

    Siqueira Luciane da L. V.


    Full Text Available The patient is a male with risk factors for coronary artery disease, who was referred for cardiac catheterization after acute myocardial infarction in the inferior wall. The patient underwent transluminal coronary angioplasty in the right coronary artery with successful stent implantation.

  1. Distal coronary hemoperfusion during percutaneous transluminal coronary angioplasty

    NARCIS (Netherlands)

    Muinck, Ebo Derk de


    In this thesis several aspects of passive and active coronary perfusion during coronary angioplasty are investigated. The autoperfusion balloon catheters that were evaluated are the Stack® and the RX-60® catheters (Advanced Cardiovascular Systems, inc., Santa Clara, California, U.S.A). The coronary

  2. Distal coronary hemoperfusion during percutaneous transluminal coronary angioplasty

    NARCIS (Netherlands)

    Muinck, Ebo Derk de


    In this thesis several aspects of passive and active coronary perfusion during coronary angioplasty are investigated. The autoperfusion balloon catheters that were evaluated are the Stack® and the RX-60® catheters (Advanced Cardiovascular Systems, inc., Santa Clara, California, U.S.A). The coronary

  3. Delayed insulin transport across endothelium in insulin-resistant JCR:LA-cp rats. (United States)

    Wascher, T C; Wölkart, G; Russell, J C; Brunner, F


    Capillary endothelial cells are thought to limit the transport of insulin across the endothelium, resulting in attenuated insulin action at target sites. Whether endothelial insulin transport is altered in dysglycemic insulin-resistant states is not clear and was therefore investigated in the JCR:LA-cp corpulent male rat, which exhibits the metabolic syndrome of obesity, insulin resistance, hyperlipidemia, and hyperinsulinemia. Lean littermates that did not develop these alterations served as controls. Animals of both groups were normotensive (mean arterial pressure 136+/-2 mmHg). Hearts from obese and lean rats aged 7 (n = 6) or 18 (n = 8) weeks were perfused in vitro at 10 ml/min per gram wet wt over 51 min with Krebs-Henseleit buffer containing 0.1 or 0.5 U human insulin/l (equivalent to 0.6 and 3 nmol/l). Interstitial fluid was collected using a validated method, and interstitial insulin was determined with a radioimmunoassay. At 0.1 U/l, insulin transfer velocity was similar in both experimental groups (half-times of transfer: 11+/-0.2 min in obese and 18+/-4 min in lean rats; NS), but at 0.5 U/l, the respective half-times were 7+/-1 min in lean and 13+/-2 min in obese rats (P < 0.05). The steady-state level of insulin in the interstitium was 34+/-1% of the vascular level at 0.1 U/l and reached the vascular level (102+/-2%) at 0.5 U/l in both lean and obese rats. In rats aged 18 weeks, the half-times of insulin transfer were 31+/-2 and 14+/-l min in obese rats and 10+/-0.3 and 7+/-0.3 min in lean rats (P < 0.05). Again, interstitial steady-state levels were similar in both groups. Finally, postprandial insulin dynamics were simulated over a period of 120 min with a peak concentration of 0.8 U/l in rats aged 27 weeks (n = 4). The maximal interstitial level was 0.38+/-0.02 U/l in lean rats and 0.24+/-0.02 U/l in obese rats (P < 0.05), and a similar difference was noted throughout insulin infusion (areas under the transudate concentration-time curves: 17 and 11 U


    NARCIS (Netherlands)



    Background. In humans, angiotensin converting enzyme (ACE) inhibition attenuates the vasoconstriction induced by sympathetic stimulation in a number of peripheral districts. Whether this is also the case in the coronary circulation is unknown, however. Methods and Results. In nine normotensive patie

  5. Influence of habitual high dietary fat intake on endothelium-dependent vasodilation. (United States)

    Dow, Caitlin A; Stauffer, Brian L; Greiner, Jared J; DeSouza, Christopher A


    High-fat diets are associated with an increased risk of cardiovascular disease. A potential underlying mechanism for the increased cardiovascular risk is endothelial dysfunction. Nitric oxide (NO)-mediated endothelium-dependent vasodilation is critical in the regulation of vascular tone and overall vascular health. The aim of this study was to determine the influence of dietary fat intake on endothelium-dependent vasodilation. Forty-four middle-aged and older sedentary, healthy adults were studied: 24 consumed a lower fat diet (LFD; 29% ± 1% calories from fat) and 20 consumed a high-fat diet (HFD; 41% ± 1% calories from fat). Four-day diet records were used to assess fat intake, and classifications were based on American Heart Association guidelines (vasodilator response to sodium nitroprusside. These data indicate that a high-fat diet is associated with endothelium-dependent vasodilator dysfunction due, in part, to diminished NO bioavailability. Impaired NO-mediated endothelium-dependent vasodilation may contribute to the increased cardiovascular risk with high dietary fat intake.

  6. Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury

    DEFF Research Database (Denmark)

    Hagensen, Mette; Raarup, Merete Krog; Mortensen, Martin Bødtker


    (GFP) in ECs. We found that the endothelium regenerated with GFP(+) ECs as a function of time, evolving from the anastomosis sites towards the centre of the transplant. A migration front of ECs at Day 7 was verified by scanning electron microscopy and by bright-field microscopy using recipient TIE2-lacZ...

  7. Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta. (United States)

    Carrasco, Omar F; Vidrio, Horacio


    The triterpene saponin escin is the active component of the extract of seeds of Aesculus hippocastanum used in the treatment of chronic venous insufficiency. Escin is also used experimentally to increase membrane permeability in isolated cells. Since endothelial dysfunction is postulated to be involved in venous insufficiency, the possible endothelium-protectant effect of escin was explored in rat aortic rings, a model widely used to study such effects with cardiovascular agents. Escin enhanced endothelium-dependent relaxation induced by acetylcholine when such relaxation had been reduced by exposure to the superoxide ion generator pyrogallol. This effect was attributed to enhanced nitric oxide production by endothelial nitric oxide synthase, a calcium-dependent enzyme, activated by the increased endothelial cell permeability to calcium induced by escin. Another effect of escin thought to contribute to its therapeutic activity is its ability to produce venous contraction. The compound was found to induce concentration-related contraction also in rat aortic rings. This response was partially inhibited by removal of the endothelium or by preincubation with indomethacin, and was completely abolished by incubation in a calcium-free perfusion fluid. Contraction was considered to be due mainly to the aforementioned effect on calcium permeability, with some mediation by release of endothelial vasoconstrictor prostanoids. It was concluded that, in rat aorta, escin possesses an endothelium-protectant action and a direct contractile effect. The former could contribute to its beneficial effect in the treatment of venous insufficiency, while the latter could constitute a limiting side effect.

  8. L-Carnitine supplementation impairs endothelium-dependent relaxation in mesenteric arteries from rats. (United States)

    Valgas da Silva, Carmem P; Rojas-Moscoso, Julio A; Antunes, Edson; Zanesco, Angelina; Priviero, Fernanda B M


    L-Carnitine (L-Car) is taken as fat burner. The risks of L-Car supplementation for the cardiovascular system are unclear. We evaluated the relaxing responses of the mesenteric and aorta rings from rats after four weeks of L-Car supplementation and/or physical training. Concentration response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), as well as cyclic GMP levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) were evaluated. Physical training decreased body weight gain that was potentiated by L-Car. In mesenteric rings, L-Car impaired endothelium-dependent relaxation whereas endothelium independent relaxation was increased. In aorta, exercise improved endothelium-dependent relaxation; however, it was partially inhibited by L-Car. SNP-induced relaxation was similar in aorta of all groups. Basal cGMP were increased in aorta of exercised rats. SOD activity and MDA levels were unaltered. In conclusion, L-Car and physical exercise promotes body weight loss; however, it impairs endothelium-dependent vaso-relaxation possibly involving alterations in muscarinic receptors/eNOS/NO signalling pathway in mesenteric artery.

  9. Current Indications for Coronary Arteriography


    Dodek, Arthur


    Coronary arteriography is not necessary in all patients with angina pectoris. Angiography is indicated to define coronary anatomy in patients who have persistent angina despite full medication. It is also indicated in patients with a markedly positive stress test, unstable angina pectoris, positive stress test following myocardial infarction, variants of angina, ventricular aneurysm complications, and in the young coronary patient. Coronary arteriography may clarify the diagnosis in patients ...

  10. Lack of association between connexin40 polymorphisms and coronary artery disease

    NARCIS (Netherlands)

    Pfenniger, Anna; van der Laan, Sander W.; Foglia, Bernard; Dunoyer-Geindre, Sylvie; Haefliger, Jacques-Antoine; Winnik, Stephan; Mach, Francois; Pasterkamp, Gerard; James, Richard W.; Kwak, Brenda R.


    Objective: Cx40 is a gap junction protein important for cell-cell communication in the endothelium. Polymorphisms in the promoter region of the human Cx40 gene, -44G>A and +71A>G, were shown to reduce Cx40 transcription by half. As mice with an endothelial-specific deletion of Cx40 are more suscepti

  11. Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes.

    Directory of Open Access Journals (Sweden)

    Sai Wang Seto

    Full Text Available BACKGROUND: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA reductase inhibitors consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown. METHODS: Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca(2+]i, [ATP]i and [glucose]o uptake measurements. RESULTS: The cromakalim (10 nM to 10 µM- and pinacidil (10 nM to 10 µM-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 µM. Simvastatin (1, 3 and 10 µM suppressed (in okadaic acid (10 nM-sensitive manner cromakalim (10 µM- and pinacidil (10 µM-mediated opening of whole-cell KATP channels of arterial myocytes. Simvastatin (10 µM and AICAR (1 mM elicited a time-dependent, compound C (1 µM-sensitive [(3H]-2-deoxy-glucose uptake and an increase in [ATP]i levels. A time (2-30 min- and concentration (0.1-10 µM-dependent increase by simvastatin of p-AMPKα-Thr(172 and p-PP2A-Tyr(307 expression was observed. The enhanced p-AMPKα-Thr(172 expression was inhibited by compound C, ryanodine (100 µM and KN93 (10 µM. Simvastatin-induced p-PP2A-Tyr(307 expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM, ouabain (10 µM, and in [glucose]o-free or [Na(+]o-free conditions. CONCLUSIONS: Simvastatin causes ryanodine-sensitive Ca(2+ release which is important for AMPKα-Thr(172 phosphorylation via Ca(2+/CaMK II. AMPKα-Thr(172 phosphorylation causes [glucose]o uptake (and an [ATP]i increase, closure of KATP channels, and phosphorylation of AMPKα-Thr(172 and PP2A-Tyr(307 resulted. Phosphorylation of PP2A-Tyr(307 occurs at a site downstream of AMPKα-Thr(172 phosphorylation.

  12. What Is Coronary Heart Disease? (United States)

    ... from the NHLBI on Twitter. What Is Coronary Heart Disease? Español Coronary heart disease (CHD) is a disease in which a waxy ... medical procedures can help prevent or treat coronary heart disease. These treatments may reduce the risk of related ...

  13. Nuclear cardiology and coronary surgery

    DEFF Research Database (Denmark)

    Eckardt, R.; Andersen, L.I.; Hesse, B.


    Rising age, repeated percutaneous coronary revascularizations, and co-morbidity such as overweight, diabetes, and hypertension, characterize a change over the last 20-30 years in coronary patients referred to coronary artery bypass grafting (CABG). This patient group represents a great part of to...

  14. YKL-40 a new biomarker in patients with acute coronary syndrome or stable coronary artery disease

    DEFF Research Database (Denmark)

    Wang, Y.Z.; Ripa, R.S.; Johansen, J.S.;


    Background. YKL-40 is involved in remodelling and angiogenesis in non-cardiac inflammatory diseases. Aim was to quantitate plasma YKL-40 in patients with ST-elevation myocardial infarction (STEMI) or stable chronic coronary artery disease (CAD), and YKL-40 gene activation in human myocardium....... Methods and results. We included 73 patients: I) 20 patients with STEMI; II) 28 patients with stable CAD; III) 15 CAD patients referred for coronary by-pass surgery. YKL-40 mRNA expression was measured in myocardium subtended by stenotic or occluded arteries and areas with no apparent disease; and IV) 10...

  15. Role of endothelium in angiotensin II formation by the rat aorta and mesenteric arterial bed

    Directory of Open Access Journals (Sweden)

    R. Leite


    Full Text Available We investigated the angiotensin II (Ang II-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin I (Ang I, and tetradecapeptide (TDP renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM. The angiotensin converting enzyme (ACE inhibitor captopril (36 µM completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 µM significantly reduced (80-90% the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95% the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition

  16. Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese Zucker rats.

    Directory of Open Access Journals (Sweden)

    Nubia S Lobato

    Full Text Available Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs and their lean counterparts (LZRs were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS, AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.

  17. The role of oxidative stress in acetylcholine-induced relaxation of endothelium-denuded arteries. (United States)

    Cacanyiova, S; Dovinova, I; Kristek, F


    Nitric oxide (NO) is produced in the endothelium in response to vasorelaxants, such as acetylcholine, and acts on vascular smooth muscle cells to induce vasorelaxation. Previously, we found that the smooth muscle of endothelium-denuded arteries expresses functional NO synthase. We hypothesized that the destruction of arterial anatomical integrity induced by denuding arteries of their endothelial layers causes the vessels to become insensitive to vasodilators as a consequence of oxidative stress. In this study, we examined whether the acetylcholine-induced vasorelaxation observed in deendothelialized arteries is mediated by NO and/or affected by oxidative stress. For functional relaxation studies, the isolated thoracic aorta and pulmonary artery of male Wistar rats were used. Vessel superoxide production was assessed in preserved and endothelium-denuded arteries by the lucigenin chemiluminescence method. In all arteries with intact endothelia, acetylcholine evoked vasorelaxation; this effect was inhibited in endothelium-denuded rings. Pretreatment of denuded rings with the free-radical scavenger tempol improved acetylcholine-induced relaxation. This effect was inhibited by the coadministration of 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ), an inhibitor of guanylate cyclase, or N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of NO synthase. The chemiluminescent assay revealed that endothelial denudation of both vessel types increased the production of superoxide radicals which has been decreased after tempol administration. Our results show that non-endothelial NO could represent an additional source of physiologically active NO and that the insensitivity of endothelium-denuded vessels to vasodilators could be a consequence of oxidative stress. These findings question the concept that endothelial cells play an obligatory role in vasorelaxation.

  18. Ambulatory blood pressure monitoring and endothelium-dependent vasodilation in the elderly athletes. (United States)

    Galetta, F; Franzoni, F; Plantinga, Y; Ghiadoni, L; Rossi, M; Prattichizzo, F; Carpi, A; Taddei, S; Santoro, G


    Regular exercise is a key component of cardiovascular risk prevention strategies, because it is associated with a variety of beneficial metabolic and vascular effects that reduce mortality and the incidence of cardiovascular adverse events. Endothelium plays an important role in the local regulation of vascular tone and structure, mainly by nitric oxide (NO) synthesis and action. Aim of the present study was to evaluate in elderly athletes the effect of regular aerobic exercise on arterial blood pressure (BP) and on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery. The study population included 30 male subjects (mean age 65.6+/-5.6 years), who had practiced endurance running at a competitive level for at least 40 years, and 28 age- and sex-matched subjects (mean age 64.5+/-4.5 years) with sedentary lifestyle and free of cardiovascular disease. Athletes and control subjects underwent standard 12-lead ECG, clinic BP, 24-h ambulatory BP monitoring and endothelium-dependent FMD and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, in the brachial artery by high-resolution ultrasonography. Systolic clinic and ambulatory 24-h BP were significantly lower in the athletes, than in the controls (Pathletes (Pathletes also had a lower 24-h, day-time and night-time heart rate (HR) (Pathletes (Pathletes showed higher FMD than elderly sedentary subjects (Pphysical activity can counteract the age-related endothelial dysfunction that characterizes sedentary aging, preserving the capacity of the endothelium-dependent vasodilation and reduces BP values improving arterial pressure control.

  19. Identification of a potent endothelium-derived angiogenic factor

    DEFF Research Database (Denmark)

    Jankowski, Vera; Tölle, Markus; Tran, Thi Nguyet Anh


    The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up4U) from the secretome of human endothelial cells. The angiogenic effect of the endothelia...

  20. Glioblastoma stem-like cells give rise to tumour endothelium

    NARCIS (Netherlands)

    R. Wang; K. Chadalavada; J. Wilshire; U. Kowalik; K.E. Hovinga; A. Geber; B. Fligelman; M. Leversha; C. Brennan; V. Tabar


    Glioblastoma (GBM) is among the most aggressive of human cancers(1). A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia(2). Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poo

  1. Case Report: Coronary arterial spasm in single right coronary artery

    Institute of Scientific and Technical Information of China (English)

    En-zhi JIA; Qi-jun SHAN; Zhi-jian YANG; Tie-bing ZHU; Lian-sheng WANG; Ke-jiang CAO; Wen-zhu MA


    We presented a case of anomalous single-coronary artery detected incidentally during routine coronary angiography. A 32-year-old male Chinese patient presented with recurrent pre-syncope and six episodes of syncope. Coronary angiography and coronary-computed tomography (CT)-angiography performed by a dual-source computed tomography (DSCT) revealed that the patient had a single large right coronary artery. A moderately large branch originated from the proximal part of the single right coronary artery and extended to the left, passing the anterior to the pulmonary artery, and divided into the anterior descending artery branch and circumflex branch at the base of the left auricular appendage. The episodes of the syncope were suspected to be caused by coronary arterial spasm, so this patient was on a regimen of 30 mg of diltiazem every 6 h and had no recurrence of syncope during follow-up.

  2. Anomalous origin of right coronary artery from left coronary sinus. (United States)

    Hamzeh, Gadah; Crespo, Alex; Estarán, Rafael; Rodríguez, Miguel A; Voces, Roberto; Aramendi, José I


    Anomalous aortic origin of the coronary arteries is uncommon but clinically significant. Manifestations vary from asymptomatic patients to those who present with angina pectoris, myocardial infarction, heart failure, syncope, arrhythmias, and sudden death. We describe 4 patients, aged 34 to 59 years, who were diagnosed with right coronary artery arising from the left sinus of Valsalva, confirmed by coronary angiography, which was surgically repaired. Three patients presented dyspnea and angina, and one with acute myocardial infarction. At operation, the right coronary artery was dissected at the take-off from the intramural course, and reimplanted into the right sinus of Valsalva. There was no mortality. One patient had associated coronary artery disease that required stent placement postoperatively. This reimplantation technique provides a good physiological and anatomical repair, eliminates a slit-like ostium, avoids compression of the coronary artery between the aorta and the pulmonary artery, and gives superior results to coronary artery bypass grafting or the unroofing technique.

  3. Coronary heart disease

    Institute of Scientific and Technical Information of China (English)


    950286 Percutaneous transluminal coronary angio-plasty for unstable angina.LIU Meilin(刘梅林), Teach Hosp,Beijing Med Univ,Beijing,100034.Chin J Intern Med 1995;34(3):169-172.Percutaneous transluminal coronary angioplasty(PTCA) was performed in 190 patients with 250 dis-eased vessels and 278 lesions from Dec.1987 to Feb.1994.All the patients had unstable angina (UA).There were 52(18.7%) type A lesions,175(62.9%)type B lesions and 51(18.3%) type C lesions.Of the

  4. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease

    NARCIS (Netherlands)

    P.W.J.C. Serruys (Patrick); M-C. Morice (Marie-Claude); A.P. Kappetein (Arie Pieter); A. Colombo (Antonio); D.R. Holmes Jr (David); M.J. Mack (Michael); E. Stahle (Elisabeth); T.E. Feldman (Ted); M.J.B.M. van den Brand (Marcel); E.J. Bass (Eric); N. van Dyck (Nic); K. Leadly (Katrin); K.D. Dawkins (Keith); F.W. Mohr (Friedrich)


    textabstractBACKGROUND Percutaneous coronary intervention (PCI) involving drug-eluting stents is increasingly used to treat complex coronary artery disease, although coronary-artery bypass grafting (CABG) has been the treatment of choice historically. Our trial compared PCI and CABG for treating pat

  5. 9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor-Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells. (United States)

    Almontashiri, Naif A M; Antoine, Darlène; Zhou, Xun; Vilmundarson, Ragnar O; Zhang, Sean X; Hao, Kennedy N; Chen, Hsiao-Huei; Stewart, Alexandre F R


    The mechanism whereby the 9p21.3 locus confers risk for coronary artery disease remains incompletely understood. Risk alleles are associated with reduced expression of the cell cycle suppressor genes CDKN2A (p16 and p14) and CDKN2B (p15) and increased vascular smooth muscle cell proliferation. We asked whether risk alleles disrupt transcription factor binding to account for this effect. A bioinformatic screen was used to predict which of 59 single nucleotide polymorphisms at the 9p21.3 locus disrupt (or create) transcription factor binding sites. Electrophoretic mobility shift and luciferase reporter assays examined the binding and functionality of the predicted regulatory sequences. Primary human aortic smooth muscle cells (HAoSMCs) were genotyped for 9p21.3, and HAoSMCs homozygous for the risk allele showed reduced p15 and p16 levels and increased proliferation. rs10811656 and rs4977757 disrupted functional TEF-1 TEC1 AbaA domain (TEAD) transcription factor binding sites. TEAD3 and TEAD4 overexpression induced p16 in HAoSMCs homozygous for the nonrisk allele, but not for the risk allele. Transforming growth factor β, known to activate p16 and also to interact with TEAD factors, failed to induce p16 or to inhibit proliferation of HAoSMCs homozygous for the risk allele. Knockdown of TEAD3 blocked transforming growth factor β-induced p16 mRNA and protein expression, and dual knockdown of TEAD3 and TEAD4 markedly reduced p16 expression in heterozygous HAoSMCs. Here, we identify a novel mechanism whereby sequences at the 9p21.3 risk locus disrupt TEAD factor binding and TEAD3-dependent transforming growth factor β induction of p16 in HAoSMCs. This mechanism accounts, in part, for the 9p21.3 coronary artery disease risk. © 2015 American Heart Association, Inc.

  6. Increase of ADAM10 level in coronary artery in-stent restenosis segments in diabetic minipigs: high ADAM10 expression promoting growth and migration in human vascular smooth muscle cells via Notch 1 and 3.

    Directory of Open Access Journals (Sweden)

    Ke Yang

    Full Text Available BACKGROUND: This study aimed to identify major proteins in the pathogenesis of coronary artery in-stent restenosis (ISR in diabetic minipigs with sirolimus-eluting stenting, and to investigate the roles of key candidate molecules, particularly ADAM10, in human arterial smooth muscle cells (HASMCs. METHODS AND RESULTS: The stents were implanted in the coronary arteries of 15 diabetic and 26 non-diabetic minipigs, and angiography was repeated at six months. The intima of one vascular segment with significant ISR and one with non-ISR in diabetic minipigs were isolated and cultured in conditioned medium (CM. The CM was analyzed by LC-MS/MS to uncover proteins whose levels were significantly increased (≥ 1.5-fold in ISR than in non-ISR tissues. After literature searching, we focused on the identified proteins, whose biological functions were most potentially related to ISR pathophysiology. Among them, ADAM10 was significantly increased in diabetic and non-diabetic ISR tissues as compared with non-ISR controls. In cell experiments, retrovirus-mediated overexpression of ADAM10 promoted growth and migration of HASMCs. The effects of ADAM10 were more remarkable in high-glucose culture than in low-glucose culture. Using shRNA and an inhibitor of γ-secretase (GSI, we found that the influences of ADAM10 were in part mediated by Notch1 and notch 3 pathway, which up-regulated Notch downstream genes and enhanced nuclear translocation of the small intracellular component of Notch1 and Notch3. CONCLUSIONS: This study has identified significantly increased expression of ADAM10 in the ISR versus non-ISR segment in diabetic minipigs and implicates ADAM10 in the enhanced neointimal formation observed in diabetes after vascular injury.

  7. Human Umbilical Cord Mesenchymal Stromal Cell Transplantation in Myocardial Ischemia (HUC-HEART Trial). A Study Protocol of a Phase 1/2, Controlled and Randomized Trial in Combination with Coronary Artery Bypass Grafting. (United States)

    Can, Alp; Ulus, Ahmet Tulga; Cinar, Ozgur; Topal Celikkan, Ferda; Simsek, Erdal; Akyol, Mesut; Canpolat, Ugur; Erturk, Murat; Kara, Fadil; Ilhan, Osman


    Mesenchymal stem cells (MSCs), which may be obtained from the bone marrow, have been studied for more than a decade in the setting of coronary artery disease (CAD). Adipose tissue-derived MSCs have recently come into focus and are being tested in a series of clinical trials. MSC-like cells have also been derived from a variety of sources, including umbilical cord stroma, or HUC-MSCs. The HUC-HEART trail ( Identifier: NCT02323477) is a phase 1/2, controlled, multicenter, randomized clinical study of the intramyocardial delivery of allogeneic HUC-MSCs in patients with chronic ischemic cardiomyopathy. A total of 79 patients (ages 30-80) with left ventricle ejection fractions ranging between 25 and 45% will be randomized in a 2:1:1 pattern in order to receive an intramyocardial injection of either HUC-MSCs or autologous bone marrow-derived mononuclear cells (BM-MNCs) in combination with coronary arterial bypass grafting (CABG) surgery. The control group of patients will receive no cells and undergo CABG alone. Human HUC-MSCs will be isolated, propagated and banked in accordance with a cGMP protocol, whereas the autologous BM-MNCs will be isolated via aspiration from the iliac crest and subsequently process in a closed-circuit cell purification system shortly before cell transplantation. The cell injections will be implemented in 10 peri-infarct areas. Baseline and post-transplantation outcome measures will be primarily utilized to test both the safety and the efficacy of the administered cells for up to 12 months.

  8. Type 1 diabetes and hypercholesterolaemia reveal the contribution of endothelium-derived hyperpolarizing factor to endothelium-dependent relaxation of the rat aorta. (United States)

    Malakul, Wachirawadee; Thirawarapan, Suwan; Suvitayavat, Wisuda; Woodman, Owen L


    1. The present study evaluated the effect of diabetes, hypercholesterolaemia and their combination on the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to relaxation of rat isolated aortic rings and the potential contribution of oxidant stress to the disturbance of endothelial function. 2. Thoracic aortic rings from control, diabetic, hypercholesterolaemic and diabetic plus hypercholesterolaemic rats were suspended in organ baths for tension recording. Generation of superoxide by the aorta was measured using lucigenin-enhanced chemiluminescence. 3. The maximal response to acetylcholine (ACh) was significantly reduced in diabetic or hypercholesterolaemic rats compared with control rats. In rats with diabetes plus hypercholesterolaemia, both the sensitivity and maximal response to ACh was impaired. In control rats, the response to ACh was abolished by the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) or inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, in rats with diabetes, hypercholesterolaemia or both, relaxation to ACh was resistant to inhibition by L-NNA or ODQ, but abolished by additional inhibition of K(Ca) channels with charybdotoxin plus apamin. 4. The generation of superoxide was not significantly enhanced in aortic rings from either diabetic or hypercholesterolaemic rats, but was significantly increased in aortic rings from rats with diabetes plus hypercholesterolaemia. 5. These results suggest that when diabetes and hypercholesterolaemia impair endothelium-dependent relaxation, due to a diminished contribution from NO, a compensatory contribution of EDHF to endothelium-dependent relaxation of the aorta is revealed. The attenuation of NO-mediated relaxation, at least in the presence of both diabetes and hypercholesterolaemia, is associated with enhanced superoxide generation.

  9. Atherosclerosis of coronary blood vessels - local or systemic inflamation? (United States)

    Pejkov, Hristo; Kedev, Sasko; Panov, Saso; Srbinovska-Kostovska, Elizabeta; Lang, Irene


    The presence of atherosclerotic lesions in the blood vessels is a predisposition for the development and occurrence of acute ischaemic attacks. Bigger atherosclerotic lesions in the coronary blood vessels cause lumen occlusion, which is a cause of acute myocardial infarction. Endothelial dysfunction is defined as an ability of the endothelium to produce vasorelaxing nitric oxide (NO), or deregulation of the other vasoactive substances, such as angiotensin II and endothelin [13]. This definition describes endothelial dysfunction as an improper vasomotor constriction of the vessel, that leads to lumen occlusion of the already existing atherosclerotic lesions. According to the modern model, the development of atherosclerotic plaque and inappropriate endothelial NO production have a synergistic role in patho-physiological and molecular processes in the blood vessels [14]. Lesions in the coronary arteries are deposits of huge quantities of foamy cells and fibrous plaques. The thin fibrous plaques are 10-20% of the total plaque population and are the cause of 80-90% of clinical cases due to their ability to rupture [48]. According to all the results from published studies by far, it has been pointed out that the plaque stability, not the absolute size influences the rupture potential. Elucidating the risk factors that may modify in the atherogenesis and the consequent atherothrombic effect is the first step to this goal.

  10. Coronary artery anatomy and variants

    Energy Technology Data Exchange (ETDEWEB)

    Malago, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicoli, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto [Policlinico G.B. Rossi, University of Verona, Department of Radiology, Verona (Italy)


    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions. (orig.)

  11. [Pregnancy and coronary artery dissection]. (United States)

    Martínez-Quintana, Efrén; Rodríguez-González, Fayna


    Acute myocardial infarction during pregnancy is associated with high maternal and fetal mortality. Coronary atherosclerosis is the most common cause due to an increase in the age of the patients and the association with cardiovascular risk factors such as smoking, hypertension, diabetes mellitus, preeclampsia, and the existence of family history of coronary disease. However, thrombosis, coronary dissection or coronary vasospasms are other causes that may justify it. We report the case of a 33 weeks pregnant first-time mother, without cardiovascular risk factors, who presented an acute coronary event in the context of atherosclerotic disease and coronary dissection after percutaneous coronary intervention. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  12. Does the quantitative assessment of coronary artery dimensions predict the physiologic significance of a coronary stenosis?

    NARCIS (Netherlands)

    F. Zijlstra (Felix); J.C.W. van Ommeren (Jan-Kees); J.H.C. Reiber (Johan); P.W.J.C. Serruys (Patrick)


    textabstractTo study the relationship between the quantitatively assessed coronary artery dimensions and the regional coronary flow reserve as measured by digital subtraction cineangiography, we investigated 17 coronary arteries with a single discrete proximal stenosis and 12 normal coronary

  13. Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats

    Institute of Scientific and Technical Information of China (English)

    Yi SHI; Ricky YK MAN; Paul M VANHOUTTE


    Aim: The present experiments were designed to study the changes in endothe-lium-dependent contractions with aging. Methods: The rat femoral arteries of 20-week and 1-year-old rats with and without endothelium were suspended in organ chambers to record isometric tension. The production of oxygen-derived free radicals in the endothelium was measured with 2',7'-dichiorodihydrofluorescein diacetate (DCF) using confocal microscopy. Protein presences were determined by Western blotting. Results: In the arteries from the 1-year-old rats, endothe-lium-dependent relaxations to A23187 were reduced, but the endothelium-depen-dent contractions to A23187 (in the presence of Nω-nitro-L-arginine methyl ester hydrochloride [L-NAME; an inhibitor of nitric oxide synthase]) were augmented, demonstrating endothelial dysfunction with aging. Indomethacin normalized the responses, suggesting that a cyclooxygenase (COX)-dependent contraction is prominent in aging. The endothelium-dependent contractions were also prevented by terntroban (a blocker of thromboxane-prostanoid receptors), confirming the activation of thromboxane-prostanoid receptors on vascular smooth muscle. Valeryl salicylate and NS-398 (preferential inhibitors of COX-1 and COX-2, respectively) partially reduced the response, indicating that both COX-1 and COX-2 are involved. Western blotting confirmed the upregulation of both isoforms in the arteries of the 1-year-old rats. In the presence of L-NAME, A23187 increased the DCF fluores-cence in the endothelium, demonstrating that the production of oxygen-derived free radicals contributes to endothelium-dependent contractions. The activity of catalase was reduced in the arteries with endothelium of 1-year-old rats, indicating that hydrogen peroxide is the likely mediator of increased oxidative stress in the aging endothelium. Conclusion: Endothelium-dependent contractions are aug-mented with aging. Oxidative stress potentiates the response, and both COX-1 and COX-2 are

  14. Transradial artery coronary angioplasty. (United States)

    Kiemeneij, F; Laarman, G J; de Melker, E


    This study explored the feasibility and safety of percutaneous coronary balloon angioplasty (PTCA) with miniaturized PTCA equipment via the radial artery. Coronary angioplasty (PTCA) via the femoral or brachial arteries may be associated with rare vascular complications such as bleeding and damage to the artery and adjacent structures. It was postulated that PTCA via the radial artery with miniaturized angioplasty equipment is feasible and that no major puncture site-related complications occur because hemostasis is obtained easily and because no major structures are near the radial artery. With double blood supply to the hand, radial artery occlusion is well tolerated. In 100 patients with collateral blood supply to the right hand, PTCA was attempted with 6F guiding catheters and rapid-exchange balloon catheters for exertional angina (87 patients) or nonexertional angina (13 patients). Angioplasty was attempted in 122 lesions (type A n = 67 [55%], Type B n = 37 [30%], and type C n = 18 [15%]). Pre- and post-PTCA computerized quantitative coronary analysis was performed. Radial artery function and structure were assessed clinically and with Doppler and two-dimensional ultrasound on the day of discharge. Coronary catheterization via the radial artery was successful in 94 patients (94%). The 6 remaining patients had successful PTCA via the femoral artery (n = 5) or the brachial artery (n = 1). Procedural success (120 of 122 lesions) was achieved in 92 patients (98%) via the radial artery and in 98 patients of the total study population.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. [Acute coronary syndrome -- 2012]. (United States)

    Becker, Dávid; Merkely, Béla


    The acute coronary syndrome is the most severe form of coronary artery disease. It is an immediate threat of life and the mortality rate can be high without proper therapy and patient management. Based on the first ECG, two different forms can be distinguished: acute coronary syndrome with and without ST elevation. Besides adequate medication, management of these patients is an essential part of treatment. In case of ST elevation, coronarography and percutaneous coronary intervention is needed in general, within 24 hours from the onset of symptoms. When ST elevation is not detected on the ECG, individual ischemic risk factors and predictable mortality of the patient may define the necessity and the date of the invasive examination. The Hungarian hemodynamic laboratory network covers almost the whole country and, therefore, practically each patient may receive a state-of-the-art therapy. Although indicators of cardiovascular diseases are still prominent, the mortality rate of myocardial Infarction is decreasing in Hungary due to the well-organized invasive care.

  16. Tetrahydrobiopterin restores impaired coronary microvascular dysfunction in hypercholesterolaemia

    Energy Technology Data Exchange (ETDEWEB)

    Wyss, Christophe A.; Koepfli, Pascal; Namdar, Mehdi; Siegrist, Patrick T.; Kaufmann, Philipp A. [University Hospital, Nuclear Cardiology, Cardiovascular Center, Zurich (Switzerland); Luscher, Thomas F. [University Hospital, Division of Cardiology, Cardiovascular Center, Zurich (Switzerland); Camici, Paolo G. [Hammersmith Hospital, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London (United Kingdom)


    Tetrahydrobiopterin (BH{sub 4}) is an essential co-factor for the synthesis of nitric oxide (NO), and BH{sub 4} deficiency may cause impaired NO synthase (NOS) activity. We studied whether BH{sub 4} deficiency contributes to the coronary microcirculatory dysfunction observed in patients with hypercholesterolaemia. Myocardial blood flow (MBF; ml min{sup -1} g{sup -1}) was measured at rest, during adenosine-induced (140 {mu}g kg{sup -1} min{sup -1} over 7 min) hyperaemia (mainly non-endothelium dependent) and immediately after supine bicycle exercise (endothelium-dependent) stress in ten healthy volunteers and in nine hypercholesterolaemic subjects using {sup 15}O-labelled water and positron emission tomography. Measurements were repeated 60 min later, after intravenous infusion of BH{sub 4} (10 mg kg{sup -1} body weight over 30 min). Adenosine-induced hyperaemic MBF is considered to represent (near) maximal flow. Flow reserve utilisation was calculated as the ratio of exercise-induced to adenosine-induced hyperaemic MBF and expressed as percent to indicate how much of the maximal (adenosine-induced) hyperaemia can be achieved by bicycle stress. BH{sub 4} increased exercise-induced hyperaemia in controls (2.96{+-}0.58 vs 3.41{+-}0.73 ml min{sup -1} g{sup -1}, p<0.05) and hypercholesterolaemic subjects (2.47{+-}0.78 vs 2.70{+-}0.72 ml min{sup -1} g{sup -1}, p<0.01) but had no influence on MBF at rest or during adenosine-induced hyperaemia in controls (4.52{+-}1.10 vs 4.85{+-}0.45 ml min{sup -1} g{sup -1}, p=NS) or hypercholesterolaemic subjects (4.86{+-}1.18 vs 4.53{+-}0.93 ml min{sup -1} g{sup -1}, p=NS). Flow reserve utilisation remained unchanged in controls (70{+-}17% vs 71{+-}19%, p=NS) but increased significantly in hypercholesterolaemic subjects (53{+-}15% vs 66{+-}14%, p<0.05). BH{sub 4} restores flow reserve utilisation of the coronary microcirculation in hypercholesterolaemic subjects, suggesting that BH{sub 4} deficiency may contribute to coronary

  17. [Acute coronary syndrome suspicion in patient with left coronary artery arising from right coronary sinus]. (United States)

    Kern, Adam; Górny, Jerzy; Rzeszowski, Bartłomiej; Witkowska, Ewa; Wasilewski, Grzegorz


    We present a case of 73 year-old patient who underwent coronary angiography due to suspicion of acute coronary syndrome without persistent ST segment elevation. The angiographic result showed no lesions that could cause recurrent chest pain,but it also revealed a seldom coronary artery abnormality - left coronary artery arising from right coronary sinus. Performed computed tomography of the chest confirmed the result of the coronarography. But apart from that it found the signs of neoplastic disease which was probably responsible for clinical presentation.

  18. Impact of coronary tortuosity on coronary pressure: numerical simulation study.

    Directory of Open Access Journals (Sweden)

    Yang Li

    Full Text Available BACKGROUND: Coronary tortuosity (CT is a common coronary angiographic finding. Whether CT leads to an apparent reduction in coronary pressure distal to the tortuous segment of the coronary artery is still unknown. The purpose of this study is to determine the impact of CT on coronary pressure distribution by numerical simulation. METHODS: 21 idealized models were created to investigate the influence of coronary tortuosity angle (CTA and coronary tortuosity number (CTN on coronary pressure distribution. A 2D incompressible Newtonian flow was assumed and the computational simulation was performed using finite volume method. CTA of 30°, 60°, 90°, 120° and CTN of 0, 1, 2, 3, 4, 5 were discussed under both steady and pulsatile conditions, and the changes of outlet pressure and inlet velocity during the cardiac cycle were considered. RESULTS: Coronary pressure distribution was affected both by CTA and CTN. We found that the pressure drop between the start and the end of the CT segment decreased with CTA, and the length of the CT segment also declined with CTA. An increase in CTN resulted in an increase in the pressure drop. CONCLUSIONS: Compared to no-CT, CT can results in more decrease of coronary blood pressure in dependence on the severity of tortuosity and severe CT may cause myocardial ischemia.

  19. Cross-reacting antibacterial auto-antibodies are produced within coronary atherosclerotic plaques of acute coronary syndrome patients.

    Directory of Open Access Journals (Sweden)

    Filippo Canducci

    Full Text Available Coronary atherosclerosis, the main condition predisposing to acute myocardial infarction, has an inflammatory component caused by stimuli that are yet unknown. We molecularly investigated the nature of the immune response within human coronary lesion in four coronary plaques obtained by endoluminal atherectomy from four patients. We constructed phage-display libraries containing the IgG1/kappa antibody fragments produced by B-lymphocytes present in each plaque. By immunoaffinity, we selected from these libraries a monoclonal antibody, arbitrarily named Fab7816, able to react both with coronary and carotid atherosclerotic tissue samples. We also demonstrated by confocal microscopy that this monoclonal antibody recognized human transgelin type 1, a cytoskeleton protein involved in atherogenesis, and that it co-localized with fibrocyte-like cells transgelin+, CD68+, CD45+ in human sections of coronary and carotid plaques. In vitro fibrocytes obtained by differentiating CD14+ cells isolated from peripheral blood mononuclear cells also interacted with Fab7816, thus supporting the hypothesis of a specific recognition of fibrocytes into the atherosclerotic lesions. Interestingly, the same antibody, cross-reacted with the outer membrane proteins of Proteus mirabilis and Klebsiella pneumoniae (and possibly with homologous proteins of other enterobacteriaceae present in the microbiota. From all the other three libraries, we were able to clone, by immunoaffinity selection, human monoclonal antibodies cross-reacting with bacterial outer membrane proteins and with transgelin. These findings demonstrated that in human atherosclerotic plaques a local cross-reactive immune response takes place.

  20. Neoatherosclerosis:Coronary stents seal atherosclerotic lesions but result in making a new problem of atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    Hidenori; Komiyama; Masamichi; Takano; Noritake; Hata; Yoshihiko; Seino; Wataru; Shimizu; Kyoichi; Mizuno


    Chronic inflammation of the native vessel wall with infiltration of lipid-laden foamy macrophages through impaired endothelium results in atherosclerosis. Percutaneous coronary intervention, including metallic stent implantation, is now widely utilized for the treatment of atherosclerotic lesions of the coronary artery. Baremetal stents and the subsequently developed drugeluting stents seal the atherosclerosis and resolve lumen stenosis or obstruction of the epicardial coronary artery and myocardial ischemia. After stent implantation, neointima proliferates within the stented segment. Chronic inflammation caused by a foreign body reaction to the implanted stent and subsequent neovascularization, which is characterized by the continuous recruitment of macrophages into the vessel, result in the transformation of the usual neointima into an atheromatous neointima. Neointima with an atherosclerotic appearance, such as that caused by thin-cap fibroatheromas, is now recognized as neoatherosclerosis, which can sometimes cause in-stent restenosis and acute thrombotic occlusion originating from the stent segment following disruption of the atheroma. Neoatherosclerosis is emerging as a new coronary stent-associated problem that has not yet been resolved. In this review article, we will discuss possible mechanisms, clinical challenges, and the future outlook of neoatherosclerosis.

  1. CT coronary angiography vs. invasive coronary angiography in CHD

    Directory of Open Access Journals (Sweden)

    Anja Hagen


    Full Text Available Scientific background: Various diagnostic tests including conventional invasive coronary angiography and non-invasive computed tomography (CT coronary angiography are used in the diagnosis of coronary heart disease (CHD. Research questions: The present report aims to evaluate the clinical efficacy, diagnostic accuracy, prognostic value cost-effectiveness as well as the ethical, social and legal implications of CT coronary angiography versus invasive coronary angiography in the diagnosis of CHD. Methods: A systematic literature search was conducted in electronic data bases (MEDLINE, EMBASE etc. in October 2010 and was completed with a manual search. The literature search was restricted to articles published from 2006 in German or English. Two independent reviewers were involved in the selection of the relevant publications. The medical evaluation was based on systematic reviews of diagnostic studies with invasive coronary angiography as the reference standard and on diagnostic studies with intracoronary pressure measurement as the reference standard. Study results were combined in a meta-analysis with 95 % confidence intervals (CI. Additionally, data on radiation doses from current non-systematic reviews were taken into account. A health economic evaluation was performed by modelling from the social perspective with clinical assumptions derived from the meta-analysis and economic assumptions derived from contemporary German sources. Data on special indications (bypass or in-stent-restenosis were not included in the evaluation. Only data obtained using CT scanners with at least 64 slices were considered. Results: No studies were found regarding the clinical efficacy or prognostic value of CT coronary angiography versus conventional invasive coronary angiography in the diagnosis of CHD. Overall, 15 systematic reviews with data from 44 diagnostic studies using invasive coronary angiography as the reference standard (identification of obstructive

  2. Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Shanshan [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Department of Pediatrics, Baodi District People’s Hospital of Tianjin City, Tianjin, 301800 (China); Wang, Jiaxing [Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191 (China); Zhang, Xu; Shi, Ying; Li, Bochuan; Bao, Qiankun [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Pang, Wei [Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191 (China); Ai, Ding [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Zhu, Yi [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191 (China); He, Jinlong, E-mail: [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China)


    Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor–deficient (Ldlr{sup −/−}) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanism in vitro. Compared with Ldlr{sup −/−} mouse aortas, EC-ABCG1-Tg/Ldlr{sup −/−} aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr{sup −/−} mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow. In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECs in vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response. - Highlights: • EC-ABCG1-Tg mice in a Ldlr{sup −/−} background showed decreased atherosclerosis. • Overexpression of ABCG1 in ECs decreased OSS-induced EC activation. • NLRP3 and NF-κB might be an underlying mechanism of ABCG1 protective role.

  3. Angiography and coronary function, a clinical approach

    NARCIS (Netherlands)

    Stoel, Martin Gerrit


    Coronary angiography has the potential to determine coronary function in addition to merely showing coronary anatomy. In this thesis, we describe several facets of angiographic evaluation of coronary flow velocity and function. Measurement of the length of the coronary vessels by means of a guide

  4. Characterisation of the human oral microbiome in patients with coronary artery disease using next-generation sequencing of 16SrRNA amplicons

    Directory of Open Access Journals (Sweden)

    Thangam Menon


    Full Text Available Introduction: Oral health is suspected to be linked to heart disease since species of bacteria that cause periodontitis and dental caries have been found in the atherosclerotic plaque in arteries in the heart. Objectives: The aim of this study was to characterize the oral microbiome in patients with coronary artery disease (CAD and in a patient with dental caries (DC without any clinical symptoms of CAD. Methods: DNA was extracted from the oral swabs collected from the patients and sequencing was performed by next generation sequencing method using Illumina (MiSeq platform. The resulting sequencing data set was analysed using QIIME. Results: A total of 31 phyla were found in all the samples. The predominant phylum found in both CAD and DC was Firmicutes (46.09% & 38.98%, Proteobacteria (17.73% & 9.79%, Fusobacteria (13.44% & 17.95%, Bacteroidetes (11.82% & 22.73%, Actinobacteria (8.33% & 7.71% and TM7 (2.25% & 2.71%. We found a similarity in the bacterial diversity in the two groups of patients. Conclusion: A comparison of the oral microbiome in patients with CAD and DC shows a similarity in the composition of the oral microbiota with variations in the proportion of a few genera.

  5. The ent-15α-Acetoxykaur-16-en-19-oic Acid Relaxes Rat Artery Mesenteric Superior via Endothelium-Dependent and Endothelium-Independent Mechanisms

    Directory of Open Access Journals (Sweden)

    Êurica Adélia Nogueira Ribeiro


    Full Text Available The objective of the study was to investigate the mechanism of the relaxant activity of the ent-15α-acetoxykaur-16-en-19-oic acid (KA-acetoxy. In rat mesenteric artery rings, KA-acetoxy induced a concentration-dependent relaxation in vessels precontracted with phenylephrine. In the absence of endothelium, the vasorelaxation was significantly shifted to the right without reduction of the maximum effect. Endothelium-dependent relaxation was significantly attenuated by pretreatment with L-NAME, an inhibitor of the NO-synthase (NOS, indomethacin, an inhibitor of the cyclooxygenase, L-NAME + indomethacin, atropine, a nonselective antagonist of the muscarinic receptors, ODQ, selective inhibitor of the guanylyl cyclase enzyme, or hydroxocobalamin, a nitric oxide scavenger. The relaxation was completely reversed in the presence of L-NAME + 1 mM L-arginine or L-arginine, an NO precursor. Diterpene-induced relaxation was not affected by TEA, a nonselective inhibitor of K+ channels. The KA-acetoxy antagonized CaCl2-induced contractions in a concentration-dependent manner and also inhibited an 80 mM KCl-induced contraction. The KA-acetoxy did not interfere with Ca2+ release from intracellular stores. The vasorelaxant induced by KA-acetoxy seems to involve the inhibition of the Ca2+ influx and also, at least in part, by endothelial muscarinic receptors activation, NO and PGI2 release.

  6. Pharmacology of Endothelium-Dependent and Independent Relaxation of Rabbit Aorta

    DEFF Research Database (Denmark)

    Larsen, Kirsten Vendelbo


    tetraethylammonium (TEA) and 4-aminopyridine (4-AP), but unaffected by glibenclamid. It is concluded that the acetylcholine-evoked relaxation of rabbit aorta is dependent on: the endothelium; the activation of muscarinic receptors; independent of prostanoids; and mediatedn by NO alone. Th eNO released...... by acetlcholine stimulates a relaxation by activating soluble guanylate cyclase (sGC) and voltage dependent (KV) and Ca2+ dependent (KCa) potassium channels in the smooth muscle. Repeated addition of acetylcholine caused the development of tachyphylaxis. The relaxationevoked by a single concentration...... of the first relaxation, caused a marked attenuation of the evoked relaxation. It is concluded that the fade of the acetylcholine-evoked relaxation is due to an effect on the part of the signal transduction pathway that is activated in the endothelium. The fade is not due to: inactivation of acetylcholine...

  7. Mathematical model for blood flow autoregulation by endothelium-derived relaxing factor

    CERN Document Server

    Chernyavsky, I L; Chernyavsky, Igor L.; Kudryashov, Nikolai A.


    The fluid shear stress is an important regulator of the cardiovascular system via the endothelium-derived relaxing factor (EDRF) that is Nitric Oxide. This mechanism involves biochemical reactions in an arterial wall. The autoregulation process is managed by the vascular tonus and gives the negative feedback for the shear stress changing. A new mathematical model for the autoregulation of a blood flow through arteria under the constant transmural pressure is presented. Endothelium-derived relaxing factor Nitric Oxide, the multi-layer structure of an arterial wall, and kinetic-diffusion processes are taken into consideration. The limit case of the thin-wall artery is analytically studied. The stability condition for a stationary point of the linearized system is given. The exact stationary solutions of the origin system are found. The numerical simulation for the autoregulation system is presented. It is shown the arteria adaptation to an initial radial perturbation and the transition of the system to new equi...

  8. Astragaloside IV Improves Metabolic Syndrome and Endothelium Dysfunction in Fructose-Fed Rats

    Directory of Open Access Journals (Sweden)

    Feng Zhao


    Full Text Available The prevalence of metabolic syndrome has increased in modern society and the condition is proving to be a common precursor of cardiovascular disease. The aim of the present study was to investigate whether astragaloside IV, a major active constituent of Astragalus membranaceus (Fisch Bge., is able to prevent the development of hypertension and endothelial dysfunction in fructose-fed rats. Rats were fed with 10% fructose in their drinking water for 8 weeks. From the beginning of week 5, two groups of fructose-fed rats were treated with 0.5 or 2 mg/kg, i.p., astragaloside IV. Another group of fructose-fed rats, injected with the same volume of vehicle (dimethylsulfoxide, DMSO from week 5, served as the control group. At the end of the treatment period, blood pressure, blood glucose, glucose tolerance, blood insulin and lipids were determined. In addition, in vitro experiments were conducted at the end of the eight week treatment period to evaluate endothelium-dependent aortic vasorelaxation, as well as myocardial and aortic tissue levels of nitrate and nitrite (NOx and cGMP. Fructose-fed rats developed clustering signs of metabolic syndrome, such as increased bodyweight, mild hypertension, hyperinsulinaemia, hypertriglyceridaemia, impaired glucose tolerance and impaired endothelium-dependent vasorelaxation. Administration of astragaloside IV reduced blood pressure and triglyceride levels in fructose-fed rats and high dose of astragaloside IV also improved glucose tolerance and endothelium-dependent vasorelaxation. The astragaloside IV-induced improvement in vasorelaxation was associated with increased levels of aortic NOx and cGMP and was abrogated by blockade of nitric oxide synthase with NG-nitro-l-arginine methyl ester (l-NAME. On the basis of its favourable effects on lipid metabolism, endothelium-dependent vasorelaxation and the nitric oxide–cGMP-related pathway, astragaloside IV may be useful in ameliorating food-induced metabolic syndrome.

  9. Ascorbic acid improves impaired venous and arterial endothelium dependent dilation in smokers

    Institute of Scientific and Technical Information of China (English)

    Márcio Gon(c)alves de SOUSA; Juan Carlos YUGAR-TOLEDO; Marcelo RUBIRA; Sílvia Elaine FERREIRA-MELO; Rodrigo PLENTZ; Deise BARBIERI; Fernanda CONSOLIM-COLOMBO; Maria Cláudia IRIGOYEN; Heitor MORENO Jr


    Aim: To compare the acute effects of ascorbic acid on vasodilation of veins and arteries in vivo. Methods: Twenty-six healthy non-smokers and 23 healthy moderate smokers were recruited in this study. The dorsal hand vein compliance technique and flow-mediated dilation were used. Dose-response curves to bradykinin and sodium nitroprusside were constructed to test the endothelium-dependent and -independent relaxation before and after acute infusion of ascorbic acid. Results: Smokers had an impaired venodilation with bradykinin compared with non-smokers (68.3%±13.2% vs 93.7%±20.1%, respectively; P<0.05). Ascorbic acid administration in the dorsal hand vein significantly increased the venodilation with bradykinin in smokers (68.3%± 13.2% vs 89.5%±6.3% before and after infusion, respectively; P<0.05) but not in non-smokers (93.7%±20.1% vs 86.4%±12.4% before and after infusion, respectively). Similarly, the arterial response in smokers had an impaired endothelium-dependent dilation compared with that in non-smokers (8.8%±2.7% vs 15.2%±2.3%, respectively; P<0.05) and ascorbic acid restored this response in smokers (8.8%±2.7% vs 18.7%±6.5% before and after infusion, respectively; P<0.05), but no difference was seen in non-smokers (15.2%±2.3% vs 14.0%±4.4% before and after infusion, respectively). The endothelium-independent dilation did not differ in both the groups studied. No important hemodynamic change was detected using the Portapress device. Conclusion: Smokers had impaired endothelium-dependent vasodilation responsiveness in both arterial and venous systems. Ascorbic acid restores this responsiveness in smokers.

  10. Relationship between vascular endothelium and periodontal disease in atherosclerotic lesions: Review article (United States)

    Saffi, Marco Aurélio Lumertz; Furtado, Mariana Vargas; Polanczyk, Carisi Anne; Montenegro, Márlon Munhoz; Ribeiro, Ingrid Webb Josephson; Kampits, Cassio; Haas, Alex Nogueira; Rösing, Cassiano Kuchenbecker; Rabelo-Silva, Eneida Rejane


    Inflammation and endothelial dysfunction are linked to the pathogenesis of atherosclerotic disease. Recent studies suggest that periodontal infection and the ensuing increase in the levels of inflammatory markers may be associated with myocardial infarction, peripheral vascular disease and cerebrovascular disease. The present article aimed at reviewing contemporary data on the pathophysiology of vascular endothelium and its association with periodontitis in the scenario of cardiovascular disease. PMID:25632316

  11. Role of the endothelium in placental dysfunction after fetal cardiac bypass. (United States)

    Reddy, V M; McElhinney, D B; Rajasinghe, H A; Liddicoat, J R; Hendricks-Munoz, K; Fineman, J R; Hanley, F L


    Fetal cardiac bypass causes placental dysfunction, characterized by increased placental vascular resistance, decreased placental blood flow, hypoxia, and acidosis. Vasoactive factors produced by the vascular endothelium, such as nitric oxide and endothelin 1, are important regulators of placental vascular tone and may contribute to this placental dysfunction. To investigate the role of the vascular endothelium in placental dysfunction related to fetal cardiac bypass, we studied 3 groups of fetal sheep. In the first group (n = 7) we determined placental hemodynamic responses before and after bypass to an endothelium-dependent vasodilator (acetylcholine), an endothelium-independent vasodilator (nitroprusside), and endothelin 1. In the second group (n = 8) a nonspecific endothelin receptor blocker (PD 145065) was administered and placental hemodynamic values were measured before and after bypass. In the third group (n = 5) endothelin 1 levels were measured before and after bypass. Before fetal cardiac bypass exogenous endothelin 1 decreased placental blood flow by 9% and increased placental resistance by 9%. After bypass endothelin 1 decreased placental flow by 47% and increased resistance by 106%. There was also a significant attenuation of the placental vascular relaxation response to acetylcholine after bypass, whereas the response to nitroprusside was not significantly altered. In fetuses that received the PD 145065, placental vascular resistance increased significantly less than in control fetuses (28% versus 62%). Similarly, placental blood flow decreased significantly more (from 6. 3 +/- 3.1 to 28.3 +/- 10.4 pg/mL; P =.01) in control fetuses than in fetuses receiving PD 145065 (33% versus 20%). Umbilical venous endothelin 1 levels increased significantly in fetuses exposed to fetal bypass but did not change in control fetuses. The basal endothelial regulatory mechanisms of placental vascular tone were deranged after fetal cardiac bypass. Endothelin receptor

  12. Relationship between vascular endothelium and periodontal disease in atherosclerotic lesions: Review article

    Institute of Scientific and Technical Information of China (English)

    Marco; Aurélio; Lumertz; Saffi; Mariana; Vargas; Furtado; Carisi; Anne; Polanczyk; Márlon; Munhoz; Montenegro; Ingrid; Webb; Josephson; Ribeiro; Cassio; Kampits; Alex; Nogueira; Haas; Cassiano; Kuchenbecker; R?sing; Eneida; Rejane; Rabelo-Silva


    Inflammation and endothelial dysfunction are linked to the pathogenesis of atherosclerotic disease. Recent studies suggest that periodontal infection and the ensuing increase in the levels of inflammatory markers may be associated with myocardial infarction, peripheral vascular disease and cerebrovascular disease. The present article aimed at reviewing contemporary data on the pathophysiology of vascular endothelium and its association with periodontitis in the scenario of cardiovascular disease.

  13. Neovascularization of coronary tunica intima (DIT is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

    Directory of Open Access Journals (Sweden)

    Subbotin Vladimir M


    Full Text Available Abstract Background An accepted hypothesis states that coronary atherosclerosis (CA is initiated by endothelial dysfunction due to inflammation and high levels of LDL-C, followed by deposition of lipids and macrophages from the luminal blood into the arterial intima, resulting in plaque formation. The success of statins in preventing CA promised much for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review logical properties of the hypothesis underlining our efforts, and to reconsider whether our perception of CA is consistent with facts about the normal and diseased coronary artery. Analysis To begin with, it must be noted that the normal coronary intima is not a single-layer endothelium covering a thin acellular compartment, as claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT, in which cells are arranged in many layers. If low density lipoprotein cholesterol (LDL-C invades the DIT from the coronary lumen, the initial depositions ought to be most proximal to blood, i.e. in the inner DIT. The facts show that the opposite is true, and lipids are initially deposited in the outer DIT. This contradiction is resolved by observing that the normal DIT is always avascular, receiving nutrients by diffusion from the lumen, whereas in CA the outer DIT is always neovascularized from adventitial vasa vasorum. The proteoglycan biglycan, confined to the outer DIT in both normal and diseased coronary arteries, has high binding capacity for LDL-C. However, the normal DIT is avascular and biglycan-LDL-C interactions are prevented by diffusion distance and LDL-C size (20 nm, whereas in CA, biglycan in the outer DIT can extract lipoproteins by direct contact with the blood. These facts lead to the single simplest explanation of all observations: (1 lipid deposition is initially localized in the outer DIT; (2 CA

  14. Impaired endothelium independent vasodilation in the cutaneous microvasculature of young obese adults. (United States)

    Patik, Jordan C; Christmas, Kevin M; Hurr, Chansol; Brothers, R Matthew


    Microvascular dysfunction contributes to the development of cardiovascular and metabolic disease. This study tested the hypothesis that young obese (BMI>30 kg m(-2)), otherwise healthy, adults (N=15) have impaired microvascular function relative to age and sex matched, lean (BMIvasodilator methacholine (MCh) and the other for the endothelium-independent vasodilator sodium nitroprusside (SNP). Local temperature at each site was clamped at 33 °C and cutaneous blood flow was indexed by laser Doppler flowmetry (LDF). LDF was recorded while 7 doses of each drug (MCh: 10(-6)-1M; SNP: 5 × 10(-8)-5 × 10(-2)M) were infused at a rate of 2 μl/min for 8 min per dose. Both sites finished with heating to 43 °C and 5 × 10(-2)M SNP to achieve site specific maximal vasodilation. Mean arterial blood pressure (MAP) was assessed in the last minute of each dose and was used for subsequent calculation of cutaneous vascular conductance (CVC; LDF/MAP) and responses were normalized to each individual site's maximal response (%CVCmax). Group four-parameter dose response curves were compared with an extra sum of squares F-test. SNP EC50 was greater in obese relative to lean (-2.931 ± 0.10 vs -3.746 ± 0.18 Log[SNP]M, P0.05). These results suggest attenuated endothelium-independent response to nitric oxide while endothelium-dependent vasodilation function is maintained.


    Directory of Open Access Journals (Sweden)

    A. P. Shchekotova


    Full Text Available Aim — to estimate endothelium lesion, quantity and thrombocyte aggregation function correlation in viral chronic hepatitis C (CHC and hepatic cirrhosis (HC.Materials and methods. 50 CHC patients and 28 HC patients were examined. Using IFA method the total nitric oxide, endothelin‑1, vasculoendothelial growth factor levels, Willebrand factor (vWF activity were investigated, blood plasma desquamated endotheliocyte (DEC number was calculated with Hladovec method, 1978, thrombocyte aggregation (TA with ADP, collagen, ristocetine was determined.Results. DEC and vWF demonstrated correlation in CHC (p = 0.014 and HC (p = 0.000004. In HC patients reliable correlation of all the investigated indices of endothelium lesion with the thrombocyte number and TA was detected, but in CHC patients no correlations were revealed. Thus, significant elevation of TA with ristocetine was noted only in CHC. Decrease in thrombocyte amount among CHC patients and,especially in HC, and heightened vWF activity could change true TA indices. The corrected TA, whose indices in hepatic diseases significantlyincreased, was calculated taking into account the correction factor vWF / thrombocytes that in CHC did not differ from that of healthy patients and in HC was essentially higher.Conclusion. Endothelium dysfunction markers in CH and HC demonstrate correlation with thrombocyte reduction and TA elevation. Determinationof corrected TA permits to reveal disturbances of thrombocyte hemostasis in the form of elevated aggregation in all CHC and HC patients.

  16. [The endothelium of the vessels and proxidative-antioxidative balans in pregnancy rats with endothoxinaemia]. (United States)

    Milosh, T S; Maksimovich N Ye


    Actual problem of modern obstetrics is the infection in pregnancy which leads the deadborn, early children's death rate ind disease. In Belarus disease of newborns at specific infections for postnatal the period has made 14.1 per thousand, and death rate of 0.38 per thousand. The purpose of researches--to study a condition endothelium and activity of lipid peroxidation products at pregnant rats with endothoxinaemia. In experiments on 49 pregnancy rats with intramuscular injection of endotoxine (Lipopolysaccharide E. coli Serotype O127:B8 "Sigma") during the period placentation dysfunction development endohelium is established, that was shown more expressed in 2,3 times (p < 0.05) constriction by reaction on noradrenalin, increase in 18,3 times (p < 0.001) quantities circulating endothelium cages and decrease in 14 times (p < 0.001) the deendent endothelium vasodilatation under influence acetilcholine, to the dress increase of level of lipid peroxidation products: concentration of diene conjugates on 91% (p < 0.001), malone dialdegide--on 56% (p < 0.001), Shiff bases--on 7.9% (p < 0.05); and decrease in indicators of antioxidant protection: maintenances retinol on 29% (p < 0.05), α-tocopherol--on 6% (p < 0.001).

  17. Detrimental effects of chemotherapeutics and other drugs on the endothelium: A call for endothelial toxicity profiling. (United States)

    Wojcik, Tomasz; Szczesny, Ewa; Chlopicki, Stefan


    The vascular endothelium is a real "maestro of circulation", and endothelial dysfunction leads to atherothrombosis, its cardiovascular complications, as well as to many other diseases. It is surprising that quite a large number of drugs seem to hamper the vasoprotective mechanisms of the endothelium, possibly promoting the development of cardiovascular diseases in patients initially treated for non-cardiological conditions. Toxicity profiling (including cardiac and liver toxicity assessment) is a routine procedure performed during pre-clinical drug development. Unfortunately, endothelium-dependent side effects are not taken into account in standard toxicity profiling protocols, as the "endothelial safety" of drugs is not required in order to enter the clinical phase of drug development. Presumably, this might be one of the reasons why several efficient therapeutics, including rofecoxib (COX-2 inhibitor), torcetrapib (CETP-inhibitor), and bardoxolone (Nrf2 activator), have unexpectedly displayed clinically significant cardiovascular hazard, resulting in their withdrawal from the market or alarming comments, respectively. In this review, we will briefly characterize the endothelial activity profiles of chemotherapeutics, antidepressants and antipsychotics-all drugs prescribed for severe, life-threatening and/or life-long diseases-and will show that at least some of them may display clinically relevant detrimental effects on endothelial function.


    Directory of Open Access Journals (Sweden)

    L. I. Katelnizkaya


    Full Text Available Aim. To study endothelium vasomotor function (EF in patients with ischemic heart disease (IHD and the influence of angiotensin converting enzyme inhibitor enalapril (Enam, Dr .Reddy’s, India on it. Material and methods. 87 patients were examined totally. 49 patients were suffering from IHD: 18 patients were younger than 60 years old and 31 patients were older . The combination of arterial hypertension (HT and IHD were registered in 38 patients: 18 patients were below and 20 patients were above 60 years old. All patients additionally to basic IHD therapy took enalapril in dose 2,5-30 mg/daily during 12 weeks. Before the beginning and in the end of treatment cuff test, test with nitroglycerine, bicycle exercise test and Holter monitoring were made, the thickness of intima-media complex of carotid artery and the level of endothelin-1 in blood plasma were defined. Results. EF disorders were shown in IHD, maximal disorders were determined in patients with combination of IHD and HT. EF disorders were also more expressive in patients of elder group. Enalapril restored of cuff tests results, nitroglycerine tests results, reduced a number of myocardial ischemia episodes and provided target blood pressure in 60, 5% patients with HT. Conclusion. Enalapril improves endothelium vasomotor function, endothelium reaction on nitroglycerine and clinical course of IHD and HT.

  19. Short term effects of small incision lenticule extraction surgery on corneal endothelium

    Directory of Open Access Journals (Sweden)

    Dan-Yang Wang


    Full Text Available AIM: To assess the effects of small incision lenticule extraction (SMILE surgery on the corneal endothelium at 1d to 1mo postoperatively. METHODS: A retrospective, observational study was conducted on 47 patients (47 eyes who received SMILE surgery. Patients were grouped according to contact lens wear condition. The corneal endothelium was examined preoperatively and at 1d, 1wk and 1mo postoperatively. The corneal endothelium was analyzed for endothelial cell density (ECD, percentage of hexagonal cells, and coefficient of variation (CV of cell size. RESULTS: There were no significant decrease in the ECD, percentage of hexagonal cells or increase in CV at 1d, 1wk and 1mo postoperatively (P>0.05. However, there was a small increase of ECD by 2.88% in contact lens wearers (78.26±113.62 cell/mm2, P<0.05. CONCLUSION: SMILE has no significant adverse effects on the corneal ECD and morphology during 1mo follow-up time.

  20. Feasibility and safety of porcine Descemet’s membrane as a carrier for generating tissue-engineered corneal endothelium

    National Research Council Canada - National Science Library


    The aim of this study was to evaluate the feasibility and safety of porcine Descemet’s membrane (DM) as a carrier for the generation of tissue-engineered corneal endothelium by analyzing porcine endogenous retroviruses...

  1. Ability of combined Near-Infrared Spectroscopy-Intravascular Ultrasound (NIRS-IVUS) imaging to detect lipid core plaques and estimate cap thickness in human autopsy coronary arteries (United States)

    Grainger, S. J.; Su, J. L.; Greiner, C. A.; Saybolt, M. D.; Wilensky, R. L.; Raichlen, J. S.; Madden, S. P.; Muller, J. E.


    The ability to determine plaque cap thickness during catheterization is thought to be of clinical importance for plaque vulnerability assessment. While methods to compositionally assess cap integrity are in development, a method utilizing currently available tools to measure cap thickness is highly desirable. NIRS-IVUS is a commercially available dual imaging method in current clinical use that may provide cap thickness information to the skilled reader; however, this is as yet unproven. Ten autopsy hearts (n=15 arterial segments) were scanned with the multimodality NIRS-IVUS catheter (TVC Imaging System, Infraredx, Inc.) to identify lipid core plaques (LCPs). Skilled readers made predictions of cap thickness over regions of chemogram LCP, using NIRS-IVUS. Artery segments were perfusion fixed and cut into 2 mm serial blocks. Thin sections stained with Movat's pentachrome were analyzed for cap thickness at LCP regions. Block level predictions were compared to histology, as classified by a blinded pathologist. Within 15 arterial segments, 117 chemogram blocks were found by NIRS to contain LCP. Utilizing NIRSIVUS, chemogram blocks were divided into 4 categories: thin capped fibroatheromas (TCFA), thick capped fibroatheromas (ThCFA), pathological intimal thickening (PIT)/lipid pool (no defined cap), and calcified/unable to determine cap thickness. Sensitivities/specificities for thin cap fibroatheromas, thick cap fibroatheromas, and PIT/lipid pools were 0.54/0.99, 0.68/0.88, and 0.80/0.97, respectively. The overall accuracy rate was 70.1% (including 22 blocks unable to predict, p = 0.075). In the absence of calcium, NIRS-IVUS imaging provided predictions of cap thickness over LCP with moderate accuracy. The ability of this multimodality imaging method to identify vulnerable coronary plaques requires further assessment in both larger autopsy studies, and clinical studies in patients undergoing NIRS-IVUS imaging.

  2. Progression and regression of coronary atherosclerosis : role of diet, lipoproteins and lipases

    NARCIS (Netherlands)

    J.D. Barth (Jacques Dov)


    textabstractThe evolution and natural course of human coronary artery disease and risk factor mitigation programs can be studied by comparing sequential coronary angiograms of the same patient at different moments in time.1 Although tens of thousands of angiograms are performed each year to elucidat

  3. Matrix metalloproteinases in premature coronary atherosclerosis: influence of inhibitors, inflammation, and genetic polymorphisms

    NARCIS (Netherlands)

    Nanni, S.; Melandri, G.; Hanemaaijer, R.; Cervi, V.; Tomasi, L.; Altimari, A.; Lent, N. van; Tricoci, P.; Bacchi, L.; Branzi, A.


    Matrix metalloproteinases (MMPs) are thought to participate in the pathogenesis of coronary artery disease (CAD), particularly in the occurrence of acute coronary syndrome (ACS). Little is known about human in vivo MMP regulation in CAD. The expression and regulation of MMPs and their tissue inhibit

  4. The development of coronary vascular system

    Directory of Open Access Journals (Sweden)

    Олена Олександрівна Яковець


    Full Text Available Aim. Set the terms of occurrence and morphological markers of coronary vessels in the embryonic period of human ontogenesis.Material and methods. To realize the aim of our work the embryos of human heart from 5 th to 8 th week of prenatal development period were investigated in the amount of 60. The obtained specimens were evaluated by immunohistochemical study. For this purpose, the original monoclonal antibodies have been used, such as transcription factor Prox-1, cell proliferation marker Ki-67, an endothelial marker CD-34 and smooth-muscle actin (α-SMA. To identify the reaction the solution of chromogen 3-diaminobenzidine tetrachloride was applied, which is manifested in a rich brown color in the sensitive cells of the cardiac wall.Conclusions: The morphological specialization of vascular links of coronary system in the embryonic period has a natural sequence - acquisition of venous properties at first and parallel differentiation of arterial structures. After arteriovenous determination the next phase begins – lymphatic specialization of venous endothelial cells with the formation of lymphatic links of coronary vascular system

  5. Endothelium-dependent and -independent vasorelaxant actions and mechanisms induced by total flavonoids of Elsholtzia splendens in rat aortas. (United States)

    Wang, Hui-Ping; Lu, Jian-Feng; Zhang, Guo-Lin; Li, Xu-Yun; Peng, Hong-Yun; Lu, Yuan; Zhao, Liang; Ye, Zhi-Guo; Bruce, Iain C; Xia, Qiang; Qian, Ling-Bo


    Elsholtzia splendens (ES) is, rich in flavonoids, used to repair copper contaminated soil in China, which has been reported to benefit cardiovascular systems as folk medicine. However, few direct evidences have been found to clarify the vasorelaxation effect of total flavonoids of ES (TFES). The vasoactive effect of TFES and its underlying mechanisms in rat thoracic aortas were investigated using the organ bath system. TFES (5-200mg/L) caused a concentration-dependent vasorelaxation in endothelium-intact rings, which was not abolished but significantly reduced by the removal of endothelium. The nitric oxide synthase (NOS) inhibitor N(ω)-nitro-l-arginine methyl ester (100μM) and the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,2-α]quinoxalin-1-one (30μM) significantly blocked the endothelium-dependent vasorelaxation of TFES. Meanwhile, NOS activity in endothelium-intact aortas was concentration-dependently elevated by TFES. However, indomethacin (10μM) did not affect TFES-induced vasorelaxation. Endothelium-independent vasorelaxation of TFES was significantly attenuated by KATP channel blocker glibenclamide. The accumulative Ca(2+)-induced contraction in endothelium-denuded aortic rings primed with KCl or phenylephrine was markedly weakened by TFES. These results revealed that the NOS/NO/cGMP pathway is likely involved in the endothelium-dependent vasorelaxation induced by TFES, while activating KATP channel, inhibiting intracellular Ca(2+) release, blocking Ca(2+) channels and decreasing Ca(2+) influx into vascular smooth muscle cells might contribute to the endothelium-independent vasorelaxation conferred by TFES.

  6. Hypoadiponectinemia predicts impaired endothelium-independent vasodilation in newly diagnosed type 2 diabetic patients: an 8-year prospective study

    Institute of Scientific and Technical Information of China (English)

    LI Hui; XIAO Yang; LIU Hui; CHEN Xiao-yan; LI Xin-ying; TANG Wei-li; LIU Shi-ping; XU Ai-min; ZHOU Zhi-guang


    Background Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties.The aim of this study was to investigate whether low adiponectin levels predict the impairment of endothelial function in newly diagnosed type 2 diabetic patients in an 8-year prospective study.Methods In the prospective study,we enrolled 133 newly diagnosed type 2 diabetic patients without subclinical atherosclerosis and gave them intensive therapy; the mean treatment period was 8 years.Intensive treatment was a stepwise implementation of behavior modification and pharmacological therapy targeting hyperglycaemia,hypertension,dyslipidaemia and obesity.We measured baseline circulating adiponectin with an enzyme-linked immunosorbent assay,endothelium-dependent and -independent vasodilation by high-resolution vascular ultrasound.At year 8,102 patients were reexamined for endothelium-dependent and -independent vasodilation.Results Sex-adjusted adiponectin level was positively correlated with endothelium-independent vasodilation both at baseline (r=0.150,P=0.043) and at year 8 (r=0.339,P=0.001),whereas no association was found between adiponectin and endothelium-dependent vasodilation.In a stepwise multivariate linear regression model,adiponectin was an independent predictor for impaired endothelium-independent vasodilation at year 8 (P=0.001).Conclusions Plasma adiponectin concentration was associated with endothelium-independent vasodilation and hypoadiponectinemia predicted the impairment of endothelium-independent vasodilation in newly diagnosed type 2 diabetic patients under multifactorial intervention.These data support the causative link of impairment of endothelium-independent vasodilation with hypoadiponectinemia.

  7. Low-density lipoprotein concentration in the normal left coronary artery tree

    Directory of Open Access Journals (Sweden)

    Louridas George E


    Full Text Available Abstract Background The blood flow and transportation of molecules in the cardiovascular system plays a crucial role in the genesis and progression of atherosclerosis. This computational study elucidates the Low Density Lipoprotein (LDL site concentration in the entire normal human 3D tree of the LCA. Methods A 3D geometry model of the normal human LCA tree is constructed. Angiographic data used for geometry construction correspond to end-diastole. The resulted model includes the LMCA, LAD, LCxA and their main branches. The numerical simulation couples the flow equations with the transport equation applying realistic boundary conditions at the wall. Results High concentration of LDL values appears at bifurcation opposite to the flow dividers in the proximal regions of the Left Coronary Artery (LCA tree, where atherosclerosis frequently occurs. The area-averaged normalized luminal surface LDL concentrations over the entire LCA tree are, 1.0348, 1.054 and 1.23, for the low, median and high water infiltration velocities, respectively. For the high, median and low molecular diffusivities, the peak values of the normalized LDL luminal surface concentration at the LMCA bifurcation reach 1.065, 1.080 and 1.205, respectively. LCA tree walls are exposed to a cholesterolemic environment although the applied mass and flow conditions refer to normal human geometry and normal mass-flow conditions. Conclusion The relationship between WSS and luminal surface concentration of LDL indicates that LDL is elevated at locations where WSS is low. Concave sides of the LCA tree exhibit higher concentration of LDL than the convex sides. Decreased molecular diffusivity increases the LDL concentration. Increased water infiltration velocity increases the LDL concentration. The regional area of high luminal surface concentration is increased with increasing water infiltration velocity. Regions of high LDL luminal surface concentration do not necessarily co-locate to the

  8. Spontaneous Coronary Artery Dissection. (United States)

    Tweet, Marysia S; Gulati, Rajiv; Hayes, Sharonne N


    Spontaneous coronary artery dissection is an important etiology of nonatherosclerotic acute coronary syndrome, myocardial infarction, and sudden death. Innovations in the catheterization laboratory including optical coherence tomography and intravascular ultrasound have enhanced the ability to visualize intimal disruption and intramural hematoma associated with SCAD. Formerly considered "rare," these technological advances and heightened awareness suggest that SCAD is more prevalent than prior estimates. SCAD is associated with female sex, young age, extreme emotional stress, or extreme exertion, pregnancy, and fibromuscular dysplasia. The clinical characteristics and management strategies of SCAD patients are different than for atherosclerotic heart disease and deserve specific consideration. This review will highlight recent discoveries about SCAD as well as describe current efforts to elucidate remaining gaps in knowledge.

  9. The discovery of endothelin: the power of bioassay and the role of serendipity in the discovery of endothelium-derived vasocative substances. (United States)

    Rubanyi, Gabor M


    Significant discoveries in biology and medicine are rare. The progress in these fields is predominantly incremental, but sometimes new observations revolutionize the field by opening new directions in research for decades to come. Two cornerstone observations in the late 1970s and early 1980s are examples of such "revolutionary" events. The first, by Furchgott and Zawadzki, was the discovery of the "obligatory role of the endothelium in vasorelaxation by acetylcholine". The other, by Hickey and colleagues, was the first description and characterization of a vasoconstrictor polypeptide produced by endothelial cells in culture. Both of these observations were achieved by the application of bioassay and serendipity played an important role in each of them. They both represent starting points for rapid growth in research activity world-wide leading to the identification of EDRF as nitric oxide, and the polypeptide EDCF as endothelin a few years later. These early observations also raised interest and initiated intensive R&D activity in the pharma industry culminating in the regulatory approval and marketing of novel medicines treating human diseases. This review describes the events leading to the discovery and early characterization of the peptidergic endothelium-derived constrictor factor, and its purification, sequencing and naming it endothelin.

  10. Depression and Coronary Heart Disease



    There are exciting findings in the field of depression and coronary heart disease. Whether diagnosed or simply self-reported, depression continues to mark very high risk for a recurrent acute coronary syndrome or for death in patients with coronary heart disease. Many intriguing mechanisms have been posited to be implicated in the association between depression and heart disease, and randomized controlled trials of depression treatment are beginning to delineate the types of depression manage...

  11. Coronary heart disease

    Institute of Scientific and Technical Information of China (English)


    920658 Assessment of plasma catechola-mine and β-endorphin contents in patientswith silent myocardial ischemia and anginapectoris. WU Lin(吴林), et al. 1st Hosp, BeijingMed Univ, Beijing, 100034. Cbin J Cardiol1992; 20(2): 90-91. Thirteen Patients with totally silent myocar-dial ischemia(group 1)and 15 patients with ef-fort angina(group 2)were studied. The coronary

  12. Endothelin ETA receptors and endothelium partially mediate the positive inotropic and lusitropic effects of angiotensin II. (United States)

    Castro-Chaves, Paulo; Roncon-Albuquerque, Roberto; Leite-Moreira, Adelino F


    We analyzed the influence of endothelin-1 and endocardial endothelium on the myocardial effects of angiotensin-II. Angiotensin-II (10(-9)-10(-5) M) was tested in rabbit right papillary muscles in absence (Protocol-A) or presence of PD-145065 (10(-7) M; Protocol-B), BQ-123 (10(-7) M; Protocol-C) or losartan (10(-6) M; Protocol-E), as well as, after removing the endocardial endothelium with Triton X-100 0.5% (Protocol-D). In Protocol-F increasing concentrations of endothelin-1 (10(-10)-10(-8) M) were added in presence of angiotensin-II (10(-7) M) after selective removal of the endocardial endothelium. In Protocol-A, angiotensin-II had dose-dependent positive inotropic and lusitropic effects, maximal at 10(-6) M increasing 122+/-13% active tension, 117+/-16% dT/dtmax and 86+/-9% dT/dtmin. In Protocols B, C and D the inotropic and lusitropic effects of angiotensin-II were significantly attenuated. The same concentration (10(-6) M) of angiotensin-II increased respectively 48+/-11%, 59+/-27% and 72+/-16% active tension; 54+/-14%, 54+/-20% and 32+/-9% dT/dtmax; and 39+/-8%, 48+/-19% and 59+/-11% dT/dtmin; and 40+/-10%. EC(50) for active tension significantly increased from -7.8+/-0.1 logM in Protocol A to -7.1+/-0.3, -6.7+/-0.4 and -6.8+/-0.3 logM in Protocols B, C and D respectively, while Emax decreased from 106+/-14% in Protocol A to 50+/-14 and 51+/-19% in Protocols B and C respectively, but did not significantly change in Protocol D (114+/-25%). Losartan completely blocked the inotropic and lusitropic effects of angiotensin-II, while the attenuation of these effects after the selective removal of the endocardial endothelium was blunted by concomitant administration of endothelin-1 (Protocol F). In conclusion, angiotensin-II has a dose-dependent positive inotropic effect that depends, to a great extent, on endothelin ETA receptor activation and intact endocardial endothelium.

  13. Endothelium negatively modulates the vascular relaxation induced by nitric oxide donor, due to uncoupling NO synthase. (United States)

    Bonaventura, Daniella; Lunardi, Claure N; Rodrigues, Gerson J; Neto, Mário A; Vercesi, Juliana A; de Lima, Renata G; da Silva, Roberto S; Bendhack, Lusiane M


    Nitrosyl ruthenium complexes have been characterized as nitric oxide (NO) donors that induce relaxation in the denuded rat aorta. There are some differences in their vascular relaxation mechanisms compared with sodium nitroprusside. This study investigates whether the endothelium could interfere with the [Ru(terpy)(bdq)NO](3+)-TERPY-induced vascular relaxation, by analyzing the maximal relaxation (Emax) and potency (pD(2)) of TERPY. Vascular reactivity experiments showed that the endothelium negatively modulates (pD(2): 6.17+/-0.07) the TERPY relaxation in intact rat aortic rings compared with the denuded rat aorta (pD(2): 6.65+/-0.07). This effect is abolished by a non-selective NO-synthase (NOS) inhibitor L-NAME (pD(2): 6.46+/-0.10), by the superoxide anion (O(2)(-)) scavenger TIRON (pD(2): 6.49+/-0.08), and by an NOS cofactor BH(4) (pD(2): 6.80+/-0.10). The selective dye for O(2)(-) (DHE) shows that TERPY enhances O(2)(-) concentration in isolated endothelial cells (intensity of fluorescence (IF):11258.00+/-317.75) compared with the basal concentration (IF: 7760.67+/-381.50), and this enhancement is blocked by L-NAME (IF: 8892.33+/-1074.41). Similar results were observed in vascular smooth muscle cells (concentration of superoxide after TERPY: 2.63+/-0.17% and after TERPY+L-NAME: -4.63+/-0.14%). Considering that TERPY could induce uncoupling NOS, thus producing O(2)(-), we have also investigated the involvement of prostanoids in the negative modulation of the endothelium. The non-selective cyclooxygenase (COX) inhibitor indomethacin and the selective tromboxane (TXA(2)) receptor antagonist SQ29548 reduce the effect of the endothelium on TERPY relaxation (pD(2) INDO: 6.80+/-0.17 and SQ29548: 6.85+/-0.15, respectively). However, a selective prostaglandin F(2alpha) receptor antagonist (AH6809) does not change the endothelium effect. Moreover, TERPY enhances the concentration of TXA(2) stable metabolite (TXB(2)), but this effect is blocked by L-NAME and TIRON. The

  14. [Intermediate coronary care units: rationale, infrastructure, equipment, and referral criteria]. (United States)

    Alonso, Joaquín J; Sanz, Ginés; Guindo, Josep; García-Moll, Xavier; Bardají, Alfredo; Bueno, Héctor


    The Spanish Working Group on Coronary Artery Disease of Spanish Society of Cardiology has considered to be necessary the development of this document on the need, structure and organization of Intermediate Cardiac Care Units (ICCU). Acute coronary syndrome registries show that an important percentage of patients receive a suboptimal care, due to an inadequate management of health resources or absence of them. Intermediate cardiac care units arise to solve these challenges and to manage in an efficient way these expensive and limited resources. Their aims are: a) to provide each patient the level of care required; b) to optimize the structural, technical and human resources, and c) to make easier continuous care and care gradient. As a result, ICCU should be established as an essential part of the cardiology department aim to cardiac patients requiring monitoring and medical care superior to those available in a regular cardiac ward but whose risk does not justify the technical and human costs of a Coronary Unit. This document describes the structure (equipment, human resources, management) required to reach the goals previously reported and includes recommendations about indications of admission in a ICCU. These indications include: a) patients with NSTE-ACS with intermediate or high risk but hemodynamically stable, and b) low risk STEAMI or high risk STEAMI stabilized after an initial admission at the Coronary Unit. The admission of some patients undergoing invasive procedures or suffering non-coronary acute cardiac diseases, is also considered.

  15. Coffee Consumption and Coronary Calcification: The Rotterdam Coronary Calcification Study

    NARCIS (Netherlands)

    Woudenbergh, van G.J.; Vliegenthart, R.; Rooij, van F.J.A.; Hofman, A.; Oudkerk, M.; Witteman, J.C.M.; Geleijnse, J.M.


    Background¿ The role of coffee in the cardiovascular system is not yet clear. We examined the relation of coffee intake with coronary calcification in a population-based cohort. Methods and Results¿ The study involved 1570 older men and women without coronary heart disease who participated in the Ro

  16. Coffee consumption and coronary calcification - The Rotterdam Coronary Calcification Study

    NARCIS (Netherlands)

    van Woudenbergh, Geertruida J.; Vliegenthart, Rozemarijn; van Rooij, Frank J. A.; Hofman, Albert; Oudkerk, Matthijs; Witteman, Jacqueline C. M.; Geleijnse, Johanna M.


    Background-The role of coffee in the cardiovascular system is not yet clear. We examined the relation of coffee intake with coronary calcification in a population-based cohort. Methods and Results-The study involved 1570 older men and women without coronary heart disease who participated in the Rott

  17. Coffee consumption and coronary calcification: The Rotterdam coronary calcification study

    NARCIS (Netherlands)

    G.J. van Woudenbergh (Geertruida); R. Vliegenthart (Rozemarijn); F.J.A. van Rooij (Frank); A. Hofman (Albert); M. Oudkerk (Matthijs); J.C.M. Witteman (Jacqueline); J.M. Geleijnse (Marianne)


    textabstractBACKGROUND - The role of coffee in the cardiovascular system is not yet clear. We examined the relation of coffee intake with coronary calcification in a population-based cohort. METHODS AND RESULTS - The study involved 1570 older men and women without coronary heart disease who particip

  18. Dominância coronariana em corações humanos em moldes por corrosão Coronary dominance patterns in the human heart investigated by corrosion casting

    Directory of Open Access Journals (Sweden)

    Décio Cavalet Soares Abuchaim


    Full Text Available OBJETIVO: Esse trabalho tem como objetivo analisar os padrões de dominância circulatória de corações humanos, o número de ramos que a artéria coronária direita fornece ao ventrículo esquerdo, o número de ramos que a artéria coronária esquerda fornece ao direito e a presença de anastomoses intercoronarianas, com sua localização e frequência. MÉTODOS: Foram produzidos 25 moldes de corações submetidos à instilação de acrílico colorido e posterior corrosão com ácido clorídrico, no Laboratório de Cirurgia Experimental da FURB. Peças com lesões e cicatrizes não foram usadas. RESULTADOS: Os corações pertenciam a indivíduos de ambos os sexos, sendo 17 (68% de indivíduos do sexo masculino, com idade média de 40,2 anos (15 a 70 anos. A dominância direita ocorreu em 18 (72% peças, com 1, 2, 3 e 4 ramos em 2, 14, 2 e 1 moldes, respectivamente; a dominância esquerda foi observada em 5 (20% casos, com 1 ramo em 4 moldes e 2 em 1 molde; e a dominância balanceada foi verificada em 2 (8% moldes. Houve diferença significativa entre a dominância direita e esquerda (α > 5%, direita e balanceada (α > 5% e sem significância entre esquerda e balanceada (α OBJECTIVES: The aim of this work was to analyze the dominance patterns of the circulation of the human heart, the number of branches from the right coronary artery to the left ventricle, the number of branches from the left coronary artery to the right ventricle and the frequency and location of intercoronary anastomoses. METHODS: Casts were made of 25 hearts by the injection of colored acrylic resin and subsequent corrosion using hydrochloric acid at the experimental surgery laboratory of Furb. Specimens with lesions or scars were discarded. RESULTS: The hearts, from both men (17 - 68% and women (8 - 32%, had a mean age of 40.2 (15 to 70 years-old. Right dominance occurred in 18 (72% subjects, with 1, 2, 3 and 4 branches leading to the left ventricle in 2, 14, 2 and 2

  19. No effect of aluminium upon the hydrolysis of ATP in the coronary circulation of the isolated working rat heart. (United States)

    Korchazhkina, O; Wright, G; Exley, C


    Adenosine 5'-triphosphate (ATP) is now recognised as an important extracellular signalling molecule. Its action at a number of specific receptors is mediated by the activity of ectonucleotidases. We have optimised a high performance liquid chromatography (HPLC) method to allow the simultaneous determination of ATP, and the products of its hydrolysis, in the coronary effluent of an isolated working rat heart. The method is extremely sensitive allowing picomolar quantities of product to be determined. We have used this method to investigate the influence of aluminium on the hydrolysis of ATP by an ecto-ATPase located in the luminal surface of the coronary endothelium of the rat heart. Aluminium did not influence the hydrolysis of ATP by this enzyme.

  20. CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma. (United States)

    Wadkin, James C R; Patten, Daniel A; Kamarajah, Sivesh K; Shepherd, Emma L; Novitskaya, Vera; Berditchevski, Fedor; Adams, David H; Weston, Chris J; Shetty, Shishir


    CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention.NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in

  1. Number and function of bone-marrow derived angiogenic cells and coronary flow reserve in women without obstructive coronary artery disease: a substudy of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE.

    Directory of Open Access Journals (Sweden)

    Rajesh Mohandas

    Full Text Available BACKGROUND: In women with ischemia and no obstructive coronary artery disease, the Women's Ischemic Syndrome Evaluation (WISE observed that microvascular coronary dysfunction (MCD is the best independent predictor of adverse cardiovascular events. Since coronary microvascular tone is regulated in part by endothelium, we hypothesized that circulating endothelial cells (CEC, which reflect endothelial injury, and the number and function of bone-marrow derived angiogenic cells (BMDAC, which could help repair damaged endothelium, may serve as biomarkers for decreased coronary flow reserve (CFR and MCD. METHODS: We studied 32 women from the WISE cohort. CFR measurements in response to intracoronary adenosine were taken as an index of MCD. We enumerated BMDAC colonies and CEC in peripheral blood samples. BMDAC function was assessed by assay of migration of CD34+ cells toward SDF-1 and measurement of bioavailable nitric oxide (NO. These findings were compared with a healthy reference group and also entered into a multivariable model with CFR as the dependent variable. RESULTS: Compared with a healthy reference group, women with MCD had lower numbers of BMDAC colonies [16 (0, 81 vs. 24 (14, 88; P = 0.01] and NO [936 (156, 1875 vs. 1168 (668, 1823; P = 0.02]. Multivariable regression analysis showed strong correlation of CFR to the combination of BMDAC colony count and CD34+ cell function (migration and NO (R(2 = 0.45; P<0.05. CONCLUSIONS: The BMDAC function and numbers of BMDAC colonies are decreased in symptomatic women with MCD and are independently associated with CFR. These circulating cells may provide mechanistic insights into MCD in women with ischemia.

  2. Chelation for Coronary Heart Disease (United States)

    ... V W X Y Z Chelation for Coronary Heart Disease Share: © AHA Coronary heart disease is a leading cause of death among both ... health approach . The use of disodium EDTA for heart disease has not been approved by the U.S. Food ...

  3. Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions

    DEFF Research Database (Denmark)

    Poulsen, Christian Bo; Al-Mashhadi, Ahmed Ludvigsen; von Wachenfeldt, Karin;


    BACKGROUND: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs. METHODS AND ...

  4. Circulating factors induce coronary endothelial cell activation following exposure to inhaled diesel exhaust and nitrogen dioxide in humans: Evidence from a novel translational in vitro model** (United States)

    The vascular toxicity of inhaled agents may be caused by soluble factors that are released into the systemic circulation. To confirm this in a straightforward manner, we obtained plasma from healthy human volunteers before and after exposure to diesel exhaust (DE) and nitrogen di...

  5. Robotics and coronary artery surgery. (United States)

    Magee, Mitchell J; Mack, Michael J


    Significant progress in cardiac surgery, and specifically the surgical management of coronary artery disease, has been due in large part to enabling technology. Robotic systems have been recently developed and refined for use in cardiac surgery to facilitate, among other procedures, a totally endoscopic approach to coronary artery bypass surgery. These systems enhance precision through endoscopic approaches by specifically addressing the inherent limitations of conventional endoscopic coronary microsurgical instrumentation via computerized, digital interface, telemanipulation technology. With a combined experience of 125 patients, several groups have independently demonstrated the clinical feasibility of totally endoscopic coronary artery bypass with two commercially available robotic telemanipulation systems. Additional enabling technology is needed to overcome the challenges currently limiting development and widespread application of totally endoscopic off-pump multivessel coronary artery bypass surgery.

  6. Long‐term recovery of the human corneal endothelium after toxic injury by benzalkonium chloride (United States)

    Hughes, E H; Pretorius, M; Eleftheriadis, H; Liu, C S C


    Introduction The inadvertent intra‐ocular administration of benzalkonium chloride‐preserved hydroxypropyl methylcellulose during cataract surgery at another hospital in 1999 resulted in toxic corneal endothelial injury and profound postoperative corneal oedema as a result of endothelial decompensation. The long‐term effect of this adverse event was assessed. Methods All 19 patients were invited to return for examination including corneal endothelial specular microscopy and pachymetry seven years after the incident. Results were compared with data from one year after the incident. Results Five patients attended for examination, one had received a penetrating keratoplasty and was, therefore, excluded. Ten patients had died and four had moved out of the region and were unable to attend. All four study patients were pain free and achieved 6/12 or better. Mean central corneal thickness reduced by 13% from 652.6 μm at one year to 563.4 μm. Mean central corneal endothelial cell density (n  =  3) increased 28% from 663.7 cells/mm2 at one year to 835.7 cells/mm2 (p<0.05). Conclusions After toxic injury, corneal endothelial function may have a remarkable capacity for recovery even after the first postoperative year. The rise in central endothelial cell density may represent cell migration from less affected areas or cellular proliferation. Should this unfortunate event recur, clinicians may expect continued recovery beyond one year. PMID:17504856

  7. Rapid in vitro derivation of endothelium directly from human cancer cells.

    Directory of Open Access Journals (Sweden)

    Jennifer D Elster

    Full Text Available The development of an independent blood supply by a tumor is essential for maintaining growth beyond a certain limited size and for providing a portal for metastatic dissemination. Host-derived endothelial cells (ECs residing in and compromising the tumor vasculature originate via distinct processes known as sprouting angiogenesis and vasculogenesis. More recently ECs originating directly from the tumor cells themselves have been described although the basis for this phenomenon remains poorly understood. Here we describe in vitro conditions that allow lung and ovarian cancer cells to undergo a rapid and efficient transition into ECs that are indistinguishable from those obtained in vivo. A variety of methods were used to establish that the acquired phenotypes and behaviors of these tumor-derived ECs (TDECs closely resemble those of authentic ECs. Xenografts arising from co-inoculated in vitro-derived TDECs and tumor cells were also more highly vascularized than control tumors; moreover, their blood vessels were on average larger and frequently contained admixtures of host-derived ECs and TDECs derived from the initial inoculum. These results demonstrate that cancer cells can be manipulated under well-defined in vitro conditions to initiate a tumor cell-to-EC transition that is largely cell-autonomous, highly efficient and closely mimics the in vivo process. These studies provide a suitable means by which to identify and perhaps modify the earliest steps in TDEC generation.

  8. Iron ion irradiation increases promotes adhesion of monocytic cells to arterial vascular endothelium (United States)

    Kucik, Dennis; Khaled, Saman; Gupta, Kiran; Wu, Xing; Yu, Tao; Chang, Polly; Kabarowski, Janusz

    Radiation causes inflammation, and chronic, low-level vascular inflammation is a risk factor for atherosclerosis. Consistent with this, exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. Part of the inflammatory response to radiation is a change in the adhesiveness of the endothelial cells that line the blood vessels, triggering inappropriate accumulation of leukocytes, leading to later, damaging effects of inflammation. Although some studies have been done on the effects of gamma irradiation on vascular endothelium, the response of endothelium to heavy ion radiation likely to be encountered in prolonged space flight has not been determined. We investigated how irradiation of aortic endothelial cells with iron ions affects adhesiveness of cultured aortic endothelial cells for monocytic cells and the consequences of this for development of atherosclerosis. Aortic endothelial cells were irradiated with 600 MeV iron ions at Brookhaven National Laboratory and adhesion-related changes were measured. Cells remained viable for at least 72 hours, and were even able to repair acute damage to cell junctions. We found that iron ion irradiation altered expression levels of specific endothelial cell adhesion molecules. Further, these changes had functional consequences. Using a flow chamber adhesion assay to measure adhesion of monocytic cells to endothelial cells under physiological shear stress, we found that adhesivity of vascular endothelium was enhanced in as little as 24 hours after irradiation. Further, the radiation dose dependence was not monotonic, suggesting that it was not simply the result of endothelial cell damage. We also irradiated aortic arches and carotid arteries of Apolipoprotein-E-deficient mice. Histologic analysis of these mice will be conducted to determine whether effects of radiation on endothelial adhesiveness result in consequences for development of atherosclerosis. (Supported by NSBRI

  9. Integrins mediate mechanical compression-induced endothelium-dependent vasodilation through endothelial nitric oxide pathway. (United States)

    Lu, Xiao; Kassab, Ghassan S


    Cardiac and skeletal muscle contraction lead to compression of intramuscular arterioles, which, in turn, leads to their vasodilation (a process that may enhance blood flow during muscle activity). Although endothelium-derived nitric oxide (NO) has been implicated in compression-induced vasodilation, the mechanism whereby arterial compression elicits NO production is unclear. We cannulated isolated swine (n = 39) myocardial (n = 69) and skeletal muscle (n = 60) arteriole segments and exposed them to cyclic transmural pressure generated by either intraluminal or extraluminal pressure pulses to simulate compression in contracting muscle. We found that the vasodilation elicited by internal or external pressure pulses was equivalent; moreover, vasodilation in response to pressure depended on changes in arteriole diameter. Agonist-induced endothelium-dependent and -independent vasodilation was used to verify endothelial and vascular smooth muscle cell viability. Vasodilation in response to cyclic changes in transmural pressure was smaller than that elicited by pharmacological activation of the NO signaling pathway. It was attenuated by inhibition of NO synthase and by mechanical removal of the endothelium. Stemming from previous observations that endothelial integrin is implicated in vasodilation in response to shear stress, we found that function-blocking integrin α5β1 or αvβ3 antibodies attenuated cyclic compression-induced vasodilation and NOx (NO(-)2 and NO(-)3) production, as did an RGD peptide that competitively inhibits ligand binding to some integrins. We therefore conclude that integrin plays a role in cyclic compression-induced endothelial NO production and thereby in the vasodilation of small arteries during cyclic transmural pressure loading.

  10. Modulation of ADPase and t-PA release by radiographic contrast media in bovine aortic endothelium. (United States)

    Caprino, L; Togna, A R; Zappacosta, B; Giardina, B; Togna, G


    Vascular endothelial injuries induced by intravascular administration of radiographic contrast agents may be clinically relevant to the development of thrombosis and platelet activation. In this connection, we investigated the in vitro effects induced by iodamide, iopamidol, and ioxaglate on vascular endothelial ADPase activity and tissue plasminogen activator (t-PA) release in bovine aortic endothelium, in order to extend knowledge required to evaluate endothelial compatibility of radiographic contrast media. Undiluted and Tris-diluted contrast agent formulations were employed, and mannitol and sucrose hyperosmolar solutions were used as comparison. Results demonstrated that the high-osmolar ionic contrast agent iodamide, and to a lesser extent, the low-osmolar nonionic agent iopamidol, stimulated endothelial ADPase activity of the aortic endothelium; the low-osmolar ionic agent ioxaglate left endothelial ADPase activity unchanged. Furthermore, the diluted formulations of iodamide and iopamidol, as well as high-osmolar mannitol and sucrose solutions, were devoid of activity in ADPase. This suggests that the endothelial ADPase stimulation induced by both radiographic contrast media was a hyperosmolar-independent pharmacodynamic activity. Iopamidol and ioxaglate reduced endogenous t-PA release from bovine aortic endothelium only in undiluted formulation, while iodamide showed this inhibiting action in both diluted and undiluted formulations. No effect was observed when using mannitol solutions at different osmolarity values. Our in vitro findings agree with published data on the different thrombotic tendency attributed to the contrast agents used, suggesting endothelial enzymatic activities (ADPase and t-PA release) as suitable tools for evaluating endothelial vessel wall compatibility with radiographic contrast media.

  11. Functional role of gap junctions in cytokine-induced leukocyte adhesion to endothelium in vivo (United States)

    Véliz, Loreto P.; González, Francisco G.; Duling, Brian R.; Sáez, Juan C.; Boric, Mauricio P.


    To assess the hypothesis that gap junctions (GJs) participate on leukocyte-endothelium interactions in the inflammatory response, we compared leukocyte adhesion and transmigration elicited by cytokine stimulation in the presence or absence of GJ blockers in the hamster cheek pouch and also in the cremaster muscle of wild-type (WT) and endothelium-specific connexin 43 (Cx43) null mice (Cx43e−/−). In the cheek pouch, topical tumor necrosis factor-α (TNF-α; 150 ng/ml, 15 min) caused a sustained increment in the number of leukocytes adhered to venular endothelium (LAV) and located at perivenular regions (LPV). Superfusion with the GJ blockers 18-α-glycyrrhetinic acid (AGA; 75 μM) or 18-β-glycyrrhetinic acid (50 μM) abolished the TNF-α-induced increase in LAV and LPV; carbenoxolone (75 μM) or oleamide (100 μM) reduced LAV by 50 and 75%, respectively, and LPV to a lesser extent. None of these GJ blockers modified venular diameter, blood flow, or leukocyte rolling. In contrast, glycyrrhizin (75 μM), a non-GJ blocker analog of AGA, was devoid of effect. Interestingly, when AGA was removed 90 min after TNF-α stimulation, LAV started to rise at a similar rate as in control. Conversely, application of AGA 90 min after TNF-α reduced the number of previously adhered cells. In WT mice, intrascrotal injection of TNF-α (0.5 μg/0.3 ml) increased LAV (fourfold) and LPV (threefold) compared with saline-injected controls. In contrast to the observations i