Porphyromonas gingivalis Differentially Modulates Cell Death Profile in Ox-LDL and TNF-α Pre-Treated Endothelial Cells.

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Isaac Maximiliano Bugueno

Full Text Available Clinical studies demonstrated a potential link between atherosclerosis and periodontitis. Porphyromonas gingivalis (Pg, one of the main periodontal pathogen, has been associated to atheromatous plaque worsening. However, synergism between infection and other endothelial stressors such as oxidized-LDL or TNF-α especially on endothelial cell (EC death has not been investigated. This study aims to assess the role of Pg on EC death in an inflammatory context and to determine potential molecular pathways involved.Human umbilical vein ECs (HUVECs were infected with Pg (MOI 100 or stimulated by its lipopolysaccharide (Pg-LPS (1μg/ml for 24 to 48 hours. Cell viability was measured with AlamarBlue test, type of cell death induced was assessed using Annexin V/propidium iodide staining. mRNA expression regarding caspase-1, -3, -9, Bcl-2, Bax-1 and Apaf-1 has been evaluated with RT-qPCR. Caspases enzymatic activity and concentration of APAF-1 protein were evaluated to confirm mRNA results.Pg infection and Pg-LPS stimulation induced EC death. A cumulative effect has been observed in Ox-LDL pre-treated ECs infected or stimulated. This effect was not observed in TNF-α pre-treated cells. Pg infection promotes EC necrosis, however, in infected Ox-LDL pre-treated ECs, apoptosis was promoted. This effect was not observed in TNF-α pre-treated cells highlighting specificity of molecular pathways activated. Regarding mRNA expression, Pg increased expression of pro-apoptotic genes including caspases-1,-3,-9, Bax-1 and decreased expression of anti-apoptotic Bcl-2. In Ox-LDL pre-treated ECs, Pg increased significantly the expression of Apaf-1. These results were confirmed at the protein level.This study contributes to demonstrate that Pg and its Pg-LPS could exacerbate Ox-LDL and TNF-α induced endothelial injury through increase of EC death. Interestingly, molecular pathways are differentially modulated by the infection in function of the pre-stimulation.

Electronegative LDL: A Circulating Modified LDL with a Role in Inflammation

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Montserrat Estruch

2013-01-01

Full Text Available Electronegative low density lipoprotein (LDL(− is a minor modified fraction of LDL found in blood. It comprises a heterogeneous population of LDL particles modified by various mechanisms sharing as a common feature increased electronegativity. Modification by oxidation is one of these mechanisms. LDL(− has inflammatory properties similar to those of oxidized LDL (oxLDL, such as inflammatory cytokine release in leukocytes and endothelial cells. However, in contrast with oxLDL, LDL(− also has some anti-inflammatory effects on cultured cells. The inflammatory and anti-inflammatory properties ascribed to LDL(− suggest that it could have a dual biological effect.

The effect of oxLDL on microvesicle release from platelets, measured by a sensitive flow cytometry method.

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Tine Bo Nielsen

2015-11-01

Full Text Available Microvesicles (MVs are submicron vesicles with sizes of 0.1-1.0-µm in diameter, released from various cell types upon activation or apoptosis. Their involvement in a variety of diseases has been intensively investigated. In blood, platelets are potent MV secretors, and oxLDL, a platelet ligand, induce platelet activation and thus potentially MV secretion. This interaction occurs through binding of oxLDL with CD36, located on the platelet membrane. In this study we investigated the effect of in vitro incubation of platelets with oxLDL on MV release. Furthermore, we compared the results obtained when separating MVs larger than 0.5-µm as a measure of results obtained from less sensitive conventional flow cytometers with MVs below the 0.5-µm limit. MV size-distribution was analysed in plasma from 11 healthy volunteers (4 females, 7 males. MVs were identified as < 1-μm and positive for lactadherin binding and cell specific markers. Platelet rich plasma (PRP was incubated without and with oxLDL or LDL (as control to investigate the impact on platelet activation, evident by release of MVs. Size-calibrated fluorescent beads were used to establish the MV gate, and separate small- and large-size vesicles. CD41+ and CD41+CD36+ MVs increased by 6-8 fold in PRP, when left at room temperature, and the presence of cell specific markers increased. Total MV count was unaffected. Incubations with oxLDL did not increase the MV release or affect the distribution of small- and large-size MVs. We found a large inter-individual variation in the fraction of small- and large-size MVs of 73%. In conclusion, we propose that pro-coagulant activity and activation of platelets induced by interaction of platelet CD36 with oxLDL may not involve release of MVs. Furthermore, our results demonstrate great inter-individual variability in size-distribution of platelet derived MVs and thereby stresses the importance for generation of standardized protocols for MV quantification

Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation.

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Bieghs, Veerle; Walenbergh, Sofie M A; Hendrikx, Tim; van Gorp, Patrick J; Verheyen, Fons; Olde Damink, Steven W; Masclee, Ad A; Koek, Ger H; Hofker, Marten H; Binder, Christoph J; Shiri-Sverdlov, Ronit

2013-08-01

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation. The transition from steatosis towards NASH represents a key step in pathogenesis, as it will set the stage for further severe liver damage. Under normal conditions, lipoproteins that are endocytosed by Kupffer cells (KCs) are easily transferred from the lysosomes into the cytoplasm. Oxidized LDL (oxLDL) that is taken up by the macrophages in vitro is trapped within the lysosomes, while acetylated LDL (acLDL) is leading to normal lysosomal hydrolysis, resulting in cytoplasmic storage. We have recently demonstrated that hepatic inflammation is correlated with lysosomal trapping of lipids. So far, a link between lysosomal trapping of oxLDL and inflammation was not established. We hypothesized that lysosomal trapping of oxLDL in KCs will lead to hepatic inflammation. Ldlr(-/-) mice were injected with LDL, acLDL and oxLDL and sacrificed after 2, 6 and 24 h. Electron microscopy of KCs demonstrated that after oxLDL injection, small lipid inclusions were present inside the lysosomes after all time points and were mostly pronounced after 6 and 24 h. In contrast, no lipid inclusions were present inside KCs after LDL or acLDL injection. Hepatic expression of several inflammatory genes and scavenger receptors was higher after oxLDL injections compared with LDL or acLDL. These data suggest that trapping of oxLDL inside lysosomes of KCs in vivo is causally linked to increased hepatic inflammatory gene expression. Our novel observations provide new bases for prevention and treatment of NASH. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS-mediated mitochondrial and p53-related apoptotic pathways

Energy Technology Data Exchange (ETDEWEB)

Chang, Chun-Yu [Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Shen, Chao-Yu [School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan (China); Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan (China); School of Medicine, Chung Shan Medical University, Taichung, Taiwan (China); Kang, Chao-Kai [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, (China); Sher, Yuh-Pyng [Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (China); Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan (China); Sheu, Wayne H.-H. [Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (China); School of Medicine, National Yang Ming University, Taipei, Taiwan (China); School of Medicine, National Defense Medical Center, Taipei, Taiwan (China); Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw [Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan (China); Lee, Tsung-Han, E-mail: thlee@email.nchu.edu.tw [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, (China); Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan (China); Department of Biological Science and Technology, China Medical University, Taichung, Taiwan (China)

2014-09-15

Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100 μM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis-related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways. - Highlights: • Oxidized LDL induced cytotoxicity and apoptosis in HK-2 cells. • Pretreatment with taurine attenuated oxLDL-induced nephrotoxicity. • Taurine protected against renal damages through inhibition of ROS generation. • Taurine prevented apoptosis through modulation of the p53 phosphorylation.

Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS-mediated mitochondrial and p53-related apoptotic pathways

International Nuclear Information System (INIS)

Chang, Chun-Yu; Shen, Chao-Yu; Kang, Chao-Kai; Sher, Yuh-Pyng; Sheu, Wayne H.-H.; Chang, Chia-Che; Lee, Tsung-Han

2014-01-01

Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100 μM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis-related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways. - Highlights: • Oxidized LDL induced cytotoxicity and apoptosis in HK-2 cells. • Pretreatment with taurine attenuated oxLDL-induced nephrotoxicity. • Taurine protected against renal damages through inhibition of ROS generation. • Taurine prevented apoptosis through modulation of the p53 phosphorylation

Curcumin prevents the oxidation and lipid modification of LDL and its inhibition of prostacyclin generation by endothelial cells in culture.

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Mahfouz, Mohamedain M; Zhou, Sherry Q; Kummerow, Fred A

2009-11-01

Low-density lipoprotein (LDL) was isolated from human plasma and oxidized by 5microM copper sulfate for 4h at 37 degrees C in the absence and presence of 1, 3, 5, 10, or 20microM of curcumin. LDL oxidized in the absence of curcumin (oxLDL) showed an increased levels of conjugated dienes, lipid peroxides (TBARS) and lysolecithin (lysoPC) and a significant loss of polyunsaturated fatty acids (PUFA). LDL oxidized with 5microM copper sulfate in the presence of curcumin caused a significant decrease of conjugated diene, lipid peroxides, lysoPC and significant increase of PUFA compared to oxLDL. These changes were dose dependent and reached a maximum at 5microM curcumin. Incubation of human endothelial cells (EC) with 200microg protein/ml of oxLDL caused a significant decrease of prostacyclin (PGI(2)) generation. LDL oxidized in presence of 5microM curcumin did not show any inhibition of PGI(2) generation compared to the control cells. These results indicate that curcumin is an effective chain-breaking antioxidant which prevents oxidation and lipid modification of LDL. The inhibition of oxLDL on PGI(2) is considered a contributing factor in the pathogenesis of thrombosis and atherosclerosis. Curcumin supplementation could be an effective strategy in preventing LDL oxidation and its impact on atherosclerosis and lesion formation.

Inhibitory effect of Piper betel leaf extracts on copper-mediated LDL oxidation and oxLDL-induced lipid accumulation via inducing reverse cholesterol transport in macrophages.

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Ma, Gwo-Chin; Wu, Pei-Fang; Tseng, Hsien-Chun; Chyau, Charng-Cherng; Lu, Hsiu-Chin; Chou, Fen-Pi

2013-12-15

Piper betel leaf (PBL) has the biological capabilities of detoxification and can work as an anti-inflammatory agent and an anti-oxidant. In this study, we evaluated the anti-oxidative activity of the extract of Piper betel leaves (PBLs) on the basis of Cu(2+)-mediated oxidation, and its ability to prevent foam cell formation in a model for oxidised low density lipoprotein (oxLDL)-induced lipid accumulation in macrophages. Our data demonstrated that PBLs were able to inhibit LDL oxidation in vitro and are able to reduce the lipid accumulation in macrophages. We showed the underlying mechanisms to be the following: PBLs up-regulated the protein levels of the class A and class B scavenger receptors, the membrane lipid transporter ABCA1, and its upstream regulator Liver X receptor (LXR) in the macrophages exposed to oxLDL. The results suggested that PBLs activated the reverse cholesterol transport mechanism to enhance the metabolism of the oxLDL that could prevent both lipid accumulation and foam cell formation and further minimise the possible damage of vessels caused by the oxLDL. Copyright © 2013 Elsevier Ltd. All rights reserved.

The effect of olive oil polyphenols on antibodies against oxidized LDL. A randomized clinical trial

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Castañer, Olga; Fitó, Montserrat; López-Sabater, M Carmen

2011-01-01

BACKGROUND & AIM: Oxidized LDL (oxLDL) is a highly immunogenic particle that plays a key role in the development of atherosclerosis. Some data suggest a protective role of OxLDL autoantibodies (OLAB) in atherosclerosis. Our aim was to assess the effect of olive oil polyphenols on the immunogenicity...... of oxLDL to autoantibody generation. METHODS: In a crossover, controlled trial, 200 healthy men were randomly assigned to 3-week sequences of 25 mL/day of 3 olive oils with high (366 mg/kg), medium (164 mg/kg), and low (2.7 mg/kg) phenolic content. RESULTS: Plasma OLAB concentration was inversely...

The effect of olive oil polyphenols on antibodies against oxidized LDL. A randomized clinical trial

DEFF Research Database (Denmark)

Castañer, Olga; Fitó, Montserrat; López-Sabater, M Carmen

2011-01-01

of oxLDL to autoantibody generation. METHODS: In a crossover, controlled trial, 200 healthy men were randomly assigned to 3-week sequences of 25 mL/day of 3 olive oils with high (366 mg/kg), medium (164 mg/kg), and low (2.7 mg/kg) phenolic content. RESULTS: Plasma OLAB concentration was inversely......BACKGROUND & AIM: Oxidized LDL (oxLDL) is a highly immunogenic particle that plays a key role in the development of atherosclerosis. Some data suggest a protective role of OxLDL autoantibodies (OLAB) in atherosclerosis. Our aim was to assess the effect of olive oil polyphenols on the immunogenicity...

Correlation of Apo B-48 and Apo B-100 with Oxidized LDL in Men with Central Obesity

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Maria Diah Fibriani

2010-08-01

Full Text Available BACKGROUND: Obesity has a central role in the metabolic syndrome, which raises the risk for atherosclerotic cardiovascular disease (ASVCD. Apo B-48 and Apo B-100 are the necessary structural proteins required for the assembly and secretion of chylomicron and VLDL which have role in atherogenesis. The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Oxidation of LDL is a hallmark of atherosclerosis development. The aim of this study was to asses the association between Apo B-48 and Apo B-100 with Oxidized-LDL as marker of atherosclerosis risk in central obesity. We hope that the result of this study can help to make a new strategy for the prevention and treatment of vascular disease. RESULTS: There were 68 patients aged 39.6±7.3 years, Apo B-48 concentration was 7.47±5.36 μg/mL, Apo B-100 was 117.26±25.74 mg/dL, and ox-LDL was 137.05±18.88 U/L. This study showed a significant correlation between Apo B-100 and ox-LDL (r=0.608, p<0.05 and correlation between Apo B-48 and ox-LDL (r= 0.171, p<0.05. The levels of Apo B-100 were significantly different between obese with Mets and obese without Mets individuals (p<0.05. CONCLUSIONS: This study suggested that Apo B-100 concentration increase in obese in Mets as compared with obese without Mets. Apo B-48 and Apo B-100 were correlated with Oxidized LDL, but correlation between Apo B-100 and ox-LDL more significant that Apo B-48and ox-LDL. KEYWORDS: obesity, atherogenesis, Apo B-48, Apo B-100, ox-LDL.

Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody.

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Camaré, Caroline; Trayssac, Magali; Garmy-Susini, Barbara; Mucher, Elodie; Sabbadini, Roger; Salvayre, Robert; Negre-Salvayre, Anne

2015-01-01

Neovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial; both angiogenic and anti-angiogenic effects have been reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid, sphingosine 1-phosphate (S1P), in this process is not known. Thus, we investigated whether S1P is involved in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody can prevent this effect. Angiogenesis was assessed by capillary tube formation by human microvascular endothelial cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice. Human oxLDL exhibited a biphasic angiogenic effect on HMEC-1; low concentrations were angiogenic, higher concentrations were cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signalling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentrations of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by i.p. injection of the anti-S1P antibody. These data highlight the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and demonstrate that the anti-S1P antibody effectively blocks the angiogenic effect of oxLDL. © 2014 The British Pharmacological Society.

Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells

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Hossain, Ekhtear [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Ota, Akinobu, E-mail: aota@aichi-med-u.ac.jp [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Karnan, Sivasundaram; Damdindorj, Lkhagvasuren [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Takahashi, Miyuki [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Konishi, Yuko; Konishi, Hiroyuki; Hosokawa, Yoshitaka [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan)

2013-12-15

Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic-induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin-like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N-acetylcysteine (NAC), or an NF-κB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF-κB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced atherosclerosis. - Highlights: • Sodium arsenite (SA) increases LOX-1 expression in mouse aortic endothelial cells. • SA enhances cellular uptake of oxidized LDL in dose-dependent manner. • SA-induced ROS generation enhances phosphorylation of NF-κB. • SA upregulates LOX-1 expression through ROS-activated NF-κB signaling pathway.

Determination of auto-antibodies to native and oxidized low-density lipoproteins (LDL) in serum of patients underwent coronariography in the Medical-Surgical Research Center (MSRC)

International Nuclear Information System (INIS)

Conde CerdeiraI, Hector; Soto Lopez, Yosdel; Aroche Aportela, Ronald

2010-01-01

Low-density lipoprotein (LDL) oxidation is an important event in atherosclerosis development. The relationship between oxidized LDL (oxLDL) autoantibodies and coronary artery disease (CAD) remains controversial. IgM and IgG autoantibodies to oxLDL were measured in twenty patients undergoing clinically indicated coronary angiography, and in ten young healthy volunteers from the Center of Molecular Immunology. The levels of IgM autoantibodies to oxLDL did not differ between no CAD patients and healthy subjects, but the levels of IgM autoantibodies to oxLDL of these two groups were higher compared with the one of CAD patient group. Our results, although preliminary, supports the hypothesis that this kind of Abs might be inversely associated with the presence of atherosclerosis

Oxidized LDL Promotes Apoptosis and Expression of Pro ...

African Journals Online (AJOL)

Accumulation of lipid within non-adipose tissues can induce inflammation by promoting macrophage infiltration and activation. Oxidized lipoproteins (oxLDL) have been known to induce cellular dysfunction in resident macrophages through pro-inflammatory and pro-apoptotic properties. However research into the ...

Lectin-like oxidized LDL receptor-1 expresses in mouse bone marrow-derived mesenchymal stem cells and stimulates their proliferation

International Nuclear Information System (INIS)

Zhang, Fenxi; Wang, Congrui; Jing, Suhua; Ren, Tongming; Li, Yonghai; Cao, Yulin; Lin, Juntang

2013-01-01

The bone marrow-derived mesenchymal stem cells (bmMSCs) have been widely used in cell transplant therapy, and the proliferative ability of bmMSCs is one of the determinants of the therapy efficiency. Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) as a transmembrane protein is responsible for binding, internalizing and degrading oxidized low density lipoprotein (ox-LDL). It has been identified that LOX-1 is expressed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts and monocytes. In these cells, low concentration of ox-LDL (<40 μg/mL) stimulates their proliferation via LOX-1 activation. However, it is poor understood that whether LOX-1 is expressed in bmMSCs and which role it plays. In this study, we investigated the status of LOX-1 expression in bmMSCs and its function on bmMSC proliferation. Our results showed that primary bmMSCs exhibiting a typical fibroblast-like morphology are positive for CD44 and CD90, but negative for CD34 and CD45. LOX-1 in both mRNA and protein levels is highly expressed in bmMSCs. Meanwhile, bmMSCs exhibit a strong potential to take up ox-LDL. Moreover, LOX-1 expression in bmMSCs is upregulated by ox-LDL with a dose- and time-dependent manner. Presence of ox-LDL also enhances the proliferation of bmMSCs. Knockdown of LOX-1 expression significantly inhibits ox-LDL-induced bmMSC proliferation. These findings indicate that LOX-1 plays a role in bmMSC proliferation. - Highlights: ► LOX-1 expresses in bmMSCs and mediates uptake of ox-LDL. ► Ox-LDL stimulates upregulation of LOX-1 in bmMSCs. ► Ox-LDL promotes bmMSC proliferation and expression of Mdm2, phosphor-Akt, phosphor-ERK1/2 and phosphor-NF-κB. ► LOX-1 siRNA inhibits ox-LDL-induced bmMSC proliferation and expression cell survival signals

Lectin-like oxidized LDL receptor-1 expresses in mouse bone marrow-derived mesenchymal stem cells and stimulates their proliferation

Energy Technology Data Exchange (ETDEWEB)

Zhang, Fenxi [Department of Anatomy, Sanquan College, Xinxiang Medical University, Xinxiang 453003 (China); Stem Cell and Biotheraphy Technology Research Center, College of Lifescience and Technology, Xinxiang Medical University, Xinxiang 453003 (China); Wang, Congrui [Stem Cell and Biotheraphy Technology Research Center, College of Lifescience and Technology, Xinxiang Medical University, Xinxiang 453003 (China); Jing, Suhua [ICU Center, The Third Hospital of Xinxiang Medical University, Xinxiang 453003 (China); Ren, Tongming [Department of Anatomy, Sanquan College, Xinxiang Medical University, Xinxiang 453003 (China); Li, Yonghai; Cao, Yulin [Stem Cell and Biotheraphy Technology Research Center, College of Lifescience and Technology, Xinxiang Medical University, Xinxiang 453003 (China); Lin, Juntang, E-mail: juntang.lin@googlemail.com [Stem Cell and Biotheraphy Technology Research Center, College of Lifescience and Technology, Xinxiang Medical University, Xinxiang 453003 (China)

2013-04-15

The bone marrow-derived mesenchymal stem cells (bmMSCs) have been widely used in cell transplant therapy, and the proliferative ability of bmMSCs is one of the determinants of the therapy efficiency. Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) as a transmembrane protein is responsible for binding, internalizing and degrading oxidized low density lipoprotein (ox-LDL). It has been identified that LOX-1 is expressed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts and monocytes. In these cells, low concentration of ox-LDL (<40 μg/mL) stimulates their proliferation via LOX-1 activation. However, it is poor understood that whether LOX-1 is expressed in bmMSCs and which role it plays. In this study, we investigated the status of LOX-1 expression in bmMSCs and its function on bmMSC proliferation. Our results showed that primary bmMSCs exhibiting a typical fibroblast-like morphology are positive for CD44 and CD90, but negative for CD34 and CD45. LOX-1 in both mRNA and protein levels is highly expressed in bmMSCs. Meanwhile, bmMSCs exhibit a strong potential to take up ox-LDL. Moreover, LOX-1 expression in bmMSCs is upregulated by ox-LDL with a dose- and time-dependent manner. Presence of ox-LDL also enhances the proliferation of bmMSCs. Knockdown of LOX-1 expression significantly inhibits ox-LDL-induced bmMSC proliferation. These findings indicate that LOX-1 plays a role in bmMSC proliferation. - Highlights: ► LOX-1 expresses in bmMSCs and mediates uptake of ox-LDL. ► Ox-LDL stimulates upregulation of LOX-1 in bmMSCs. ► Ox-LDL promotes bmMSC proliferation and expression of Mdm2, phosphor-Akt, phosphor-ERK1/2 and phosphor-NF-κB. ► LOX-1 siRNA inhibits ox-LDL-induced bmMSC proliferation and expression cell survival signals.

Anticorpos contra LDL-ox e síndrome coronariana aguda Anticuerpos contra LDL-ox y síndrome coronario agudo Antibodies against OxLDL and acute coronary syndrome

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Ana Maria Brito Medeiros

2010-07-01

significativamente más elevados (p =0,017 en los casos (0,40 ± 0,22, que en los controles (0,33 ± 0,23. Por otro lado, los títulos de antipeptD fueron significativamente menores (p BACKGROUND: The oxidation of low-density lipoprotein (oxLDL induces the formation of immunogenic epitopes in molecules. The presence of autoantibodies against oxLDL has been demonstrated in the serum of patients with coronary artery disease (CAD. However, the role of these autoantibodies in the pathophysiology of acute coronary syndromes (ACS and their clinical significance remain undefined. OBJECTIVE: To evaluate the association between antibodies against oxLDL and ACS. METHODS: Titers of IgG autoantibodies against oxLDL by copper (anti-oxLDL and anti-D synthetic peptide derived from apolipoprotein B (antipeptD were determined by Enzyme-linked immunosorbent assay (ELISA in 90 patients, in the first 12 hours of ACS (cases and in 90 patients with chronic CAD (controls. RESULTS: The results showed that the titers of anti-oxLDL were significantly higher (p = 0.017 in cases (0.40 ± 0.22 than in controls (0.33 ± 0.23. On the other hand, the titers of antipeptD were significantly lower (p < 0.01 in cases (0.28 ± 0.23 than in controls (0.45 ± 0.30. The difference in the titers of both antibodies between the two groups was independent of age, sex, hypertension, diabetes mellitus, dyslipidemia, body mass index, smoking, lipid profile, statin use and family history of CAD. CONCLUSION: The results showed that the titers of anti-oxLDL were significantly higher in patients with acute coronary syndrome as compared to patients with coronary artery disease and may be associated with atherosclerotic plaque instability.

Postpartum weight retention is associated with elevated ratio of oxidized LDL lipids to HDL-cholesterol.

Science.gov (United States)

Puhkala, Jatta; Luoto, Riitta; Ahotupa, Markku; Raitanen, Jani; Vasankari, Tommi

2013-12-01

Oxidized LDL lipids (ox-LDL) are associated with lifestyle diseases such as cardiovascular diseases, metabolic syndrome and type 2 diabetes. The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids. The study is a nested comparative research of a cluster-randomized controlled trial, NELLI (lifestyle and counselling during pregnancy). During early pregnancy (8-12 weeks) and 1 year postpartum, 141 women participated in measurements for determining of plasma lipids: total cholesterol (T-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triacylglycerols (TAG) and ox-LDL. Subjects were stratified into tertiles (weight loss, unaltered weight and weight gain groups) based on their weight change from baseline to follow-up. Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids. Among the group of weight gainers, concentration of TAG reduced less (-0.14 vs. -0.33, p = 0.002), HDL-C reduced more (-0.31 vs. -0.16, p = 0.003) and ox-LDL/HDL-C ratio increased (3.0 vs. -0.2, p = 0.003) when compared to group of weight loss. Both T-C and LDL-C elevated more (0.14 vs. -0.21, p = 0.008; 0.31 vs. 0.07, p = 0.015) and TAG and ox-LDL reduced less (-0.33 vs. 0.20, p = 0.033; -3.33 vs. -0.68, p = 0.026) in unaltered weight group compared to weight loss group. The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight. Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile.

Post-prandial effects of hazelnut-enriched high fat meal on LDL oxidative status, oxidative and inflammatory gene expression of healthy subjects: a randomized trial.

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Di Renzo, L; Merra, G; Botta, R; Gualtieri, P; Manzo, A; Perrone, M A; Mazza, M; Cascapera, S; De Lorenzo, A

2017-04-01

Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. Micronutrients modulate the immune system and exert a protective action by reducing low-density lipoproteins oxidation (ox-LDL) via induction of antioxidant enzymes. The clinical study was a randomized and cross-over trial, conducted through the CONSORT flowchart. We evaluated the gene expression of 103 genes related to oxidative stress (HOSp) and human inflammasome pathways (HIp), and ox-LDL level at fasting and after 40 g raw "Tonda Gentile delle Langhe" hazelnut consumption, in association with a McDonald's® Meal (McDM) in 22 healthy human volunteers. Ox-LDL levels significantly increased comparing no dietary treatment (NDT) vs. McDM, and decreased comparing McDM vs. McDM + H (p<0.05). Percentage of significant genes expressed after each dietary treatment were the follows: (A) NDT vs. McDM: 3.88% HIp and 17.48% HOSp; (B) NDT vs. McDM + H: 17.48% HIp and 23.30% HOSp; (C) McDM vs. McDM + H: 17.48% HIp and 33.98% HOSp. Hazelnut consumption reduced post prandial risk factors of atherosclerosis, such as ox-LDL, and the expression of inflammation and oxidative stress related genes. Chronic studies on larger population are necessary before definitive conclusions.

Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation

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He, Fengping; Xu, Xin; Yuan, Shuguo; Tan, Liangqiu; Gao, Lingjun; Ma, Shaochun; Zhang, Shebin; Ma, Zhanzhong; Jiang, Wei; Liu, Fenglian; Chen, Baofeng; Zhang, Beibei; Pang, Jungang; Huang, Xiuyan; Weng, Jiaqiang

2016-08-01

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

Hyperglycemia and oxidized-LDL exert a deleterious effect on endothelial progenitor cell migration in type 2 diabetes mellitus.

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Hamed, Saher; Brenner, Benjamin; Abassi, Zaid; Aharon, Anat; Daoud, Deeb; Roguin, Ariel

2010-09-01

Type 2 diabetes mellitus (DM) patients with coronary artery disease (CAD) have elevated plasma oxidized-LDL (OxLDL) levels and impaired neovascularization. Hyperglycemia and hyperlipidemia impair endothelial progenitor cell (EPC) migration, and endothelial nitric oxide (NO) bioavailability and NO synthase (NOS) activity are essential for EPC migration. Stromal-derived factor-1alpha (SDF1alpha) contributes to EPC mobilization and homing by stimulating the CXC receptor-4 (CXCR4) on the EPC plasmalemma to activate the Pi3K/Akt/eNOS signaling pathway. Therefore, we investigated the effect of high glucose (HG) and OxLDL on the migration and NO bioavailability of EPCs from healthy individuals, and then correlated the findings with those of EPCs from type 2 DM patients with and without CAD. EPCs from 15 healthy and 55 patients were exposed to HG, OxLDL, or both before evaluating EPC count, migration and NO production, and expression of CXCR4 and members of Pi3K/Akt/eNOS signaling cascade. Counts, migration, CXCR4 expression, and NO production were significantly reduced in EPCs from DM and CAD patients compared with that obtained in EPCs from healthy, and were further reduced in DM patients with CAD. The expression of CXCR4 and activation of Pi3K/Akt/eNOS signaling cascade were suppressed in OxLDL- and HG-treated EPCs, and this suppression was exacerbated when EPCs were treated simultaneously with HG and OxLDL. Hyperglycemia and elevated circulating OxLDL in DM patients with CAD severely impair EPC migration. These results suggest that the underlying mechanism for this impaired EPC migration is linked to the CXCR4/Pi3K/Akt/eNOS signaling pathway. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study.

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Elkan, Ann-Charlotte; Sjöberg, Beatrice; Kolsrud, Björn; Ringertz, Bo; Hafström, Ingiäld; Frostegård, Johan

2008-01-01

The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs). Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months. Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels.

Changes in LDL Oxidative Status and Oxidative and Inflammatory Gene Expression after Red Wine Intake in Healthy People: A Randomized Trial

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Di Renzo, Laura; Marsella, Luigi Tonino; Gualtieri, Paola; Gratteri, Santo; Tomasi, Diego; Gaiotti, Federica

2015-01-01

Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. Micronutrients modulate immune system and exert a protective action by reducing low density lipoproteins (LDL) oxidation via induction of antioxidant enzymes. We evaluated the gene expression of oxidative stress (HOSp), inflammasome (HIp), and human drug metabolism pathways (HDM) and ox-LDL level at baseline and after the intake of red wine naturally enriched with resveratrol (NPVRW), in association with or without a McDonald's meal (McDM). The ox-LDL levels significantly increase comparing baseline (B) versus McDM and decreased comparing McDM versus McDM + NPVRW (P ≤ 0.05). Percentages of significant genes expressed after each nutritional intervention were the following: (1) B versus McDM, 2.88% HOSp, 2.40% of HIp, and 3.37% of HDMp; (2) B versus McDM + NPVRW, 1.44% of HOSp, 4.81% of HIp, and 0.96% of HDMp; (3) McDM versus McDM + NPVRW, 2.40% of HOSp, 2.40% of HIp, and 5.77% of HDMp; (4) B versus NPVRW, 4.80% HOSp, 3.85% HIp, and 3.85% HDMp. NPVRW intake reduced postprandial ox-LDL and the expression of inflammation and oxidative stress related genes. Chronic studies on larger population are necessary before definitive conclusions. PMID:26101461

Changes in LDL Oxidative Status and Oxidative and Inflammatory Gene Expression after Red Wine Intake in Healthy People: A Randomized Trial

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Laura Di Renzo

2015-01-01

Full Text Available Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. Micronutrients modulate immune system and exert a protective action by reducing low density lipoproteins (LDL oxidation via induction of antioxidant enzymes. We evaluated the gene expression of oxidative stress (HOSp, inflammasome (HIp, and human drug metabolism pathways (HDM and ox-LDL level at baseline and after the intake of red wine naturally enriched with resveratrol (NPVRW, in association with or without a McDonald’s meal (McDM. The ox-LDL levels significantly increase comparing baseline (B versus McDM and decreased comparing McDM versus McDM + NPVRW (P≤0.05. Percentages of significant genes expressed after each nutritional intervention were the following: (1 B versus McDM, 2.88% HOSp, 2.40% of HIp, and 3.37% of HDMp; (2 B versus McDM + NPVRW, 1.44% of HOSp, 4.81% of HIp, and 0.96% of HDMp; (3 McDM versus McDM + NPVRW, 2.40% of HOSp, 2.40% of HIp, and 5.77% of HDMp; (4 B versus NPVRW, 4.80% HOSp, 3.85% HIp, and 3.85% HDMp. NPVRW intake reduced postprandial ox-LDL and the expression of inflammation and oxidative stress related genes. Chronic studies on larger population are necessary before definitive conclusions.

LDL-oxidation, serum uric acid, kidney function and pulse-wave velocity: Data from the Brisighella Heart Study cohort.

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Cicero, Arrigo F G; Kuwabara, Masanari; Johnson, Richard; Bove, Marilisa; Fogacci, Federica; Rosticci, Martina; Giovannini, Marina; D'Addato, Sergio; Borghi, Claudio

2018-06-15

Serum uric acid (SUA) and oxidized LDL (oxLDL) may be associated with arterial aging. The aim of our study was to evaluate the relationship between SUA, oxLDL and arterial stiffness in subjects with normal renal function and in patients with mild or moderate renal impairment. From the database of the 2012 Brisighella Heart Study, we compared age-matched adult, non-smoker subjects without cardiovascular disease and with normal renal function (n = 205), subjects with stage II chronic kidney disease (CKD) (n = 118) and subjects with stage III CKD (n = 94). All subjects underwent a determination of the LDL oxidative susceptibility, oxLDL levels, SUA and Pulse Wave Velocity (PWV). By univariate analysis, PWV correlated with a large number of clinical, haemodynamic and metabolic parameters, including estimated glomerular filtration rate (eGFR) in subjects with normal renal function and in those with stage II or III CKD. Stepwise multiple regression analyses showed that in the presence of normal renal function or stage II CKD, the main predictors of PWV were age, systolic blood pressure (SBP), ox-LDL, apolipoprotein B and SUA (p function, but not in the subjects with more compromised eGFR. This study confirms the complex relationship of SUA with cardiovascular and metabolic disease in the patient with established renal disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL.

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Yang, Yong; Wang, Yan-Fu; Yang, Xiao-Fang; Wang, Zhao-Hui; Lian, Yi-Tian; Yang, Ying; Li, Xiao-Wei; Gao, Xiang; Chen, Jian; Shu, Yan-Wen; Cheng, Long-Xian; Liao, Yu-Hua; Liu, Kun

2013-01-01

Cholesterol-metabolism-associated molecules, including scavenger receptor class A (SR-A), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD36, ACAT1, ABCA1, ABCG1, and scavenger receptor class B type I, can modulate cholesterol metabolism in the transformation from macrophages to foam cells. Voltage-gated potassium channel Kv1.3 has increasingly been demonstrated to play an important role in the modulation of macrophage function. Here, we investigate the role of Kv1.3 in modulating cholesterol-metabolism-associated molecules in human acute monocytic leukemia cell-derived macrophages (THP-1 macrophages) and human monocyte-derived macrophages exposed to oxidized LDL (ox-LDL). Human Kv1.3 and Kv1.5 channels (hKv1.3 and hKv1.5) are expressed in macrophages and form a heteromultimeric channel. The hKv1.3-E314 antibody that we had generated as a specific hKv1.3 blocker inhibited outward delayed rectifier potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specific hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol efflux in THP-1 macrophages and human monocyte-derived macrophages exposed to ox-LDL. The hKv1.3-E314 antibody downregulated SR-A, LOX-1, and ACAT1 expression and upregulated ABCA1 expression in THP-1 macrophages and human monocyte-derived macrophages. Our results reveal that specific Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefits the treatment of atherosclerotic lesions.

Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study

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Elkan, Ann-Charlotte; Sjöberg, Beatrice; Kolsrud, Björn; Ringertz, Bo; Hafström, Ingiäld; Frostegård, Johan

2008-01-01

Introduction The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs). Methods Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months. Results Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels. PMID:18348715

Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats

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Sieglinde Zelzer

2015-05-01

Full Text Available Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66 were grouped into normal diet (n = 30 and high-fat diet (n = 36 groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3 treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL, malondialdehyde (MDA, 4-hydroxynonenal (HNE, the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats.

Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats.

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Zelzer, Sieglinde; Mangge, Harald; Pailer, Sabine; Ainoedhofer, Herwig; Kieslinger, Petra; Stojakovic, Tatjana; Scharnagl, Hubert; Prüller, Florian; Weghuber, Daniel; Datz, Christian; Haybaeck, Johannes; Obermayer-Pietsch, Barbara; Trummer, Christian; Gostner, Johanna; Gruber, Hans-Jürgen

2015-05-21

Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding) on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66) were grouped into normal diet (n = 30) and high-fat diet (n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL), malondialdehyde (MDA), 4-hydroxynonenal (HNE), the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats.

Oxidized LDL Induces Alternative Macrophage Phenotype through Activation of CD36 and PAFR

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Francisco J. Rios

2013-01-01

Full Text Available OxLDL is recognized by macrophage scavenger receptors, including CD36; we have recently found that Platelet-Activating Factor Receptor (PAFR is also involved. Since PAFR in macrophages is associated with suppressor function, we examined the effect of oxLDL on macrophage phenotype. It was found that the presence of oxLDL during macrophage differentiation induced high mRNA levels to IL-10, mannose receptor, PPARγ and arginase-1 and low levels of IL-12 and iNOS. When human THP-1 macrophages were pre-treated with oxLDL then stimulated with LPS, the production of IL-10 and TGF-β significantly increased, whereas that of IL-6 and IL-8 decreased. In murine TG-elicited macrophages, this protocol significantly reduced NO, iNOS and COX2 expression. Thus, oxLDL induced macrophage differentiation and activation towards the alternatively activated M2-phenotype. In murine macrophages, oxLDL induced TGF-β, arginase-1 and IL-10 mRNA expression, which were significantly reduced by pre-treatment with PAFR antagonists (WEB and CV or with antibodies to CD36. The mRNA expression of IL-12, RANTES and CXCL2 were not affected. We showed that this profile of macrophage activation is dependent on the engagement of both CD36 and PAFR. We conclude that oxLDL induces alternative macrophage activation by mechanisms involving CD36 and PAFR.

Inhibition of the NLRP3 inflammasome attenuates foam cell formation of THP-1 macrophages by suppressing ox-LDL uptake and promoting cholesterol efflux.

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Chen, Liang; Yao, Qiying; Xu, Siwei; Wang, Hongyan; Qu, Peng

2018-01-01

The NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the development of atherosclerosis. The activated NLRP3 inflammasome has been reported to promote macrophage foam cell formation, but not all studies have obtained the same result, and how NLRP3 inflammasome is involved in the formation of foam cells remains elusive. We used selective NLRP3 inflammasome inhibitors and NLRP3-deficient THP-1 cells to assess the effect of NLRP3 inflammasome inhibition on macrophage foam cell formation, oxidized low-density lipoprotein (ox-LDL) uptake, esterification, and cholesterol efflux, as well as the expression of associated proteins. Inhibition of the NLRP3 inflammasome attenuated foam cell formation, diminished ox-LDL uptake, and promoted cholesterol efflux from THP-1 macrophages. Moreover, it downregulated CD36, acyl coenzyme A: cholesterol acyltransferase-1 and neutral cholesterol ester hydrolase expression; upregulated ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) expression; but had no effect on the expression of scavenger receptor class A and ATP-binding cassette transporter G1. Collectively, our findings show that inhibition of the NLRP3 inflammasome decreases foam cell formation of THP-1 macrophages via suppression of ox-LDL uptake and enhancement of cholesterol efflux, which may be due to downregulation of CD36 expression and upregulation of ABCA1 and SR-BI expression, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL[S

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Yang, Yong; Wang, Yan-Fu; Yang, Xiao-Fang; Wang, Zhao-Hui; Lian, Yi-Tian; Yang, Ying; Li, Xiao-Wei; Gao, Xiang; Chen, Jian; Shu, Yan-Wen; Cheng, Long-Xian; Liao, Yu-Hua; Liu, Kun

2013-01-01

Cholesterol-metabolism-associated molecules, including scavenger receptor class A (SR-A), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD36, ACAT1, ABCA1, ABCG1, and scavenger receptor class B type I, can modulate cholesterol metabolism in the transformation from macrophages to foam cells. Voltage-gated potassium channel Kv1.3 has increasingly been demonstrated to play an important role in the modulation of macrophage function. Here, we investigate the role of Kv1.3 in modulating cholesterol-metabolism-associated molecules in human acute monocytic leukemia cell-derived macrophages (THP-1 macrophages) and human monocyte-derived macrophages exposed to oxidized LDL (ox-LDL). Human Kv1.3 and Kv1.5 channels (hKv1.3 and hKv1.5) are expressed in macrophages and form a heteromultimeric channel. The hKv1.3-E314 antibody that we had generated as a specific hKv1.3 blocker inhibited outward delayed rectifier potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specific hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol efflux in THP-1 macrophages and human monocyte-derived macrophages exposed to ox-LDL. The hKv1.3-E314 antibody downregulated SR-A, LOX-1, and ACAT1 expression and upregulated ABCA1 expression in THP-1 macrophages and human monocyte-derived macrophages. Our results reveal that specific Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefits the treatment of atherosclerotic lesions. PMID:23099443

Anti-atherosclerotic potential of gossypetin via inhibiting LDL oxidation and foam cell formation

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Chen, Jing-Hsien; Tsai, Chia-Wen; Wang, Chi-Ping; Lin, Hui-Hsuan

2013-01-01

Gossypetin, a flavone originally isolated from Hibiscus species, has been shown to possess antioxidant, antimicrobial, and antimutagenic activities. Here, we investigated the mechanism(s) underlying the anti-atherosclerotic potential of gossypetin. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) scavenging activity assay showed that the addition of > 50 μM of gossypetin could scavenge over 50% of DPPH radicals. The inhibitory effects of gossypetin on the lipid and protein oxidation of LDL were defined by thiobarbituric acid reactive substance (TBARS) assay, the relative electrophoretic mobility (REM) of oxidized LDL (ox-LDL), and fragmentation of apoB in the Cu 2+ -induced oxidation of LDL. Gossypetin showed potential in reducing ox-LDL-induced foam cell formation and intracellular lipid accumulation, and uptake ability of macrophages under non-cytotoxic concentrations. Molecular data showed that these influences of gossypetin might be mediated via peroxisome proliferator-activated receptor α (PPARα)/liver-X receptor α (LXRα)/ATP-binding cassette transporter A1 (ABCA1) and PPARγ/scavenger receptor CD36 pathways, as demonstrated by the transfection of PPARα siRNA or PPARγ expression vector. Our data implied that gossypetin regulated the PPAR signals, which in turn led to stimulation of cholesterol removal from macrophages and delay atherosclerosis. These results suggested that gossypetin potentially could be developed as an anti-atherosclerotic agent. - Highlights: • The anti-atherosclerotic effect of gossypetin in vitro was examined. • Gossypetin inhibited LDL oxidation. • Gossypetin showed potential in reducing on the formation of foam cells. • Gossypetin functions against ox-LDL through PPARa activation and PPARγ depression

Anti-atherosclerotic potential of gossypetin via inhibiting LDL oxidation and foam cell formation

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Chen, Jing-Hsien [School of Nutrition, Chung Shan Medical University, Taichung, Taiwan (China); Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Tsai, Chia-Wen [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Wang, Chi-Ping [Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Lin, Hui-Hsuan, E-mail: linhh@csmu.edu.tw [Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)

2013-10-15

Gossypetin, a flavone originally isolated from Hibiscus species, has been shown to possess antioxidant, antimicrobial, and antimutagenic activities. Here, we investigated the mechanism(s) underlying the anti-atherosclerotic potential of gossypetin. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) scavenging activity assay showed that the addition of > 50 μM of gossypetin could scavenge over 50% of DPPH radicals. The inhibitory effects of gossypetin on the lipid and protein oxidation of LDL were defined by thiobarbituric acid reactive substance (TBARS) assay, the relative electrophoretic mobility (REM) of oxidized LDL (ox-LDL), and fragmentation of apoB in the Cu{sup 2+}-induced oxidation of LDL. Gossypetin showed potential in reducing ox-LDL-induced foam cell formation and intracellular lipid accumulation, and uptake ability of macrophages under non-cytotoxic concentrations. Molecular data showed that these influences of gossypetin might be mediated via peroxisome proliferator-activated receptor α (PPARα)/liver-X receptor α (LXRα)/ATP-binding cassette transporter A1 (ABCA1) and PPARγ/scavenger receptor CD36 pathways, as demonstrated by the transfection of PPARα siRNA or PPARγ expression vector. Our data implied that gossypetin regulated the PPAR signals, which in turn led to stimulation of cholesterol removal from macrophages and delay atherosclerosis. These results suggested that gossypetin potentially could be developed as an anti-atherosclerotic agent. - Highlights: • The anti-atherosclerotic effect of gossypetin in vitro was examined. • Gossypetin inhibited LDL oxidation. • Gossypetin showed potential in reducing on the formation of foam cells. • Gossypetin functions against ox-LDL through PPARa activation and PPARγ depression.

Advanced glycation end products-modified proteins and oxidized LDL mediate down-regulation of leptin in mouse adipocytes via CD36

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Unno, Yuka; Sakai, Masakazu; Sakamoto, Yu-ichiro; Kuniyasu, Akihiko; Nakayama, Hitoshi; Nagai, Ryoji; Horiuchi, Seikoh

2004-01-01

Advanced glycation end products (AGE)-modified proteins as well as oxidized-LDL (Ox-LDL) undergo receptor-mediated endocytosis by CHO cells overexpressing CD36, a member of class B scavenger receptor family. The purpose of the present study was to examine the effects of glycolaldehyde-modified BSA (GA-BSA) as an AGE-ligand and Ox-LDL on leptin expression in adipocytes. GA-BSA decreased leptin expression at both protein and mRNA levels in 3T3-L1 adipocytes and mouse epididymal adipocytes. Ox-LDL showed a similar inhibitory effect on leptin expression in 3T3-L1 adipocytes, which effect was protected by N-acetylcysteine, a reactive oxygen species (ROS) inhibitor. Binding of 125 I-GA-BSA or 125 I-Ox-LDL to 3T3-L1 adipocytes and subsequent endocytic degradation were inhibited by a neutralizing anti-CD36 antibody. Furthermore, this antibody also suppressed Ox-LDL-induced leptin down-regulation. These results clarify that the interaction of GA-BSA and Ox-LDL with CD36 leads to down-regulation of leptin expression via ROS system(s) in 3T3-L1 adipocytes, suggesting that a potential link of AGE- and/or Ox-LDL-induced leptin down-regulation might be linked to insulin-sensitivity in metabolic syndrome

Isolation of low density lipoprotein (LDL with its modification by Copper ion and Malondialdehyde (MDA

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Doosty M

1999-06-01

Full Text Available Oxidation of low density lipoproteins (LDLs is belived to be an important step in the pathogenesis of atherosclerosis. During oxidation, LDL particle undergoes a large number of structural changes that alters its biological properties, so it becomes atherogenic. To study atherogenic proteins, usually two forms of modified LDLs, including Cu2+-oxidized LDL (ox-LDL and malondialdehyde (MDA modified LDL (mal-LDL are used. In this study, LDL was isolated from 72 ml freshly prepared plasma by sequential Floatation Ultracentrifugation (SFU, which resulted in separation of 12.5 mg LDL protein. LDL oxidation was accomplished in Phosphate Buffered Saline (PBS with 2µM cupric sulfate, and mal-LDL was prepared by incubating LDL in PBS with 0.5 M solution of freshly prepared MDA. These modifications were evaluated by measuring optical density at 234 nm, Thiobarbitoric Acid Reactive Substances (TBARS, and electrophoretic mobility at pH 8.6. The increase of 234 nm absorption reflected initiation of LDL oxidation. TBARS of ox-LDL and mal-LDL was 80 Nm MAD/mg LDL protein and 400 nm MDA/mg LDL protein, respectively. Electrophoretic mobility of ox-LDL and mal-LDL, in respect to native LDL (n-LDL, were increased.

Are Serum Levels of F2-Isoprostane and Oxidized-LDL Related to Vitamin D Status in Type 2 Diabetic Patients? A Case-Control Study

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Mohammad Hassan Javanbakht

2016-10-01

Full Text Available Background: Considerable evidence suggests that oxidative stress affects diabetes mellitus (DM and contributes to its complications. Vitamin D has been shown to possess antioxidant properties. The aim of this study was to determine the association between serum levels of calcifediol (25-OH-D, an indicator of vitamin D status, and lipid profiles with oxidative stress in patients with type 2 diabetes mellitus (T2DM. Methods: In this case-control study, 57 T2DM patients with low vitamin D status ( 30 ng/mL were enrolled. Fasting concentrations of 25-OH-D, calcium, phosphorus, parathyroid hormone (PTH, lipid profiles, fasting blood sugar (FBS, glycosylated hemoglobin (HbA1c, F2-isoprostane, and oxidized-low-density lipoprotein (ox-LDL were measured. Results: The mean fasting serum concentrations of 25-OH-D, calcium, and phosphorus in patients with low vitamin D status were significantly lower than in controls (p < 0.001. The mean concentrations of ox-LDL, F2-isoprostane, total cholesterol, and LDL were significantly higher in patients with low vitamin D status than in controls. There was a negative correlation between vitamin D levels and F2-isoprostane (r = 0.647and P = 0.0001, LDL (r = -0.218 and P = 0.030, and ox-LDL (r = -0.637 and P = 0.0001. Conclusions: The results of present study indicated that serum concentrations of 25-OH-D were inversely correlated with F2-isoprostane, LDL, and ox-LDL. Therefore, vitamin D may have a beneficial effect on the control of lipid profiles and oxidative stress in T2DM patients.

Elevated capillary tube hematocrit reflects degradation of endothelial cell glycocalyx by oxidized LDL

NARCIS (Netherlands)

Constantinescu, A. A.; Vink, H.; Spaan, J. A.

2001-01-01

Proteoglycans and plasma proteins bound to the endothelial cell glycocalyx are essential for vascular function, but at the same time, they lower capillary tube hematocrit by reducing capillary volume available to flowing blood. Because oxidized low-density lipoproteins (oxLDL) reduce the effective

Intake of Red Wine in Different Meals Modulates Oxidized LDL Level, Oxidative and Inflammatory Gene Expression in Healthy People: A Randomized Crossover Trial

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Di Renzo, Laura; Valente, Roberto; Colica, Carmen

2014-01-01

Several studies have found that adherence to the Mediterranean Diet, including consumption of red wine, is associated with beneficial effects on oxidative and inflammatory conditions. We evaluate the outcome of consumption of a McDonald's Meal (McD) and a Mediterranean Meal (MM), with and without the additive effect of red wine, in order to ascertain whether the addition of the latter has a positive impact on oxidized (ox-) LDL and on expression of oxidative and inflammatory genes. A total of 24 subjects were analyzed for ox-LDL, CAT, GPX1, SOD2, SIRT2, and CCL5 gene expression levels, before and after consumption of the 4 different meal combinations with washout intervals between each meal. When red wine is associated with McD or MM, values of ox-LDL are lowered (P < 0.05) and expression of antioxidant genes is increased, while CCL5 expression is decreased (P < 0.05). SIRT2 expression after MM and fasting with red wine is significantly correlated with downregulation of CCL5 and upregulation of CAT (P < 0.001). GPX1 increased significantly in the comparison between baseline and all conditions with red wine. We highlighted for the first time the positive effect of red wine intake combined with different but widely consumed meal types on ox-LDL and gene expression. Trial Registration. This trial is registered with ClinicalTrials.gov NCT01890070. PMID:24876915

Intake of Red Wine in Different Meals Modulates Oxidized LDL Level, Oxidative and Inflammatory Gene Expression in Healthy People: A Randomized Crossover Trial

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Laura Di Renzo

2014-01-01

Full Text Available Several studies have found that adherence to the Mediterranean Diet, including consumption of red wine, is associated with beneficial effects on oxidative and inflammatory conditions. We evaluate the outcome of consumption of a McDonald’s Meal (McD and a Mediterranean Meal (MM, with and without the additive effect of red wine, in order to ascertain whether the addition of the latter has a positive impact on oxidized (ox- LDL and on expression of oxidative and inflammatory genes. A total of 24 subjects were analyzed for ox-LDL, CAT, GPX1, SOD2, SIRT2, and CCL5 gene expression levels, before and after consumption of the 4 different meal combinations with washout intervals between each meal. When red wine is associated with McD or MM, values of ox-LDL are lowered (P<0.05 and expression of antioxidant genes is increased, while CCL5 expression is decreased (P<0.05. SIRT2 expression after MM and fasting with red wine is significantly correlated with downregulation of CCL5 and upregulation of CAT (P<0.001. GPX1 increased significantly in the comparison between baseline and all conditions with red wine. We highlighted for the first time the positive effect of red wine intake combined with different but widely consumed meal types on ox-LDL and gene expression. Trial Registration. This trial is registered with ClinicalTrials.gov NCT01890070.

Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.

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Iván González-Chavarría

Full Text Available Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.

Potential antioxidant and cytoprotective effects of essential oil extracted from Cymbopogon citratus on OxLDL and H2O2 LDL induced Human Peripheral Blood Mononuclear Cells (PBMC

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Jamuna S.

2017-06-01

Full Text Available Cymbopogon citratus (lemon grass is commonly used in traditional folk medicine. The essential oil extracted from C. citratus has been reported as a potential anti-oxidant and anti-inflammatory agent. This study has been designed to explore the protective effect of C. citratus (lemon grass against modified LDL (OxLDL and H2O2 LDL induced cytotoxicity in Peripheral Blood Mononuclear Cells (PBMC. The essential oil extracted from C. citratus (EOC was subjected to FT-IR spectroscopic analysis for the identification of functional groups. In vitro antioxidant assays were carried out to assess the electron donating capability of EOC as compared with a known standard L-ascorbic acid. The cytoprotective effects of EOC were determined in PBMC induced with modified LDL. Spectra obtained from FT-IR analysis showed the presence of functional groups in EOC such as H-bonded, OH stretching, NH stretching, aldehydeCH stretching, aldehyde/ketoneCO stretching, CC-stretching, CH3 bending, CH in plane bending. EOC has greater antioxidant property when compared with the standard L-ascorbic acid. EOC at all test concentrations demonstrated free radical scavenging activity and cytoprotective effect when challenged against modified LDL in PBMC. The above results show EOC as a promising antioxidant and cytoprotective agent.

Activating transcription factor 6 mediates oxidized LDL-induced cholesterol accumulation and apoptosis in macrophages by up-regulating CHOP expression.

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Yao, Shutong; Zong, Chuanlong; Zhang, Ying; Sang, Hui; Yang, Mingfeng; Jiao, Peng; Fang, Yongqi; Yang, Nana; Song, Guohua; Qin, Shucun

2013-01-01

This study was to explore whether activating transcription factor 6 (ATF6), an important sensor to endoplasmic reticulum (ER) stress, would mediate oxidized low-density lipoprotein (ox-LDL)- induced cholesterol accumulation and apoptosis in cultured macrophages and the underlying molecular mechanisms. Intracellular lipid droplets and total cholesterol levels were assayed by oil red O staining and enzymatic colorimetry, respectively. Cell viability and apoptosis were determined using MTT assay and AnnexinV-FITC apoptosis detection kit, respectively. The nuclear translocation of ATF6 in cells was detected by immunofluorescence analysis. Protein and mRNA levels were examined by Western blot analysis and real time-PCR, respectively. ATF6 siRNA was transfected to RAW264.7 cells by lipofectamin. Exposure of cells to ox-LDL induced glucose-regulated protein 78 (GRP78). C/EBP homologous protein (CHOP), a key-signaling component of ER stress-induced apoptosis, was up-regulated in ox-LDL-treated cells. ATF6, a factor that positively regulates CHOP expression, was activated by ox-LDL in a concentration- and time- dependent manner. The role of the ATF6-mediated ER stress pathway was further confirmed through the siRNA-mediated knockdown of ATF6, which attenuated ox-LDL-induced upregulation of CHOP, cholesterol accumulation and apoptosis in macrophages. In addition, the phosphorylation of double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), another factor that positively regulates CHOP expression, was induced in the presence of ox-LDL, and PERK-specific siRNA also inhibited the ox-LDL-induced upregulation of CHOP and apoptosis in RAW264.7 cells. These results demonstrate that ER stress-related proteins, particularly ATF6 and its downstream molecule CHOP, are involved in ox-LDL-induced cholesterol accumulation and apoptosis in macrophages.

Significance of oxidized low-density lipoprotein in body fluids as a marker related to diseased conditions.

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Itabe, Hiroyuki; Kato, Rina; Sasabe, Naoko; Obama, Takashi; Yamamoto, Matsuo

2018-03-06

Oxidatively modified low-density lipoprotein (oxLDL) is known to be involved in various diseases, including cardiovascular diseases. The presence of oxLDL in the human circulatory system and in atherosclerotic lesions has been demonstrated using monoclonal antibodies. Studies have shown the significance of circulating oxLDL in various systemic diseases, including acute myocardial infarction and diabetic mellitus. Several different enzyme-linked immunosorbent assay (ELISA) procedures to measure oxLDL were utilized. Evidence has been accumulating that reveals changes in oxLDL levels under certain pathological conditions. Since oxLDL concentration tends to correlate with low-density lipoprotein (LDL)-cholesterol, the ratio of oxLDL and LDL rather than oxLDL concentration alone has been focused attention. In addition to circulating plasma, LDL and oxLDL are found in gingival crevicular fluid (GCF), where the ratio of oxLDL to LDL in GCF is much higher than in plasma. LDL and oxLDL levels in GCF show an increase in diabetic patients and periodontal patients, suggesting that GCF might be useful in examining systemic conditions. GCF oxLDL increased when the teeth were affected by periodontitis. It is likely that oxLDL levels in plasma and GCF could reflect oxidative stress and transfer efficacy in circulatory system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages.

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Lin, Hung-Chih; Lii, Chong-Kuei; Chen, Hui-Chun; Lin, Ai-Hsuan; Yang, Ya-Chen; Chen, Haw-Wen

2018-01-01

oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent

Oxidized low-density lipoprotein in postmenopausal women

DEFF Research Database (Denmark)

Jankowski, Vera; Just, Alexander R; Pfeilschifter, Johannes

2014-01-01

BACKGROUND: Oxidized low-density lipoprotein (oxLDL) leads to atherosclerosis and cardiovascular disease, the most frequent causes of death worldwide. After menopause, lipid and lipoprotein metabolism changes and women are at greater risk of cardiovascular disease compared to fertile women. The aim.......10-0.43). Although intima-media thickness did not differ, postmenopausal women with serous oxLDL had more often atherosclerotic plaques compared to women without oxLDL (6/66 vs. 0/467; P lipoprotein, impaired glucose intolerance, and DBP were independently associated...... with the occurrence of oxLDL. If oxLDL was present, higher high-density lipoprotein and glucose intolerance were associated with higher concentrations of oxLDL. In contrast, higher blood urea concentrations were associated with lower concentrations of oxLDL. CONCLUSION: This study presents the prevalence...

Macrophage heterogeneity and cholesterol homeostasis: classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL.

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Chu, Eugene M; Tai, Daven C; Beer, Jennifer L; Hill, John S

2013-02-01

Macrophages are centrally involved during atherosclerosis development and are the predominant cell type that accumulates cholesterol in the plaque. Macrophages however, are heterogeneous in nature reflecting a variety of microenvironments and different phenotypes may be more prone to contribute towards atherosclerosis progression. Using primary human monocyte-derived macrophages, we sought to evaluate one aspect of atherogenic potential of different macrophage phenotypes by determining their propensity to associate with and accumulate oxidized low density lipoprotein (oxLDL). Classically-activated macrophages treated simultaneously with interferon γ (IFNγ) and tumor necrosis factor α (TNFα) associated with less oxLDL and accumulated less cholesterol compared to untreated controls. The combined treatment of IFNγ and TNFα reduced the mRNA expression of CD36 and the expression of both cell surface CD36 and macrophage scavenger receptor 1 (MSR1) protein. Under oxLDL loaded conditions, IFNγ and TNFα did not reduce macrophage protein expression of the transcription factor peroxisome proliferator-actived receptor γ (PPARγ) which is known to positively regulate CD36 expression. However, macrophages treated with IFNγ attenuated the ability of the PPARγ-specific agonist rosiglitazone from upregulating cell surface CD36 protein expression. Our results demonstrate that the observed reduction of cholesterol accumulation in macrophages treated with IFNγ and TNFα following oxLDL treatment was due at least in part to reduced cell surface CD36 and MSR1 protein expression. Copyright © 2012 Elsevier B.V. All rights reserved.

M1 Macrophages but Not M2 Macrophages Are Characterized by Upregulation of CRP Expression via Activation of NFκB: a Possible Role for Ox-LDL in Macrophage Polarization.

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Kaplan, Marielle; Shur, Anna; Tendler, Yvgeny

2018-04-23

Arterial macrophages comprise a heterogeneous population: pro-inflammatory (M1) and anti-inflammatory (M2). Since C-reactive protein (CRP) is produced by macrophages in atherosclerotic lesions, understanding of CRP regulation in macrophages could be crucial to decipher inflammatory patterns in atherogenesis. We aimed to analyze CRP expression in M1/M2 macrophages and to question whether it involves NFκB signaling pathway. Furthermore, we questioned whether oxidative stress affect macrophage phenotype and modulate macrophage CRP expression. M1/M2 macrophage polarization was validated using THP-1 macrophages. CRP mRNA and protein expression were determined using real-time PCR and immunohistochemistry. Involvement of NFκB was determined by nuclear translocation of p50 subunit and the use of NFκB inhibitor. Involvement of oxidative stress in macrophage phenotypes induction was studied using oxidized-LDL (Ox-LDL) and antioxidants. M1 macrophages were characterized by elevated CRP mRNA expression (by 67%), CRP protein levels (by 108%), and upregulation of NFκB activation compared to control, but these features were not shared by M2 macrophages. Macrophages incubation with Ox-LDL led to a moderate M1 phenotype combined with a M2 phenotype, correlated with increased CRP mRNA expression. Antioxidants inhibited by up to 86% IL6 expression but did not significantly affect IL10 secretion. Antioxidants significantly inhibited CRP expression in M1 macrophages, but not in M2 macrophages. Elevated expression of CRP was characteristic of M1 macrophages rather than M2 through NFκB activation. Oxidative stress could be one of the endogenous triggers for macrophage activation to a mixed M1 and M2 phenotype, in association with increased expression of CRP.

Effects of alpha-tocopherol on superoxide production and plasma intercellular adhesion molecule-1 and antibodies to oxidized LDL in chronic smokers

NARCIS (Netherlands)

Tits, van L.J.; Waart, de F.; Hak-Lemmers, H.L.M.; Heijst, P.; Graaf, de J.; Demacker, P.N.; Stalenhoef, A.F.

2001-01-01

Antioxidants have been postulated to exert beneficial effects in atherosclerosis. Atherosclerosis is associated with raised plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and autoantibodies against oxidized low-density lipoprotein (oxLDL). It is not known whether antioxidants

TRPV4 calcium-permeable channel is a novel regulator of oxidized LDL-induced macrophage foam cell formation.

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Goswami, Rishov; Merth, Michael; Sharma, Shweta; Alharbi, Mazen O; Aranda-Espinoza, Helim; Zhu, Xiaoping; Rahaman, Shaik O

2017-09-01

Cardiovascular disease is the number one cause of death in United States, and atherosclerosis, a chronic inflammatory arterial disease, is the most dominant underlying pathology. Macrophages are thought to orchestrate atherosclerosis by generating lipid-laden foam cells and by secreting inflammatory mediators. Emerging data support a role for a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function, vascular elasticity, and atherogenesis. However, the identity of the plasma membrane mechanosensor and the mechanisms by which pro-atherogenic signals are transduced/maintained are unknown. We have obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family and a known mechanosensor, is the likely mediator of oxidized low-density lipoprotein (oxLDL)-dependent macrophage foam cell formation, a critical process in atherogenesis. Specifically, we found that: i) genetic ablation of TRPV4 or pharmacologic inhibition of TRPV4 activity by a specific antagonist blocked oxLDL-induced macrophage foam cell formation, and ii) TRPV4 deficiency prevented pathophysiological range matrix stiffness or scratch-induced exacerbation of oxLDL-induced foam cell formation. Mechanistically, we found that: i) plasma membrane localization of TRPV4 was sensitized to the increasing level of matrix stiffness, ii) lack of foam cell formation in TRPV4 null cells was not due to lack of expression of CD36, a major receptor for oxLDL, and iii) TRPV4 channel activity regulated oxLDL uptake but not its binding on macrophages. Altogether, these findings identify a novel role for TRPV4 in regulating macrophage foam cell formation by modulating uptake of oxLDL. These findings suggest that therapeutic targeting of TRPV4 may provide a selective approach to the treatment of atherosclerosis. Copyright © 2017. Published by Elsevier Inc.

Catabolism of native and oxidized low density lipoproteins: in vivo insights from small animal positron emission tomography studies.

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Pietzsch, J; Bergmann, R; Wuest, F; Pawelke, B; Hultsch, C; van den Hoff, J

2005-12-01

The human organism is exposed to numerous processes that generate reactive oxygen species (ROS). ROS may directly or indirectly cause oxidative modification and damage of proteins. Protein oxidation is regarded as a crucial event in the pathogenesis of various diseases ranging from rheumatoid arthritis to Alzheimer's disease and atherosclerosis. As a representative example, oxidation of low density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Data concerning the role of circulating oxidized LDL (oxLDL) in the development and outcome of diseases are scarce. One reason for this is the shortage of methods for direct assessment of the metabolic fate of circulating oxLDL in vivo. We present an improved methodology based on the radiolabelling of apoB-100 of native LDL (nLDL) and oxLDL, respectively, with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). Radiolabelling of both nLDL and oxLDL using [(18)F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively, in vitro. The method was further evaluated with respect to the radiopharmacological properties of both [(18)F]fluorobenzoylated nLDL and oxLDL by biodistribution studies in male Wistar rats. The metabolic fate of [(18)F]fluorobenzoylated nLDL and oxLDL in rats in vivo was further delineated by dynamic positron emission tomography (PET) using a dedicated small animal tomograph (spatial resolution of 2 mm). From this study we conclude that the use of [(18)F]FB-labelled LDL particles is an attractive alternative to, e.g., LDL iodination methods, and is of value to characterize and to discriminate the kinetics and the metabolic fate of nLDL and oxLDL in small animals in vivo.

A fibre cocktail of fenugreek, guar gum and wheat bran reduces oxidative modification of LDL induced by an atherogenic diet in rats.

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Venkatesan, Nandini; Devaraj, S Niranjali; Devaraj, H

2007-01-01

LDL (low-density lipoprotein) oxidation is a key trigger factor for the development of atherosclerosis. Relatively few studies exist on the impact of dietary fibre on LDL oxidation. This study was undertaken to evaluate the influence of a novel fibre mix of fenugreek seed powder, guar gum and wheat bran (Fibernat) on LDL oxidation induced by an atherogenic diet. Male Wistar albino rats were administered one of the following diets: (1) a control diet that was fibre-free (Group I); (2) an atherogenic diet containing 1.5% cholesterol and 0.1% cholic acid (Group II) or (3) an atherogenic diet supplemented with Fibernat (Group III). Peroxidative changes in low-density lipoprotein (LDL) and the oxidative susceptibility of LDL and the LDL + VLDL (very low-density lipoprotein) fraction were determined. As a corollary to the oxidative modification theory, the titer of autoantibodies to oxidised LDL (oxLDL) was determined at various time points of the study. In addition, plasma homocysteine (tHcy) and lipoprotein (Lp (a)), apolipoprotein (apoB), cholesterol, triglyceride, phospholipid and alpha-tocopherol content of LDL were determined. A decrease in malonaldehyde (MDA) content (p<0.05) and relative electrophoretic mobility (REM) of LDL was observed in the group III rats as compared to the group II rats. An increase in lag time to oxidation (p<0.01) and decrease in maximum oxidation (p<0.01) and oxidation rate (p<0.01) were observed in the LDL + VLDL fraction of group III rats. In group II rats, formation of autoantibodies to oxLDL occurred at an earlier time point and at levels greater than in the group III rats. Fibernat, had a sparing effect on LDL alpha-tocopherol, which was about 51% higher in the group III rats than in the group II rats; apo B content of LDL was reduced by 37.6% in group III rats. LDL of group III rats displayed a decrease in free and ester cholesterol (p<0.01) as compared to that of group II. A decrease in plasma homocysteine (p<0.01) and an increase

Low-Density Lipoproteins Oxidation and Endometriosis

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Grzegorz Polak

2013-01-01

Full Text Available The etiopathogenesis of endometriosis still remains unknown. Recent data provide new valuable information concerning the role of oxidative stress in the pathophysiology of the disease. It has been proved that levels of different lipid peroxidation end products are increased in both peritoneal fluid (PF and serum of endometriotic patients. We assessed the concentration of oxidized low-density lipoproteins (oxLDL in PF of 110 women with different stages of endometriosis and 119 women with serous ( or dermoid ( ovarian cysts, as the reference groups. PF oxLDL levels were evaluated by ELISA. We found that concentrations of oxLDL in PF of endometriotic women were significantly higher compared to women with serous but not dermoid ovarian cysts. Interestingly, by analyzing concentrations of oxLDL in women with different stages of the disease, it was noted that they are significantly higher only in the subgroup of patients with stage IV endometriosis as compared to women with ovarian serous cysts. In case of minimal, mild, and moderate disease, PF oxLDL levels were similar to those noted in reference groups. Our results indicate that disrupted oxidative status in the peritoneal cavity of women with endometriosis may play a role in the pathogenesis of advanced stages of the disease.

NF-kB activity-dependent P-selectin involved in ox-LDL-induced foam cell formation in U937 cell

International Nuclear Information System (INIS)

Wang, Yi; Wang, Xiang; Sun, Minghui; Zhang, Zhenyu; Cao, Heng; Chen, Xiaoqing

2011-01-01

Highlights: → Ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. → Ox-LDL induced expression of P-selectin through degradation of IkBa and augment of NF-kB activity and protein level during macrophage-derived foam cell formation. → P-selectin and NF-kB may be identified as pivotal regulators of ox-LDL-induced foam cell formation. → Therapy based on the inhibition of P-selectin and NF-kB may complement conventional treatments to prevent atherosclerosis. -- Abstract: Oxidized low-density lipoprotein (ox-LDL) plays a critical role in regulation of atherosclerosis. However, little is known about the role of Nuclear factor kB (NF-kB) activity-dependent P-selectin in ox-LDL-induced foam cell formation during atherosclerosis. In this study, we first investigated ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. Treatment of U937 cells with ox-LDL increased lipid accumulation as well as intracellular cholesterol content. Next, a comparative analysis of gene expression profiling using cDNA microarray and Real-time-PCR indicated that ox-LDL exposure induced, in three treated groups, an extremely marked increase in the mRNA level of P-selectin. Protein levels of P-selectin and its upstream regulators IkBa and NF-kB showed that NF-kB pathway is involved in the ox-LDL-induced foam cell formation. Finally, overexpression of NF-kB significantly accelerated, whereas, inhibition of NF-kB with siRNA remarkably attenuated ox-LDL-induced macrophage-derived foam cell formation. It was concluded that the activity of NF-kB is augmented during macrophage-derived foam cell formation. Activation of NF-kB increased, whereas, inhibition of NF-kB decreased ox-LDL-induced P-selectin expression and lipid accumulation in macrophages, suggesting ox-LDL induced expression of P-selectin through degradation of IkBa and activation of NF-kB in the regulation of foam

NF-kB activity-dependent P-selectin involved in ox-LDL-induced foam cell formation in U937 cell

Energy Technology Data Exchange (ETDEWEB)

Wang, Yi, E-mail: wangyi2004a@126.com [Department of Cardiology, Shanghai First People' s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080 (China); Wang, Xiang; Sun, Minghui; Zhang, Zhenyu; Cao, Heng; Chen, Xiaoqing [Department of Cardiology, Shanghai First People' s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080 (China)

2011-08-05

Highlights: {yields} Ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. {yields} Ox-LDL induced expression of P-selectin through degradation of IkBa and augment of NF-kB activity and protein level during macrophage-derived foam cell formation. {yields} P-selectin and NF-kB may be identified as pivotal regulators of ox-LDL-induced foam cell formation. {yields} Therapy based on the inhibition of P-selectin and NF-kB may complement conventional treatments to prevent atherosclerosis. -- Abstract: Oxidized low-density lipoprotein (ox-LDL) plays a critical role in regulation of atherosclerosis. However, little is known about the role of Nuclear factor kB (NF-kB) activity-dependent P-selectin in ox-LDL-induced foam cell formation during atherosclerosis. In this study, we first investigated ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. Treatment of U937 cells with ox-LDL increased lipid accumulation as well as intracellular cholesterol content. Next, a comparative analysis of gene expression profiling using cDNA microarray and Real-time-PCR indicated that ox-LDL exposure induced, in three treated groups, an extremely marked increase in the mRNA level of P-selectin. Protein levels of P-selectin and its upstream regulators IkBa and NF-kB showed that NF-kB pathway is involved in the ox-LDL-induced foam cell formation. Finally, overexpression of NF-kB significantly accelerated, whereas, inhibition of NF-kB with siRNA remarkably attenuated ox-LDL-induced macrophage-derived foam cell formation. It was concluded that the activity of NF-kB is augmented during macrophage-derived foam cell formation. Activation of NF-kB increased, whereas, inhibition of NF-kB decreased ox-LDL-induced P-selectin expression and lipid accumulation in macrophages, suggesting ox-LDL induced expression of P-selectin through degradation of IkBa and activation of NF-kB in the

Oxidized low-density lipoproteins induced inflammatory process during atherogenesis with aging

International Nuclear Information System (INIS)

Larbi, Anis; Khalil, Abdelouahed; Douziech, Nadine; Guerard, Karl-Philippe; Fueloep, Tamas

2005-01-01

Atherosclerosis is a chronic disease developing through decades with two life-threatening complications: myocardial infarction and stroke. Oxidized low-density lipoproteins (oxLDL) produced by oxidative modifications of LDL in the subendothelial space have been demonstrated to be critically involved in atherogenesis through their intensive pro-inflammatory activity. Recently, it was shown that oxLDL have an apoptosis-inducing effect in T cells depending on time and degree of oxidation. The goal of the current study is to elucidate the molecular mechanisms underlying the apoptotic-inducing effects of oxLDL on T lymphocytes. T cells of young and elderly subjects were incubated for various periods of time with LDL oxidized to various degrees. The proliferation, the apoptosis, the MAPK ERK1/2 activation and the expression of the Bcl-2 protein family members were measured upon different LDL treatments. Thus, more the LDL are oxidized more they induce apoptosis and this effect is highly accentuated with aging. The oxLDL decrease the activation of the surviving molecule ERK1/2 and modulate the ratio of Bax/Bcl-2 towards a pro-apoptotic profile, which is also accentuated with aging. These results partly explain why atherosclerosis is increasing with aging concomitantly to its complications

Regular consumption of cocoa powder with milk increases HDL cholesterol and reduces oxidized LDL levels in subjects at high-risk of cardiovascular disease.

Science.gov (United States)

Khan, N; Monagas, M; Andres-Lacueva, C; Casas, R; Urpí-Sardà, M; Lamuela-Raventós, R M; Estruch, R

2012-12-01

Epidemiological studies suggest that regular consumption of cocoa-containing products may confer cardiovascular protection, reducing the risk of coronary heart disease (CHD). However, studies on the effects of cocoa on different cardiovascular risk factors are still scarce. The aim of this study was too evaluate the effects of chronic cocoa consumption on lipid profile, oxidized low-density lipoprotein (oxLDL) particles and plasma antioxidant vitamin concentrations in high-risk patients. Forty-two high-risk volunteers (19 men and 23 women, mean age 69.7 ± 11.5 years) were included in a randomized, crossover feeding trial. All received 40g of cocoa powder with 500 mL of skimmed milk/day(C + M) or only 500 mL/day of skimmed milk (M) for 4 weeks in a random order. Before and after each intervention period, plasma lipids, oxLDL and antioxidant vitamin concentrations were measured, as well as urinary cocoa polyphenols metabolites derived from phase II and microbial metabolisms. Compared to M, C + M intervention increases HDLc [2.67 mg/dL (95% confidence intervals, CI, 0.58-4.73; P = 0.008)] and decreases oxLDL levels [-12.3 U/L (CI,-19.3 to -5.2;P = 0.001)]. No changes between intervention groups were observed in vitamins B1, B6, B12, C and E, or folic acid concentrations. In addition, subjects who showed higher increments in urinary cocoa polyphenol metabolites exhibited significant increases in HDLc and significant decreases in oxLDL levels (P Consumption of cocoa power with milk modulates the lipid profile in high-risk subjects for CHD. In addition, the relationship observed between the urinary excretion of cocoa polyphenol metabolites and plasma HDLc and oxLDL levels suggests a beneficial role for cocoa polyphenols in lipid metabolism. Copyright © 2011 Elsevier B.V. All rights reserved.

Fluorine-18 radiolabeling of low-density lipoproteins: a potential approach for characterization and differentiation of metabolism of native and oxidized low-density lipoproteins in vivo

International Nuclear Information System (INIS)

Pietzsch, Jens; Bergmann, Ralf; Rode, Katrin; Hultsch, Christina; Pawelke, Beate; Wuest, Frank; Hoff, Joerg van den

2004-01-01

Oxidative modification of low-density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Assessing the metabolic fate of oxidized LDL (oxLDL) in vivo with radiotracer techniques is hindered by the lack of suitable sensitive and specific radiolabeling methods. We evaluated an improved methodology based on the radiolabeling of native LDL (nLDL) and oxLDL with the positron emitter fluorine-18 ( 18 F) by conjugation with N-succinimidyl-4-[ 18 F]fluorobenzoate ([ 18 F]SFB). We investigated whether radiolabeling of LDL induces adverse structural modifications. Results suggest that radiolabeling of both nLDL and oxLDL using [ 18 F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively. Thus, radiolabeling of LDL using [ 18 F]SFB could prove to be a promising approach for studying the kinetics of oxLDL in vivo

Fluorine-18 radiolabeling of low-density lipoproteins: a potential approach for characterization and differentiation of metabolism of native and oxidized low-density lipoproteins in vivo.

Science.gov (United States)

Pietzsch, Jens; Bergmann, Ralf; Rode, Katrin; Hultsch, Christina; Pawelke, Beate; Wuest, Frank; van den Hoff, Joerg

2004-11-01

Oxidative modification of low-density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Assessing the metabolic fate of oxidized LDL (oxLDL) in vivo with radiotracer techniques is hindered by the lack of suitable sensitive and specific radiolabeling methods. We evaluated an improved methodology based on the radiolabeling of native LDL (nLDL) and oxLDL with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). We investigated whether radiolabeling of LDL induces adverse structural modifications. Results suggest that radiolabeling of both nLDL and oxLDL using [(18)F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively. Thus, radiolabeling of LDL using [(18)F]SFB could prove to be a promising approach for studying the kinetics of oxLDL in vivo.

Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury

International Nuclear Information System (INIS)

Eto, Hideyuki; Miyata, Masaaki; Kume, Noriaki; Minami, Manabu; Itabe, Hiroyuki; Orihara, Koji; Hamasaki, Shuichi; Biro, Sadatoshi; Otsuji, Yutaka; Kita, Toru; Tei, Chuwa

2006-01-01

Lectin-like oxidized LDL receptor-1 (LOX-1) is an oxidized LDL receptor, and its role in restenosis after angioplasty remains unknown. We used a balloon-injury model of rabbit aorta, and reverse transcription-polymerase chain reaction revealed that LOX-1 mRNA expression was modest in the non-injured aorta, reached a peak level 2 days after injury, and remained elevated until 24 weeks after injury. Immunohistochemistry and in situ hybridization showed that LOX-1 was not detected in the media of non-injured aorta but expressed in both medial and neointimal smooth muscle cells (SMC) at 2 and 24 weeks after injury. Low concentrations of ox-LDL (10 μg/mL) stimulated the cultured SMC proliferation, which was inhibited by antisense oligonucleotides of LOX-1 mRNA. Double immunofluorescense staining showed the colocalization of LOX-1 and proliferating cell nuclear antigen in human restenotic lesion. These results suggest that LOX-1 mediates ox-LDL-induced SMC proliferation and plays a role in neointimal formation after vascular injury

Serum oxidized low-density lipoprotein level as a marker of oxidative stress in patients undergoing hyperbaric oxygen therapy.

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Keskin, Kudret; Kilci, Hakan; Aksan, Gökhan; Çetinkal, Gökhan; Yıldız, Süleyman Sezai; Kocaman Türk, Füsun; Bingöl, Gülsüm

2017-09-01

Oxidative stress (OS) is involved in the pathogenesis of atherosclerosis. Hyperbaric oxygen therapy (HBOT), in which 100% oxygen is inhaled under hyperbaric pressure, may create OS. Therefore, the aim of this research was to measure the serum oxidized low-density lipoprotein (oxLDL) level in patients undergoing HBOT. Twenty-nine patients who underwent HBOT to treat various diseases were enrolled in this study. The serum oxLDL level was measured at the beginning of the first and after the 10th therapy session. There was no significant difference between the oxLDL level of patients before and after HBOT (4.96±0.1 vs. 4.94±0.1 U/mL; p=0.36). HBOT seems to be safe in terms of oxLDL production up to 10 sessions. However, further large-scale studies investigating longer duration of HBOT treatment are required to understand the role of OS.

Fluorine-18 radiolabeling of low-density lipoproteins: a potential approach for characterization and differentiation of metabolism of native and oxidized low-density lipoproteins in vivo

Energy Technology Data Exchange (ETDEWEB)

Pietzsch, Jens [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany); Bergmann, Ralf [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany); Rode, Katrin [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany); Hultsch, Christina [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany); Pawelke, Beate [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany); Wuest, Frank [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany); Hoff, Joerg van den [PET-Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf Dresden, P.O. Box 51 01 19, D-01314 Dresden (Germany)

2004-11-01

Oxidative modification of low-density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Assessing the metabolic fate of oxidized LDL (oxLDL) in vivo with radiotracer techniques is hindered by the lack of suitable sensitive and specific radiolabeling methods. We evaluated an improved methodology based on the radiolabeling of native LDL (nLDL) and oxLDL with the positron emitter fluorine-18 ({sup 18}F) by conjugation with N-succinimidyl-4-[{sup 18}F]fluorobenzoate ([{sup 18}F]SFB). We investigated whether radiolabeling of LDL induces adverse structural modifications. Results suggest that radiolabeling of both nLDL and oxLDL using [{sup 18}F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively. Thus, radiolabeling of LDL using [{sup 18}F]SFB could prove to be a promising approach for studying the kinetics of oxLDL in vivo.

Sex Differences in the Impact of the Mediterranean Diet on LDL Particle Size Distribution and Oxidation.

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Bédard, Alexandra; Corneau, Louise; Lamarche, Benoît; Dodin, Sylvie; Lemieux, Simone

2015-05-15

Sex differences have been previously highlighted in the cardioprotective effects of the Mediterranean diet (MedDiet). The objective of this study was to investigate whether sex differences also exist with regard to LDL particle size distribution and oxidation. Participants were 37 men and 32 premenopausal women (24-53 years) with slightly elevated LDL-C concentrations (3.4-4.9 mmol/L) or total cholesterol/HDL-C ≥5.0. Variables were measured before and after a four-week isoenergetic MedDiet. Sex differences were found in response to the MedDiet for the proportion of medium LDL (255-260 Å) (p for sex-by-time interaction = 0.01) and small, dense LDL (sdLDL; <255 Å) (trend; p for sex-by-time interaction = 0.06), men experiencing an increase in the proportion of medium LDL with a concomitant reduction in the proportion of sdLDL, while an opposite trend was observed in women. A sex difference was also noted for estimated cholesterol concentrations among sdLDL (p for sex-by-time interaction = 0.03), with only men experiencing a reduction in response to the MedDiet. The MedDiet marginally reduced oxidized LDL (oxLDL) concentrations (p = 0.07), with no sex difference. Results suggest that short-term consumption of the MedDiet leads to a favorable redistribution of LDL subclasses from smaller to larger LDL only in men. These results highlight the importance of considering sex issues in cardiovascular benefits of the MedDiet.

MicroRNA-98 rescues proliferation and alleviates ox-LDL-induced apoptosis in HUVECs by targeting LOX-1

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Chen, Zhibo; Wang, Mian; He, Qiong; Li, Zilun; Zhao, Yang; Wang, Wenjian; Ma, Jieyi; Li, Yongxin; Chang, Guangqi

2017-01-01

Oxidized low-density lipoprotein (ox-LDL) is a major and critical mediator of atherosclerosis, and the underlying mechanism is thought to involve the ox-LDL-induced dysfunction of endothelial cells (ECs). MicroRNAs (miRNAs), which are a group of small non-coding RNA molecules that post-transcriptionally regulate the expression of target genes, have been associated with diverse cellular functions and the pathogenesis of various diseases, including atherosclerosis. miRNA-98 (miR-98) has been demonstrated to be involved in the regulation of cellular apoptosis; however, the role of miR-98 in ox-LDL-induced dysfunction of ECs and atherosclerosis has yet to be elucidated. Therefore, the present study aimed to investigate the role of miR-98 in ox-LDL-induced dysfunction of ECs and the underlying mechanism. It was demonstrated that miR-98 expression was markedly downregulated in ox-LDL-treated human umbilical vein ECs (HUVECs) and that miR-98 promoted the proliferation and alleviated apoptosis of HUVECs exposed to ox-LDL. In addition, the results demonstrated that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) was a direct target of miR-98 in HUVECs, as indicated by a luciferase assay. The results of the present study suggested that miR-98 may inhibit the uptake of toxic ox-LDL, maintain HUVEC proliferation and protect HUVECs against apoptosis via the suppression of LOX-1. PMID:28565756

Sex Differences in the Impact of the Mediterranean Diet on LDL Particle Size Distribution and Oxidation

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Alexandra Bédard

2015-05-01

Full Text Available Sex differences have been previously highlighted in the cardioprotective effects of the Mediterranean diet (MedDiet. The objective of this study was to investigate whether sex differences also exist with regard to LDL particle size distribution and oxidation. Participants were 37 men and 32 premenopausal women (24–53 years with slightly elevated LDL-C concentrations (3.4–4.9 mmol/L or total cholesterol/HDL-C ≥5.0. Variables were measured before and after a four-week isoenergetic MedDiet. Sex differences were found in response to the MedDiet for the proportion of medium LDL (255–260 Å (p for sex-by-time interaction = 0.01 and small, dense LDL (sdLDL; <255 Å (trend; p for sex-by-time interaction = 0.06, men experiencing an increase in the proportion of medium LDL with a concomitant reduction in the proportion of sdLDL, while an opposite trend was observed in women. A sex difference was also noted for estimated cholesterol concentrations among sdLDL (p for sex-by-time interaction = 0.03, with only men experiencing a reduction in response to the MedDiet. The MedDiet marginally reduced oxidized LDL (oxLDL concentrations (p = 0.07, with no sex difference. Results suggest that short-term consumption of the MedDiet leads to a favorable redistribution of LDL subclasses from smaller to larger LDL only in men. These results highlight the importance of considering sex issues in cardiovascular benefits of the MedDiet.

Circulating and PBMC Lp-PLA2 associate differently with oxidative stress and subclinical inflammation in nonobese women (menopausal status.

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Jean Kyung Paik

Full Text Available BACKGROUND: This study aimed to determine the association of lipoprotein-associated phospholipase A(2 (Lp-PLA(2 activity in circulation and peripheral blood mononuclear cells (PBMCs with inflammatory and oxidative stress markers in nonobese women and according to menopausal status. Lp-PLA(2 activity, a marker for cardiovascular risk is associated with inflammation and oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: Eighty postmenopausal women (53.0±4.05 yr and 96 premenopausal women (39.7±9.25 yr participated in this study. Lp-PLA(2 activities, interleukin (IL-6, tumor necrosis factor (TNF-α, and IL-1β in plasma as well as in PBMCs were measured. Plasma ox-LDL was also measured. Postmenopausal women demonstrated higher circulating levels of ox-LDL and IL-6, as well as IL-6, TNF-α, and IL-1β in PBMCs, than premenopausal women. In both groups, plasma Lp-PLA(2 activity positively correlated with Lp-PLA(2 activity in PBMCs and plasma ox-LDL. In premenopausal women, Lp-PLA(2 activities in plasma and PBMCs positively correlated with IL-6, TNF-α, and IL-1β in PBMCs. In postmenopausal women, plasma ox-LDL positively correlated with PBMC cytokine production. In subgroup analysis of postmenopausal women according to plasma ox-LDL level (median level: 48.715 U/L, a significant increase in Lp-PLA(2 activity in the plasma but not the PBMCs was found in the high ox-LDL subgroup. Plasma Lp-PLA(2 activity positively correlated with unstimulated PBMC Lp-PLA(2 activity in the low ox-LDL subgroup (r = 0.627, P<0.001, whereas in the high ox-LDL circulating Lp-PLA(2 activity positively correlated with plasma ox-LDL (r = 0.390, P = 0.014 but not with Lp-PLA(2 activity in PBMCs. CONCLUSIONS/SIGNIFICANCE: The lack of relation between circulating Lp-PLA(2 activity and Lp-PLA(2 activity in PBMCs was found in postmenopausal women with high ox-LDL. This may indicate other sources of circulating Lp-PLA(2 activity except PBMC in postmenopausal women

Electronegative LDL is linked to high-fat, high-cholesterol diet-induced nonalcoholic steatohepatitis in hamsters.

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Lai, Yu-Sheng; Yang, Tzu-Ching; Chang, Po-Yuan; Chang, Shwu-Fen; Ho, Shu-Li; Chen, Hui-Ling; Lu, Shao-Chun

2016-04-01

The pathogenesis of nonalcoholic steatohepatitis (NASH), like that of atherosclerosis, involves lipid accumulation, inflammation and fibrosis. Recent studies suggest that oxidized LDL (oxLDL) may be a risk factor for NASH, but oxLDL levels were not directly measured in these studies. The aim of this study was to examine whether there was an association between electronegative LDL [LDL(-)], a mildly oxLDL found in the blood, and the development of NASH using two animal models. Golden Syrian hamsters and C57BL/6 mice were fed a high-fat, high-cholesterol (HFC) diet for 6 or 12weeks, then liver lipid and histopathology, plasma lipoprotein profile and LDL(-) levels were examined. The HFC-diet-fed hamsters and mice had similar levels of hepatic lipid but different histopathological changes, with microvesicular steatosis, hepatocellular hypertrophy, inflammation and bridging fibrosis in the hamsters, but only in mild steatohepatitis with low inflammatory cell infiltration in the mice. It also resulted in a significant increase in plasma levels of LDL cholesterol and LDL(-) in hamsters, but only a slight increase in mice. Moreover, enlarged Kupffer cells, LDL(-) and accumulation of unesterified cholesterol were detected in the portal area of HFC-diet-fed hamsters, but not HFC-diet-fed mice. An in vitro study showed that LDL(-) from HFC-diet-fed hamsters induced TNF-α secretion in rat Kupffer cell through a LOX-1-dependent pathway. Our results strongly suggest that LDL(-) is one of the underlying causes of hepatic inflammation and plays a critical role in the development of NASH. Copyright © 2015 Elsevier Inc. All rights reserved.

Autophagic effects of Hibiscus sabdariffa leaf polyphenols and epicatechin gallate (ECG) against oxidized LDL-induced injury of human endothelial cells.

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Chen, Jing-Hsien; Lee, Ming-Shih; Wang, Chi-Ping; Hsu, Cheng-Chin; Lin, Hui-Hsuan

2017-08-01

Oxidized low-density lipoprotein (ox-LDL) contributes to the pathogenesis of atherosclerosis by promoting vascular endothelial cell injury. Hibiscus sabdariffa leaf polyphenols (HLP), rich in flavonoids, have been shown to possess antioxidant and antiatherosclerotic activities. In this study, we examined the protective role of HLP and its main compound (-)-epicatechin gallate (ECG) in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL in vitro. In a model of ox-LDL-impaired HUVECs, assessments of cell viability, cytotoxicity, cell proliferation, apoptosis, and autophagy were detected. To highlight the mechanisms of the antiapoptotic effects of HLP and ECG, the expressions of molecular proteins were measured by Western blotting, real-time PCR, and so on. HLP or ECG improved the survival of HUVECs from ox-LDL-induced viability loss. In addition, HLP or ECG showed potential in reducing ox-LDL-dependent apoptosis. Next, the ox-LDL-induced formation of acidic vesicular organelles and upregulation of the autophagy-related genes were increased by HLP or ECG. The HLP-triggered autophagic flux was further confirmed by increasing the LC3-II level under the pretreatment of an autophagy inhibitor chloroquine. Molecular data indicated the autophagic effect of HLP or ECG might be mediated via class III PI3K/Beclin-1 and PTEN/class I PI3K/Akt cascade signaling, as demonstrated by the usage of a class III PI3K inhibitor 3-methyladenine (3-MA) and a PTEN inhibitor SF1670. Our data imply that ECG-enriched HLP upregulates the autophagic pathway, which in turn led to reduce ox-LDL-induced HUVECs injury and apoptosis and provide a new mechanism for its antiatherosclerotic activity.

Association between oxidized low-density lipoprotein and cognitive impairment in patients with ischemic stroke.

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Wang, A; Liu, J; Meng, X; Li, J; Wang, H; Wang, Y; Su, Z; Zhang, N; Dai, L; Wang, Y; Wang, Y

2018-01-01

The association between oxidized low-density lipoprotein (oxLDL) and cognitive impairment is unclear. This study aimed to investigate the potential association between oxLDL and cognitive impairment among patients with acute ischemic stroke. We measured the levels of oxLDL and recorded the Mini-Mental State Examination (MMSE) score in patients with acute ischemic stroke who were recruited from the Study of Oxidative Stress in Patients with Acute Ischemic Stroke. Cognitive impairment was defined as an MMSE score of impairment was assessed by multivariate logistic or linear regression analysis. Other clinical variables of interest were also studied. A total of 3726 patients [1287 (34.54%) female] were included in this study, with a mean age of 63.62 ± 11.96 years. After adjusting for potential confounders in our logistic regression model, each SD increase in oxLDL was associated with a 26% increase in the prevalence of cognitive impairment (odds radio, 1.26; 95% confidence interval, 1.13-1.39; P impairment (all interactions, P > 0.05). Elevated levels of oxLDL were associated with a higher prevalence of cognitive impairment in patients with ischemic stroke. © 2017 EAN.

Natural Biflavonoids Modulate Macrophage–Oxidized LDL Interaction In Vitro and Promote Atheroprotection In Vivo

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Jorge H. Tabares-Guevara

2017-08-01

Full Text Available The accumulation of oxidized ApoB-100-containing lipoproteins in the vascular intima and its subsequent recognition by macrophages results in foam cell formation and inflammation, key events during atherosclerosis development. Agents targeting this process are considered potentially atheroprotective. Since natural biflavonoids exert antioxidant and anti-inflammatory effects, we evaluated the atheroprotective effect of biflavonoids obtained from the tropical fruit tree Garcinia madruno. To this end, the pure biflavonoid aglycones morelloflavone (Mo and volkensiflavone (Vo, as well as the morelloflavone’s glycoside fukugiside (Fu were tested in vitro in primary macrophages, whereas a biflavonoid fraction with defined composition (85% Mo, 10% Vo, and 5% Amentoflavone was tested in vitro and in vivo. All biflavonoid preparations were potent reactive oxygen species (ROS scavengers in the oxygen radical absorbance capacity assay, and most importantly, protected low-density lipoprotein particle from both lipid and protein oxidation. In biflavonoid-treated macrophages, the surface expression of the oxidized LDL (oxLDL receptor CD36 was significantly lower than in vehicle-treated macrophages. Uptake of fluorescently labeled oxLDL and cholesterol accumulation were also attenuated in biflavonoid-treated macrophages and followed a pattern that paralleled that of CD36 surface expression. Fu and Vo inhibited oxLDL-induced ROS production and interleukin (IL-6 secretion, respectively, whereas all aglycones, but not the glucoside Fu, inhibited the secretion of one or more of the cytokines IL-1β, IL-12p70, and monocyte chemotactic protein-1 (MCP-1 in lipopolysaccharide (LPS-stimulated macrophages. Interestingly, in macrophages primed with low-dose LPS and stimulated with cholesterol crystals, IL-1β secretion was significantly and comparably inhibited by all biflavonoid preparations. Intraperitoneal administration of the defined biflavonoid fraction into Apo

Natural Biflavonoids Modulate Macrophage–Oxidized LDL Interaction In Vitro and Promote Atheroprotection In Vivo

Science.gov (United States)

Tabares-Guevara, Jorge H.; Lara-Guzmán, Oscar J.; Londoño-Londoño, Julian A.; Sierra, Jelver A.; León-Varela, Yudy M.; Álvarez-Quintero, Rafael M.; Osorio, Edison J.; Ramirez-Pineda, José R.

2017-01-01

The accumulation of oxidized ApoB-100-containing lipoproteins in the vascular intima and its subsequent recognition by macrophages results in foam cell formation and inflammation, key events during atherosclerosis development. Agents targeting this process are considered potentially atheroprotective. Since natural biflavonoids exert antioxidant and anti-inflammatory effects, we evaluated the atheroprotective effect of biflavonoids obtained from the tropical fruit tree Garcinia madruno. To this end, the pure biflavonoid aglycones morelloflavone (Mo) and volkensiflavone (Vo), as well as the morelloflavone’s glycoside fukugiside (Fu) were tested in vitro in primary macrophages, whereas a biflavonoid fraction with defined composition (85% Mo, 10% Vo, and 5% Amentoflavone) was tested in vitro and in vivo. All biflavonoid preparations were potent reactive oxygen species (ROS) scavengers in the oxygen radical absorbance capacity assay, and most importantly, protected low-density lipoprotein particle from both lipid and protein oxidation. In biflavonoid-treated macrophages, the surface expression of the oxidized LDL (oxLDL) receptor CD36 was significantly lower than in vehicle-treated macrophages. Uptake of fluorescently labeled oxLDL and cholesterol accumulation were also attenuated in biflavonoid-treated macrophages and followed a pattern that paralleled that of CD36 surface expression. Fu and Vo inhibited oxLDL-induced ROS production and interleukin (IL)-6 secretion, respectively, whereas all aglycones, but not the glucoside Fu, inhibited the secretion of one or more of the cytokines IL-1β, IL-12p70, and monocyte chemotactic protein-1 (MCP-1) in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, in macrophages primed with low-dose LPS and stimulated with cholesterol crystals, IL-1β secretion was significantly and comparably inhibited by all biflavonoid preparations. Intraperitoneal administration of the defined biflavonoid fraction into ApoE−/− mice

Serum oxidized low density lipoprotein levels in preeclamptic and normotensive pregnants.

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Kozan, A; Yildirmak, S Turkmen; Mihmanli, V; Ayabakan, H; Cicek, Y G; Kalaslioglu, V; Doean, S; Cebeci, H Cerci

2015-01-01

BACKGROUNDS/AIM: The aim of the study was to determine serum lipids and oxidized low density lipoprotein (ox-LDL) levels in preeclamptic pregnants and compare with those of normotensives. Ox-LDL levels were determined by enzyme linked immunosorbent assay (ELISA); total cholesterol, hight density lipoprotein (HDL)-cholesterol and triglyceride levels were measured by enzymatic colorimetric assay in 26 normotensive and 27 preeclamptic pregnants. LDL and very low density lipoprotein (VLDL) cholesterol was calculated by Friedwald formula. Serum levels of Ox-LDL (U/L), total-cholesterol (mg/dL), HDL-cholesterol (mg/dL), LDL-cholesterol (mg/dL), triglyceride (mg/dL), and VLDL-cholesterol (mg/dL) in normotensive and preeclamptic pregnants were found as 130±60 and 133±69; 248±49 and 248±81; 67±14 and 61±16; 147±61 and 135±59; 207±76 and 256±87; 41±15 and 50±17, respectively. Mean values of Ox-LDL and other lipid parameters were higher than the upper limits of their reference ranges in both of groups. However no significant differences were found in Ox-LDL, total, HDL and LDL-cholesterol levels between two groups. However, the levels of triglyceride and VLDL-cholesterol were significantly higher in preeclampsia group. The present results suggest that the levels of serum Ox-LDL and other lipid parameters rise as a result of pregnancy rather than as a result of preeclampsia.

Oxidised LDL internalisation by the LOX-1 scavenger receptor is dependent on a novel cytoplasmic motif and is regulated by dynamin-2.

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Murphy, Jane E; Vohra, Ravinder S; Dunn, Sarah; Holloway, Zoe G; Monaco, Anthony P; Homer-Vanniasinkam, Shervanthi; Walker, John H; Ponnambalam, Sreenivasan

2008-07-01

The LOX-1 scavenger receptor recognises pro-atherogenic oxidised low-density lipoprotein (OxLDL) particles and is implicated in atherosclerotic plaque formation, but this mechanism is not well understood. Here we show evidence for a novel clathrin-independent and cytosolic-signal-dependent pathway that regulates LOX-1-mediated OxLDL internalisation. Cell surface labelling in the absence or presence of OxLDL ligand showed that LOX-1 is constitutively internalised from the plasma membrane and its half-life is not altered upon ligand binding and trafficking. We show that LOX-1-mediated OxLDL uptake is disrupted by overexpression of dominant-negative dynamin-2 but unaffected by CHC17 or mu2 (AP2) depletion. Site-directed mutagenesis revealed a conserved and novel cytoplasmic tripeptide motif (DDL) that regulates LOX-1-mediated endocytosis of OxLDL. Taken together, these findings indicate that LOX-1 is internalised by a clathrin-independent and dynamin-2-dependent pathway and is thus likely to mediate OxLDL trafficking in vascular tissues.

Effects of copper sulfate-oxidized or myeloperoxidase- modified LDL on lipid loading and programmed cell death in macrophages under hypoxia

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Vlaminck B

2014-09-01

Full Text Available Benoit Vlaminck,1 Damien Calay,1 Marie Genin,1 Aude Sauvage,1 Noelle Ninane,1 Karim Zouaoui Boudjeltia,2 Martine Raes,1 Carine Michiels1 1Laboratory of Biochemistry and Cellular Biology (URBC, Namur Research Institute for Life Sciences (NARILIS, University of Namur, Namur, Belgium; 2Laboratory of Experimental Medicine (ULB 222 Unit, Universite Libre de Bruxelles, CHU de Charleroi, Charleroi, Belgium Abstract: Atheromatous plaques contain heavily lipid-loaded macrophages that die, hence generating the necrotic core of these plaques. Since plaque instability and rupture is often correlated with a large necrotic core, it is important to understand the mechanisms underlying foam cell death. Furthermore, macrophages within the plaque are associated with hypoxic areas but little is known about the effect of low oxygen partial pressure on macrophage death. The aim of this work was to unravel macrophage death mechanisms induced by oxidized low-density lipoproteins (LDL both under normoxia and hypoxia. Differentiated macrophages were incubated in the presence of native, copper sulfate-oxidized, or myeloperoxidase-modified LDL. The unfolded protein response, apoptosis, and autophagy were then investigated. The unfolded protein response and autophagy were triggered by myeloperoxidase-modified LDL and, to a larger extent, by copper sulfate-oxidized LDL. Electron microscopy observations showed that oxidized LDL induced excessive autophagy and apoptosis under normoxia, which were less marked under hypoxia. Myeloperoxidase-modified LDL were more toxic and induced a higher level of apoptosis. Hypoxia markedly decreased apoptosis and cell death, as marked by caspase activation. In conclusion, the cell death pathways induced by copper sulfate-oxidized and myeloperoxidase-modified LDL are different and are differentially modulated by hypoxia. Keywords: Ox-LDL, myeloperoxidase, hypoxia, UPR, apoptosis, autophagy, macrophages

Increased Oxidation as an Additional Mechanism Underlying Reduced Clot Permeability and Impaired Fibrinolysis in Type 2 Diabetes

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Anna Lados-Krupa

2015-01-01

Full Text Available Aims. We sought to investigate whether enhanced oxidation contributes to unfavorable fibrin clot properties in patients with diabetes. Methods. We assessed plasma fibrin clot permeation (Ks, a measure of the pore size in fibrin networks and clot lysis time induced by recombinant tissue plasminogen activator (CLT in 163 consecutive type 2 diabetic patients (92 men and 71 women aged 65 ± 8.8 years with a mean glycated hemoglobin (HbA1c of 6.8%. We also measured oxidative stress markers, including nitrotyrosine, the soluble form of receptor for advanced glycation end products (sRAGE, 8-iso-prostaglandin F2α (8-iso-PGF2α, oxidized low-density lipoprotein (oxLDL, and advanced glycation end products (AGE. Results. There were inverse correlations between Ks and nitrotyrosine, sRAGE, 8-iso-PGF2α, and oxLDL. CLT showed a positive correlation with oxLDL and nitrotyrosine but not with other oxidation markers. All these associations remained significant for Ks after adjustment for fibrinogen, disease duration, and HbA1c (all P<0.05, while oxLDL was the only independent predictor of CLT. Conclusions. Our study shows that enhanced oxidative stress adversely affects plasma fibrin clot properties in type 2 diabetic patients, regardless of disease duration and glycemia control.

Increased serum oxidized low-density lipoprotein levels in pregnancies complicated by gestational diabetes mellitus

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Azam Ghaneei

2015-07-01

Full Text Available Background: Elevated serum levels of oxidized Low-density Lipoprotein (oxLDL have been found in type 2 and in poorly controlled diabetic patients. Gestational diabetes mellitus (GDM has common features with type 2 diabetes. Objective: The aim of our study was to evaluate the serum levels of oxLDL in women with GDM compared to normal pregnant women. Materials and Methods: In this cross-sectional study, ninety-two subjects were randomly allocated to either GDM (n=46 or control (n=46 groups matched for age, body mass index and parity from March 2013 to March 2014. GDM was diagnosed according to the American Diabetes Association criteria at 24-26 weeks of gestation. OxLDL was measured using enzyme-linked immunosorbent assay. T-test and Pearson correlation coefficients were applied for analyzing the data by using SPSS version 17. Results: Compared to the controls, significantly higher oxLDL levels were found in the GDM group (17.16 ± 3.71 U/L vs. 8.77 ± 1.84 U/L, respectively, p < 0.001. No significant correlations were found between oxLDL and age and BMI of the patients in the groups. Conclusion: Our study found significant increase of oxLDL in GDM emphasizing the role of short-term hyperglycemia in the formation of oxLDL during GDM. The importance of aptly diagnosis of GDM in maternal health may also be concluded.

Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy.

Science.gov (United States)

Zabirnyk, Olga; Liu, Wei; Khalil, Shadi; Sharma, Anit; Phang, James M

2010-03-01

Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible for the latter. To elucidate the role of POX in oxLDL-mediated cytotoxicity, we knocked down POX via small interfering RNA and found that this (i) further reduced viability of cancer cells treated with oxLDL; (ii) decreased oxLDL-associated reactive oxygen species generation; (iii) decreased autophagy measured via beclin-1 protein level and light-chain 3 protein (LC3)-I into LC3-II conversion. Using POX-expressing cell model, we established that single POX overexpression was sufficient to activate autophagy. Thus, it led to autophagosomes accumulation and increased conversion of LC3-I into LC3-II. Moreover, beclin-1 gene expression was directly dependent on POX catalytic activity, namely the generation of POX-dependent superoxide. We conclude that POX is critical in the cellular response to the noxious effects of oxLDL by activating protective autophagy.

Oxidized low-density lipoprotein-induced periodontal inflammation is associated with the up-regulation of cyclooxygenase-2 and microsomal prostaglandin synthase 1 in human gingival epithelial cells

International Nuclear Information System (INIS)

Nagahama, Yu; Obama, Takashi; Usui, Michihiko; Kanazawa, Yukari; Iwamoto, Sanju; Suzuki, Kazushige; Miyazaki, Akira; Yamaguchi, Tomohiro; Yamamoto, Matsuo; Itabe, Hiroyuki

2011-01-01

Highlights: → OxLDL-induced responses in human gingival epithelial cells were studied. → OxLDL enhanced the production of IL-8, IL-1β and PGE 2 in Ca9-22 cells. → An NF-κB inhibitor suppressed the expression of COX-2 and mPGES1 induced by oxLDL. → Unlike the case in macrophages, oxLDL did not increase the CD36 level. -- Abstract: Periodontitis is characterized by chronic gingival tissue inflammation, and inflammatory mediators such as IL-8 and prostaglandin E 2 (PGE 2 ) are associated with disease progression. Previously we showed that oxidatively modified low-density lipoprotein (oxLDL) was present in gingival crevicular fluid. In this study, the role of oxLDL in the gingival epithelial cell inflammatory response was further investigated using Ca9-22 cells and primary human oral keratinocytes (HOK). Treatment of Ca9-22 cells and HOK with oxLDL induced an up-regulation of IL-8 and the PGE 2 -producing enzymes, cyclooxygenase-2 and microsomal PGE 2 synthase-1. These responses induced by oxLDL were significantly suppressed by a nuclear factor-kappa B (NF-κB) inhibitor. However, unlike the result in macrophages, oxLDL did not lead to an increase in CD36 expression in these two cells. These results suggest that oxLDL elicits gingival epithelial cell inflammatory responses through an activation of the NF-κB pathway. These data suggest a mechanistic link between periodontal disease and lipid metabolism-related disorders, including atherosclerosis.

Oxidized low-density lipoprotein-induced periodontal inflammation is associated with the up-regulation of cyclooxygenase-2 and microsomal prostaglandin synthase 1 in human gingival epithelial cells

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Nagahama, Yu [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Obama, Takashi [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Usui, Michihiko [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Kanazawa, Yukari [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Iwamoto, Sanju [Department of Biochemistry, Showa University School of Medicine, Tokyo (Japan); Suzuki, Kazushige [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Miyazaki, Akira [Department of Biochemistry, Showa University School of Medicine, Tokyo (Japan); Yamaguchi, Tomohiro [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Yamamoto, Matsuo [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Itabe, Hiroyuki [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan)

2011-10-07

Highlights: {yields} OxLDL-induced responses in human gingival epithelial cells were studied. {yields} OxLDL enhanced the production of IL-8, IL-1{beta} and PGE{sub 2} in Ca9-22 cells. {yields} An NF-{kappa}B inhibitor suppressed the expression of COX-2 and mPGES1 induced by oxLDL. {yields} Unlike the case in macrophages, oxLDL did not increase the CD36 level. -- Abstract: Periodontitis is characterized by chronic gingival tissue inflammation, and inflammatory mediators such as IL-8 and prostaglandin E{sub 2} (PGE{sub 2}) are associated with disease progression. Previously we showed that oxidatively modified low-density lipoprotein (oxLDL) was present in gingival crevicular fluid. In this study, the role of oxLDL in the gingival epithelial cell inflammatory response was further investigated using Ca9-22 cells and primary human oral keratinocytes (HOK). Treatment of Ca9-22 cells and HOK with oxLDL induced an up-regulation of IL-8 and the PGE{sub 2}-producing enzymes, cyclooxygenase-2 and microsomal PGE{sub 2} synthase-1. These responses induced by oxLDL were significantly suppressed by a nuclear factor-kappa B (NF-{kappa}B) inhibitor. However, unlike the result in macrophages, oxLDL did not lead to an increase in CD36 expression in these two cells. These results suggest that oxLDL elicits gingival epithelial cell inflammatory responses through an activation of the NF-{kappa}B pathway. These data suggest a mechanistic link between periodontal disease and lipid metabolism-related disorders, including atherosclerosis.

Oxidized low density lipoprotein increases RANKL level in human vascular cells. Involvement of oxidative stress

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Mazière, Cécile, E-mail: maziere.cecile@chu-amiens.fr [Biochemistry Laboratory, South Hospital University, René Laennec Avenue, Amiens 80000 (France); Salle, Valéry [Internal Medicine, North Hospital University, Place Victor Pauchet, Amiens 80000 (France); INSERM U1088 (EA 4292), SFR CAP-Santé (FED 4231), University of Picardie – Jules Verne (France); Gomila, Cathy; Mazière, Jean-Claude [Biochemistry Laboratory, South Hospital University, René Laennec Avenue, Amiens 80000 (France)

2013-10-18

Highlights: •Oxidized LDL enhances RANKL level in human smooth muscle cells. •The effect of OxLDL is mediated by the transcription factor NFAT. •UVA, H{sub 2}O{sub 2} and buthionine sulfoximine also increase RANKL level. •All these effects are observed in human fibroblasts and endothelial cells. -- Abstract: Receptor Activator of NFκB Ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) have been shown to play a role not only in bone remodeling but also in inflammation, arterial calcification and atherosclerotic plaque rupture. In human smooth muscle cells, Cu{sup 2+}-oxidized LDL (CuLDL) 10–50 μg/ml increased reactive oxygen species (ROS) and RANKL level in a dose-dependent manner, whereas OPG level was not affected. The lipid extract of CuLDL reproduced the effects of the whole particle. Vivit, an inhibitor of the transcription factor NFAT, reduced the CuLDL-induced increase in RANKL, whereas PKA and NFκB inhibitors were ineffective. LDL oxidized by myeloperoxidase (MPO-LDL), or other pro-oxidant conditions such as ultraviolet A (UVA) irradiation, incubation with H{sub 2}O{sub 2} or with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis{sub ,} also induced an oxidative stress and enhanced RANKL level. The increase in RANKL in pro-oxidant conditions was also observed in fibroblasts and endothelial cells. Since RANKL is involved in myocardial inflammation, vascular calcification and plaque rupture, this study highlights a new mechanism whereby OxLDL might, by generation of an oxidative stress, exert a deleterious effect on different cell types of the arterial wall.

Cultured cells of the blood-brain barrier from apolipoprotein B-100 transgenic mice: effects of oxidized low-density lipoprotein treatment.

Science.gov (United States)

Lénárt, Nikolett; Walter, Fruzsina R; Bocsik, Alexandra; Sántha, Petra; Tóth, Melinda E; Harazin, András; Tóth, Andrea E; Vizler, Csaba; Török, Zsolt; Pilbat, Ana-Maria; Vígh, László; Puskás, László G; Sántha, Miklós; Deli, Mária A

2015-07-17

The apolipoprotein B-100 (ApoB-100) transgenic mouse line is a model of human atherosclerosis. Latest findings suggest the importance of ApoB-100 in the development of neurodegenerative diseases and microvascular/perivascular localization of ApoB-100 protein was demonstrated in the cerebral cortex of ApoB-100 transgenic mice. The aim of the study was to characterize cultured brain endothelial cells, pericytes and glial cells from wild-type and ApoB-100 transgenic mice and to study the effect of oxidized low-density lipoprotein (oxLDL) on these cells. Morphology of cells isolated from brains of wild type and ApoB-100 transgenic mice was characterized by immunohistochemistry and the intensity of immunolabeling was quantified by image analysis. Toxicity of oxLDL treatment was monitored by real-time impedance measurement and lactate dehydrogenase release. Reactive oxygen species and nitric oxide production, barrier permeability in triple co-culture blood-brain barrier model and membrane fluidity were also determined after low-density lipoprotein (LDL) or oxLDL treatment. The presence of ApoB-100 was confirmed in brain endothelial cells, while no morphological change was observed between wild type and transgenic cells. Oxidized but not native LDL exerted dose-dependent toxicity in all three cell types, induced barrier dysfunction and increased reactive oxygen species (ROS) production in both genotypes. A partial protection from oxLDL toxicity was seen in brain endothelial and glial cells from ApoB-100 transgenic mice. Increased membrane rigidity was measured in brain endothelial cells from ApoB-100 transgenic mice and in LDL or oxLDL treated wild type cells. The morphological and functional properties of cultured brain endothelial cells, pericytes and glial cells from ApoB-100 transgenic mice were characterized and compared to wild type cells for the first time. The membrane fluidity changes in ApoB-100 transgenic cells related to brain microvasculature indicate

Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression

DEFF Research Database (Denmark)

Tsimikas, Sotirios; Miyanohara, Atsushi; Hartvigsen, Karsten

2011-01-01

We sought to assess the in vivo importance of scavenger receptor (SR)-mediated uptake of oxidized low-density lipoprotein (OxLDL) in atherogenesis and to test the efficacy of human antibody IK17-Fab or IK17 single-chain Fv fragment (IK17-scFv), which lacks immunologic properties of intact antibod...... antibodies other than the ability to inhibit uptake of OxLDL by macrophages, to inhibit atherosclerosis....

Oxidized low-density-lipoprotein accumulation is associated with liver fibrosis in experimental cholestasis

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Güldeniz Karadeniz

2008-01-01

Full Text Available OBJECTIVE: The aim of the present study was to examine the probable relationship between the accumulation of oxLDL and hepatic fibrogenesis in cholestatic rats. INTRODUCTION: There is growing evidence to support the current theories on how oxidative stress that results in lipid peroxidation is involved in the pathogenesis of cholestatic liver injury and fibrogenesis. One of the major and early lipid peroxidation products, OxLDL, is thought to play complex roles in various immuno-inflammatory mechanisms. METHODS: A prolonged (21-day experimental bile duct ligation was performed on Wistar-albino rats. Biochemical analysis of blood, histopathologic evaluation of liver, measurement of the concentration of malondialdehyde (MDA and superoxide-dismutase (SOD in liver tissue homogenates, and immunofluorescent staining for oxLDL in liver tissue was conducted in bile-duct ligated (n = 8 and sham-operated rats (n = 8. RESULTS: Significantly higher levels of MDA and lower concentrations of SOD were detected in jaundiced rats than in the sham-operated rats. Positive oxLDL staining was also observed in liver tissue sections of jaundiced rats. Histopathological examination demonstrated that neither fibrosis nor other indications of hepatocellular injury were found in the sham-operated group, while features of severe hepatocellular injury, particularly fibrosis, were found in jaundiced rats. CONCLUSION: Our results support the finding that either oxLDLs are produced as an intermediate agent during exacerbated oxidative stress or they otherwise contribute to the various pathomechanisms underlying the process of liver fibrosis. Whatever the mechanism, it is clear that an association exists between elevated oxLDL levels and hepatocellular injury, particularly with fibrosis. Further studies are needed to evaluate the potential effects of oxLDLs on the progression of secondary biliary cirrhosis.

Changes in apolipoprotein B and oxidized low-density lipoprotein levels in gingival crevicular fluids as a result of periodontal tissue conditions.

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Ishizuka, M; Kato, R; Moriya, Y; Noguchi, E; Koide, Y; Inoue, S; Itabe, H; Yamamoto, M

2017-06-01

Periodontal disease is a chronic inflammatory disease caused by bacterial infection that can lead to tooth loss. Gingival crevicular fluid can be collected easily and noninvasively. We previously discovered the presence of apolipoprotein B (apoB), the main constituent of low-density lipoprotein, and oxidized low-density lipoprotein (oxLDL) in the gingival crevicular fluid of healthy subjects. In this study, we investigated whether periodontal conditions affect the levels of apoB and oxLDL in gingival crevicular fluid. The study population comprised 11 patients with chronic periodontitis. A pair of gingival crevicular fluid samples was collected from each patient at a healthy site and at a site with periodontitis (baseline samples). Thereafter, gingival crevicular fluid samples were collected from the same patients again at 4 and 8 wk after scaling and root planing (SRP). The levels of apoB, oxLDL, protein and cytokines in gingival crevicular fluid, in addition to gingival crevicular fluid volume, were measured. At baseline, the levels of apoB and oxLDL in gingival crevicular fluid were higher at the sites with periodontitis than at the healthy sites. The levels of apoB and oxLDL at periodontal sites decreased after SRP. The level of oxLDL in gingival crevicular fluid correlated well with the probing pocket depth. The oxLDL : apoB ratio in gingival crevicular fluid was significantly higher than that in plasma. The levels of apoB and oxLDL in gingival crevicular fluid change according to the periodontal tissue conditions. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Impact of the 24-h ultramarathon race on homocysteine, oxidized low-density lipoprotein, and paraoxonase 1 levels in professional runners.

Science.gov (United States)

Benedetti, Serena; Catalani, Simona; Peda, Federica; Luchetti, Francesca; Citarella, Roberto; Battistelli, Serafina

2018-01-01

The impact of the 24-h ultramarathon race on homocysteine (Hcy) and oxidized low-density lipoprotein (oxLDL) levels, two well-recognized cardiovascular risk factors, has not been deeply investigated. Similarly, no information exists on paraoxonase 1 (PON1), an antioxidant enzyme associated with high-density lipoproteins, which may detoxify oxLDL and Hcy-thiolactone, hence preventing their proatherogenic action. Taking this into account, a competitive 24-h ultramarathon race was organized in Reggio-Emilia (Italy) recruiting professional runners (n = 14) from the Italian Ultramarathon and Trail Association. Blood samples were collected from each participant before, during (14 h), and immediately after (24 h) the competition, thus to monitor the serum changes in Hcy, oxLDL, and PON1 levels, as well as other oxidative stress-related parameters, namely reactive oxygen metabolites (ROM) and total antioxidant capacity (PAT). As a result, a significant PON1 increase was recorded after 14 h of racing that persisted until the end of the performance. The same trend was observed for PAT values, which positively correlated to PON1 levels (R = 0.643, P<0.001). Hcy, oxLDL, and ROM remained almost unchanged throughout the competition. In conclusion, the present study suggested a protective role of PON1 in sustaining the antioxidant defense system and contrasting lipoprotein oxidative modifications over the 24-h race, and did not specifically evidence either Hcy or oxLDL accumulation in such challenging sporting events.

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

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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.

Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy

OpenAIRE

Zabirnyk, Olga; Liu, Wei; Khalil, Shadi; Sharma, Anit; Phang, James M.

2009-01-01

Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible ...

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

2016-01-01

and results Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12 weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n = 9) was performed before inclusion and after 3 months of treatment. Blood samples....... There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p = 0.......03) with no difference in CD68 or CD163 positivity. Conclusions In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal....

Oxidized low-density lipoproteins may induce expression of monocyte chemotactic protein-3 in atherosclerotic plaques

International Nuclear Information System (INIS)

Jang, Moon Kyoo; Kim, Ji Young; Jeoung, Nam Ho; Kang, Mi Ae; Choi, Myung-Sook; Oh, Goo Taeg; Nam, Kyung Tak; Lee, Won-Ha; Park, Yong Bok

2004-01-01

Genes induced or suppressed by oxidized low-density lipoproteins (oxLDL) in human monocytic THP-1 cells were searched using the differential display reverse transcriptase polymerase chain reaction. One of the differentially expressed (up-regulated) cDNA fragments was found to contain sequences corresponding to monocyte chemotactic protein-3 (MCP-3). The stimulatory effect of the oxLDL on the expression of MCP-3 mRNA was both time- and dose-dependent. Treatment with GF109203X and genistein, inhibitors of protein kinase C and tyrosine kinase, respectively, had no effect on the induction of MCP-3 mRNA by oxLDL, while treatment with cycloheximide inhibited the induction. The induction was reproduced by the lipid components in oxLDL such as 9-HODE and 13-HODE, which are known to activate the peroxisome proliferator-activated receptor γ (PPARγ). Introduction of an endogenous PPARγ ligand, 15d-PGJ2, in the culture of THP-1 cells resulted in the induction of MCP-3 gene expression. Furthermore, analyses of human atherosclerotic plaques revealed that the expressional pattern of MCP-3 in the regions of neointimal and necrotic core overlapped with that of PPARγ. These results suggest that oxLDL delivers its signal for MCP-3 expression via PPARγ, which may be further related to the atherogenesis

Effect of thyroid function on LDL oxidation.

Science.gov (United States)

Costantini, F; Pierdomenico, S D; De Cesare, D; De Remigis, P; Bucciarelli, T; Bittolo-Bon, G; Cazzolato, G; Nubile, G; Guagnano, M T; Sensi, S; Cuccurullo, F; Mezzetti, A

1998-05-01

In this study, the effect of different levels of thyroid hormone and metabolic activity on low density lipoprotein (LDL) oxidation was investigated. Thus, in 16 patients with hyperthyroidism, 16 with hypothyroidism, and 16 age- and sex-matched healthy normolipidemic control subjects, the native LDL content in lipid peroxides, vitamin E, beta-carotene, and lycopene, as well as the susceptibility of these particles to undergo lipid peroxidation, was assessed. Hyperthyroidism was associated with significantly higher lipid peroxidation, as characterized by a higher native LDL content in lipid peroxides, a lower lag phase, and a higher oxidation rate than in the other two groups. This elevated lipid peroxidation was associated with a lower LDL antioxidant concentration. Interestingly, hypothyroid patients showed an intermediate behavior. In fact, in hypothyroidism, LDL oxidation was significantly lower than in hyperthyroidism but higher than in the control group. Hypothyroidism was also characterized by the highest beta-carotene LDL content, whereas vitamin E was significantly lower than in control subjects. In hyperthyroidism but not in the other two groups, LDL oxidation was strongly influenced by free thyroxine blood content. In fact in this group, the native LDL lipid peroxide content and the lag phase were directly and indirectly, respectively, related to free thyroxine blood levels. On the contrary, in hypothyroidism LDL oxidation was strongly and significantly related to serum lipids. In conclusion, both hypothyroidism and hyperthyroidism are characterized by higher levels of LDL oxidation when compared with normolipidemic control subjects. In hyperthyroid patients, the increased lipid peroxidation was strictly related to free thyroxine levels, whereas in hypothyroidism it was strongly influenced by serum lipids.

Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation.

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Miller, Yury I; Shyy, John Y-J

2017-02-01

Oxidized low-density lipoprotein (OxLDL), which contains hundreds of different oxidized lipid molecules, is a hallmark of hyperlipidemia and atherosclerosis. The same oxidized lipids found in OxLDL are also formed in apoptotic cells, and are present in tissues as well as in the circulation under pathological conditions. In many disease contexts, oxidized lipids constitute damage signals, or patterns, that activate pattern-recognition receptors (PRRs) and significantly contribute to inflammation. Here, we review recent discoveries and emerging trends in the field of oxidized lipids and the regulation of inflammation, focusing on oxidation products of polyunsaturated fatty acids esterified into cholesteryl esters (CEs) and phospholipids (PLs). We also highlight context-dependent activation and biased agonism of Toll-like receptor-4 (TLR4) and the NLRP3 inflammasome, among other signaling pathways activated by oxidized lipids. Copyright © 2016 Elsevier Ltd. All rights reserved.

Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein.

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Li, Zhijuan; Cheng, Jianxin; Wang, Liping

2015-10-30

Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. Copyright © 2015. Published by Elsevier Inc.

Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein

International Nuclear Information System (INIS)

Li, Zhijuan; Cheng, Jianxin; Wang, Liping

2015-01-01

Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. - Highlights: • Edaravone reduces oxLDL-induced monocyte adhesion to HUVECs. • Edaravone attenuates oxLDL-induced expression of MCP-1, VCAM-1, and ICAM-1. • Edaravone reduces NF-κB transcriptional activity and p65 nuclear translocation.

Association of Inflammatory and Oxidative Stress Markers with Metabolic Syndrome in Asian Indians in India

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Veena S. Rao

2011-01-01

Full Text Available Metabolic syndrome (MetS is a primary risk factor for cardiovascular disease and is associated with a proinflammatory state. Here, we assessed the contribution of inflammatory and oxidative stress markers towards prediction of MetS. A total of 2316 individuals were recruited in Phase I of the Indian Atherosclerosis Research Study (IARS. Modified ATPIII guidelines were used for classification of subjects with MetS. Among the inflammatory and oxidative stress markers studied, levels of hsCRP (P<.0001, Neopterin (P=.036, and oxLDL (P<.0001 were significantly higher among subjects with MetS. Among the markers we tested, oxLDL stood out as a robust predictor of MetS in the IARS population (OR 4.956 95% CI 2.504–9.810; P<.0001 followed by hsCRP (OR 1.324 95% CI 1.070–1.638; P=.010. In conclusion, oxLDL is a candidate predictor for MetS in the Asian Indian population.

Saikosaponin-a Attenuates Oxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cells.

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He, Dan; Wang, Hongyan; Xu, Ling; Wang, Xiaoqing; Peng, Kuang; Wang, Lili; Liu, Pixu; Qu, Peng

2016-06-01

Saikosaponins-a (Ssa) is a major bioactive extract of Radix Bupleuri which is a traditional Chinese medicine. The roles of inflammatory response and lipid transportation in the process of atherosclerosis have drawn increasing attention. We explored the regulation of lipid transportation and immune-inflammatory role of Ssa in early atherosclerosis. The antiatherogenic actions and possible molecular mechanisms of Ssa were texted in THP-1 cells. We examined the effect of Ssa on oxidized low-density lipoprotein (ox-LDL)-induced lipid uptake, cholesterol efflux, immune-inflammatory response. THP-1 macrophages were treated with Ssa followed by ox-LDL for 24 hours. Results from western blot showed that Ssa obviously reduced lipoprotein uptake to block foam cell formation and the expression of Density Lipoprotein Receptor-1 and CD36. Ssa also significantly boosted cholesterol efflux and the expression of ATP binding cassettetransporter A1 and peroxisome proliferator-activated receptor γ. The results also indicated that Ssa inhibited ox-LDL-induced activation of AKT and nuclear factor-κB, assembly of NLRP3 inflammasome and production of proinflammatory cytokines. It is suggested that the ability against immune inflammatory response of Ssa is due to modulation of the PI3K/AKT/NF-κB/NLRP3 pathway. In conclusion, this study provides new insight into Ssa's molecular mechanism and its therapeutic potential in the treatment of atherosclerosis.

Relationship between biomarkers of inflammation, oxidative stress and endothelial/microcirculatory function in successful aging versus healthy youth: a transversal study.

Science.gov (United States)

Bottino, Daniel Alexandre; Lopes, Flávia Gomes; de Oliveira, Francisco José; Mecenas, Anete de Souza; Clapauch, Ruth; Bouskela, Eliete

2015-04-08

There is a functional decline of endothelial- dependent vasodilatation in the aging process. The aims of this study were to investigate if various microcirculatory parameters could correlate to anthropometrical variables, oxidative stress and inflammatory biomarkers in successful aging and compare the results to young healthy controls. Healthy elderly women (HE, 74.0 ± 8.7 years, n = 11) and young controls (YC, 23.1 ± 3.6 years, n = 24) were evaluated through nailfold videocapillaroscopy (NVC), venous occlusion plethysmography (VOP) and laboratorial analysis. Functional capillary density (FCD) and diameters, maximum red blood cell velocity (RBCVmax) during the reactive hyperemia response/RBCVbaseline after 1 min arterial occlusion at the finger base, time to reach RBCVmax were determined by NVC, peak increment of forearm blood flow (FBF) during the reactive hyperemia response (%Hyper) and after 0.4 mg sublingual nitroglycerin (%Nitro) by VOP and lipidogram, fibrinogen, fasting and postload glucose, oxidized LDL-cholesterol (oxLDL), sICAM, sVCAM, sE-Selectin, interleukines 1 and 6 and TNF-α by laboratorial analysis. Correlations and linear multiple regression (LMR) between %Hyper, %Nitro, microcirculatory parameters, oxidative stress and inflammatory biomarkers were investigated. sVCAM, sE-Selectin and oxLDL were higher and RBCVmax/RBCVbaseline and %Hyper lower in HE, while %Nitro and FCD remained unchanged. Fibrinogen, LDL-cholesterol, oxLDL correlated negatively to %Hyper while sVCAM correlated negatively to %Hyper and RBCVmax/RBCVbaseline. Healthy aged women presented dilated capillaries with sustained perfusion and endothelial dysfunction with preserved vascular smooth muscle reactivity. Fibrinogen, LDL-cholesterol, oxidized-LDL and sVCAM correlated negatively to endothelial function but not to microcirculatory parameters. Oxidized-LDL and sVCAM could determine %Hyper through LMR. Oxidized-LDL and sVCAM might be used as endothelial

Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein

Energy Technology Data Exchange (ETDEWEB)

Li, Zhijuan, E-mail: zjlee038@163.com; Cheng, Jianxin; Wang, Liping

2015-10-30

Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. - Highlights: • Edaravone reduces oxLDL-induced monocyte adhesion to HUVECs. • Edaravone attenuates oxLDL-induced expression of MCP-1, VCAM-1, and ICAM-1. • Edaravone reduces NF-κB transcriptional activity and p65 nuclear translocation.

Protective properties of artichoke (Cynara scolymus) against oxidative stress induced in cultured endothelial cells and monocytes.

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Zapolska-Downar, Danuta; Zapolski-Downar, Andrzej; Naruszewicz, Marek; Siennicka, Aldona; Krasnodebska, Barbara; Kołdziej, Blanka

2002-11-01

It is currently believed that oxidative stress and inflammation play a significant role in atherogenesis. Artichoke extract exhibits hypolipemic properties and contains numerous active substances with antioxidant properties in vitro. We have studied the influence of aqueous and ethanolic extracts from artichoke on intracellular oxidative stress stimulated by inflammatory mediators (TNFalpha and LPS) and ox-LDL in endothelial cells and monocytes. Oxidative stress which reflects the intracellular production of reactive oxygen species (ROS) was followed by measuring the oxidation of 2', 7'-dichlorofluorescin (DCFH) to 2', 7'-dichlorofluorescein (DCF). Agueous and ethanolic extracts from artichoke were found to inhibit basal and stimulated ROS production in endothelial cells and monocytes in dose dependent manner. In endothelial cells, the ethanolic extract (50 microg/ml) reduced ox-LDL-induced intracellular ROS production by 60% (partichoke extracts have marked protective properties against oxidative stress induced by inflammatory mediators and ox-LDL in cultured endothelial cells and monocytes.

Circulating Oxidized Low-Density Lipoprotein Levels Independently Predict 10-Year Progression of Subclinical Carotid Atherosclerosis: A Community-Based Cohort Study.

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Gao, Shen; Zhao, Dong; Qi, Yue; Wang, Wei; Wang, Miao; Sun, Jiayi; Liu, Jun; Li, Yan; Liu, Jing

2018-03-07

To investigate the association between circulating oxidized low-density lipoprotein (ox-LDL) levels and progression of subclinical atherosclerosis and to examine whether this link is independent of other low-density lipoprotein (LDL)-related parameters. Totally, 804 subjects who were free of cardiovascular disease at baseline completed risk factor surveys and carotid ultrasound measurements in 2002 and 2012. Modified Poisson regression was performed to examine the association between baseline serum ox-LDL levels and the 10-year risk of progression of carotid atherosclerosis which was defined as the development of at least one new plaque in a previously plaque-free carotid segment at re-examination. The mean age of the subjects was 58.6±7.7 years at baseline and 43.3% were men. A total of 504 (62.7%) subjects had carotid plaque progression at re-examination. Subjects in the intermediate and highest tertiles of ox-LDL had a significantly higher adjusted risk of atherosclerosis progression than those in the lowest tertile [relative risk (95% confidence interval) 1.17 (1.01-1.34) for the intermediate tertile and 1.23 (1.07-1.42) for the highest tertile]. This association was independent of baseline levels of LDL-C, total LDL particle number, and small LDL particle number. This study demonstrates that serum ox-LDL levels predict 10-year progression of subclinical atherosclerosis. Moreover, this effect is independent of the cholesterol content, the number, and the size of LDL particles.

Effects of low-dose simvastatin on the distribution of plasma cholesterol and oxidized low-density lipoprotein in three ultra-centrifugally separated low-density lipoprotein subfractions: 12- month, open-label trial.

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Homma, Yasuhiko; Michishita, Ichiro; Hayashi, Hiroshi; Shigematsu, Hiroshi

2010-10-27

The effects of statins on the distribution of oxidized LDL in plasma LDL subfractions have not been well defined. Effects of 12-month treatment with low-dose simvastatin on the distribution of cholesterol and oxidized LDL in 3 ultracentrifugally separated plasma LDL subfractions were compared in patients with hypercholesterolemia. Simvastatin was administered to 30 hypercholesterolemic subjects for 12 months at an initial dose of 5 mg/day, which was increased to 20 mg/day via 10mg/day to decrease plasma LDL-cholesterol (C) lower than 130 mg/dL. Simvastatin dose was fixed after 3 months of treatment. The amounts of cholesterol and oxidized LDL in 3 ultracentrifugally separated plasma LDL subfractions were compared between 0 and 12 months of treatment. The distribution of ox-LDL skewed to denser LDL fractions, compared with cholesterol in plasma LDL subfractions. Plasma cholesterol in low-density LDL, medium-density LDL and high-density LDL decreased significantly by 31%, 30%, and 25%, respectively (pLDL was decreased from 70 U/L to 56 U/L in medium-density LDL (p=0.042). Oxidized LDL in low-density LDL and high-density LDL did not change significantly after 12 months of treatment. Treatment with low-dose simvastatin decreased plasma cholesterol in 3 LDL subfractions and oxidized LDL in medium-density LDL. The decrease of oxidized LDL seemed to be not due to the decrease of cholesterol in plasma LDL subfractions because the decreasing patterns of cholesterol and ox-LDL were different in 3 LDL subfractions.

Cardiovascular disease markers responses in male receiving improved-fat meat-products vary by initial LDL-cholesterol levels.

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Paloma Celada

2016-11-01

Full Text Available Objectives: Cardiovascular disease (CVD is prevalent in people at high meat-product consumption. To study the effect of consuming different Pâté and Frankfurter formulations on clinical/emergent CVD biomarkers in male volunteers with different initial LDL-cholesterol levels (< and ³ 3.36 mmol/L. Method: Eighteen male volunteers with at least two CVD risk factors were enrolled in a crossover controlled study. Pork-products were consumed during 4wk: reduced-fat (RF, omega-3-enriched-RF (n-3RF, and normal-fat (NF. Pork-products were separated by 4wk washout. Lipids, lipoproteins, oxidized LDL (oxLDL, apolipoproteins (apo and their ratios, homocysteine (tHcys, arylesterase (AE, C-reactive protein (CRP, tumor necrotic factor (TNFa were tested. Results: The rate of change for AE, oxLDL, Lp(a, AE/HDL-cholesterol, LDL/apo B and AE/oxLDL ratios varied (p<0.05 among periods only in volunteers with LDLcholesterol ³3.36 mmol/L. TNFa decreased (p<0.05 among volunteers with low-normal LDL-cholesterol values while AE increased (p<0.01 in high LDL-cholesterol volunteers during the RF-period. AE increased while CRP decreased (both p<0.01 in low-normal LDL-cholesterol volunteers while AE (p<0.001 and apo B (p<0.01 increased in the high LDL-cholesterol group during the n-3RF-period. Total cholesterol (p<0.05 increased in the low/normal LDL-cholesterol group while tHcys decreased (p<0.05 in the high LDL-cholesterol group during the NF-period. Differences in response in volunteers with low-normal vs. high initial LDL-cholesterol levels to the n-3RF but not to the RF meat-products seem evident. Conclusions: Subjects with high LDL-cholesterol seem target for n-3RF products while subjects with LDL-cholesterol <3.36 mmol/L were more negatively affected by NF-products. Any generalization about functional meat product or consumption should be avoided.

Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin

NARCIS (Netherlands)

Rodenburg, Jessica; Vissers, Maud N.; Wiegman, Albert; Miller, Elizabeth R.; Ridker, Paul M.; Witztum, Joseph L.; Kastelein, John J. P.; Tsimikas, Sotirios

2006-01-01

OBJECTIVES: To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin. BACKGROUND: Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The

Oxidation of LDL and extent of peripheral atherosclerosis

NARCIS (Netherlands)

Vijver, L.P.L. van de; Kardinaal, A.F.M.; Duyvenvoorde, W. van; Kruijssen, D.A.C.M.; Grobbee, D.E.; Poppel, G. van; Princen, H.M.G.

1999-01-01

Evidence has accumulated for oxidative modification of low-density lipoproteins (LDL) to play an important role in the atherogenic process. Therefore, we investigated the relation between susceptibility of LDL to oxidation and risk of peripheral atherosclerosis among 249 men between 45 and 80 years

Long Noncoding RNA HOXC-AS1 Suppresses Ox-LDL-Induced Cholesterol Accumulation Through Promoting HOXC6 Expression in THP-1 Macrophages.

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Huang, Chuan; Hu, Yan-Wei; Zhao, Jing-Jing; Ma, Xin; Zhang, Yuan; Guo, Feng-Xia; Kang, Chun-Min; Lu, Jing-Bo; Xiu, Jian-Cheng; Sha, Yan-Hua; Gao, Ji-Juan; Wang, Yan-Chao; Li, Pan; Xu, Bang-Ming; Zheng, Lei; Wang, Qian

2016-11-01

Atherosclerosis is a common pathological basis of cardiovascular disease, which remains the leading cause of mortality. Long noncoding RNAs (lncRNAs) are newly studied non-protein-coding RNAs involved in gene regulation, but how lncRNAs exert regulatory effect on atherosclerosis remains unclear. In this study, we found that lncRNA HOXC cluster antisense RNA 1 (HOXC-AS1) and homeobox C6 (HOXC6) were downregulated in carotid atherosclerosis by performing microarray analysis. The results were verified in atherosclerotic plaques and normal arterial intima tissues by quantitative reverse transcription PCR and western blot analysis. Lentivirus-mediated overexpression of HOXC-AS1 induced HOXC6 expression at mRNA and protein levels in THP-1 macrophages. Besides, oxidized low-density lipoprotein (Ox-LDL) decreased expression of HOXC-AS1 and HOXC6 in a time-dependent manner. Induction of cholesterol accumulation by Ox-LDL could be partly suppressed by overexpression of HOXC-AS1.

Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro

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Li, Weifeng, E-mail: liwf@mail.xjtu.edu.cn; Zhi, Wenbing; Liu, Fang; He, Zehong; Wang, Xiuei; Niu, Xiaofeng, E-mail: niuxf@mail.xjtu.edu.cn

2017-04-01

Pathogenesis of atherosclerosis is characterized by the proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammatory lesions. The aim of this study is to elucidate the effect of atractylenolide I (AO-I) on smooth muscle cell inflammation, proliferation and migration induced by oxidized modified low density lipoprotein (Ox-LDL). Here, We found that atractylenolide I inhibited Ox-LDL-induced VSMCs proliferation and migration in a dose-dependent manner, and decreased the production of inflammatory cytokines and the expression of monocyte chemoattractant protein-1 (MCP-1) in VSMCs. The study also identified that AO-I prominently inhibited p38-MAPK and NF-κB activation. More importantly, the specific heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin (ZnPP) IX partially abolished the beneficial effects of atractylenolide I on Ox-LDL-induced VSMCs. Furthermore, atractylenolide I blocked the foam cell formation in macrophages induced by Ox-LDL. In summary, inhibitory roles of AO-I in VSMCs proliferation and migration, lipid peroxidation and subsequent inflammatory responses might contribute to the anti-atherosclerotic property of AO-I. - Highlights: • AO-I inhibited Ox-LDL-induced VSMCs proliferation and migration. • AO-I alleviated inflammatory response via inhibiting TNF-α, IL-6 and NO production. • AO-I restored HO-1 expression and down-regulated PCNA expression. • MCP-1 overexpression is potentially regulated by NF-κB and p38 MAPK pathway. • AO-I possesses strong anti-lipid peroxidation effect.

Assessment of oxidized low density lipoprotein, as atherosclerosis risk marker in type 1 diabetic children with short history of diabetes mellitus

International Nuclear Information System (INIS)

Hamad, A.; Hasan, S.; Qureshi, H.J.; Sami, W.

2010-01-01

To evaluate the type-1 diabetic children for early atherosclerosis risk by measuring serum oxidized lipoprotein in relation with glycemic control. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of cardiovascular disease (CVD). Oxidized low density lipoprotein (OxLDL) levels have been regarded as one of the independent determinants of atherosclerosis. Methods: This cross sectional study involved a total 79 subjects including 39 type 1 diabetics and 40 non-diabetic controls between the ages of 9 to 16 years. A detailed medical history was taken from each subject and the individuals with history of type-1 diabetes underwent clinical examination. Individuals with obesity, hypertension, smoking, and chronic infections, autoimmune and renal diseases were excluded. Serum concentrations of glucose and lipid profile were measured in duplicate by kits based on enzymatic methods. OxLDL was measured in duplicate by using standard enzyme linked immunosorbent assay (ELISA) method. Haemoglobin A1c and Body mass index (BMI) were also measured. Results: Diabetic patients had significantly elevated levels of blood glucose (320.1vs 97) and HbA1c (10.3% vs 5.21%) as compared to controls (p 0.05). Conclusion: OxLDL is a strong independent risk marker for atherosclerosis observed in diagnosed old age patients of CVD but in present study we could not find statistically significant elevated levels of OxLDL in young diabetic subjects with short duration of diabetes. (author)

Traffic air pollution and oxidized LDL.

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Lotte Jacobs

Full Text Available BACKGROUND: Epidemiologic studies indirectly suggest that air pollution accelerates atherosclerosis. We hypothesized that individual exposure to particulate matter (PM derived from fossil fuel would correlate with plasma concentrations of oxidized low-density lipoprotein (LDL, taken as a marker of atherosclerosis. We tested this hypothesis in patients with diabetes, who are at high risk for atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study of non-smoking adult outpatients with diabetes we assessed individual chronic exposure to PM by measuring the area occupied by carbon in airway macrophages, collected by sputum induction and by determining the distance from the patient's residence to a major road, through geocoding. These exposure indices were regressed against plasma concentrations of oxidized LDL, von Willebrand factor and plasminogen activator inhibitor 1 (PAI-1. We could assess the carbon load of airway macrophages in 79 subjects (58 percent. Each doubling in the distance of residence from major roads was associated with a 0.027 µm(2 decrease (95% confidence interval (CI: -0.048 to -0.0051 in the carbon load of airway macrophages. Independently from other covariates, we found that each increase of 0.25 µm(2 [interquartile range (IQR] in carbon load was associated with an increase of 7.3 U/L (95% CI: 1.3 to 13.3 in plasma oxidized LDL. Each doubling in distance of residence from major roads was associated with a decrease of -2.9 U/L (95% CI: -5.2 to -0.72 in oxidized LDL. Neither the carbon load of macrophages nor the distance from residence to major roads, were associated with plasma von Willebrand factor or PAI-1. CONCLUSIONS: The observed positive association, in a susceptible group of the general population, between plasma oxidized LDL levels and either the carbon load of airway macrophages or the proximity of the subject's residence to busy roads suggests a proatherogenic effect of traffic air pollution.

Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

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Maes, Michael; Kubera, Marta; Uytterhoeven, Marc; Vrydags, Nicolas; Bosmans, Eugene

2011-01-01

Summary Background There is evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways. The present study was carried out in order to examine whether ME/CFS is accompanied by increased levels of plasma peroxides and serum oxidized LDL (oxLDL) antibodies, two biomarkers of oxidative stress. Material/Methods Blood was collected from 56 patients with ME/CFS and 37 normal volun...

Oxidative stress and hemoglobin-cholesterol adduct in renal patients with different LDL phenotypes.

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Miljkovic, Milica; Kotur-Stevuljevic, Jelena; Stefanovic, Aleksandra; Zeljkovic, Aleksandra; Vekic, Jelena; Gojkovic, Tamara; Bogavac-Stanojevic, Natasa; Nikolic, Milan; Simic-Ogrizovic, Sanja; Spasojevic-Kalimanovska, Vesna; Jelic-Ivanovic, Zorana

2016-10-01

Unfavorable lipid profile is a major risk factor for cardiovascular disease in renal pathology. In this study, we compared chronic renal patients and healthy controls with different LDL phenotypes (A or B) in respect of various biochemical parameters related to cardiovascular disease. Oxidative stress and anti-oxidative defense parameters [thiobarbituric acid-reacting substances (TBARS), total oxidative status (TOS), total anti-oxidative status (TAS), total protein sulfhydryl (-SH) groups], as well as red blood cell cholesterol distribution were assessed in 40 renal patients and 40 control subjects by standardized assays. LDL particle diameters were determined by polyacrylamide gradient gel electrophoresis. LDL particles are subdivided according to their size into large LDL A phenotype (diameter >25.5 nm) and small LDL B phenotype (diameter ≤25.5 nm). Renal patients with LDL A phenotype had increased oxidative stress (TOS: p LDL phenotype. A notable decrease in hemoglobin-cholesterol adduct was detected in patients with LDL A phenotype (p LDL B phenotype (p LDL B phenotype was characterized with increased TBARS (p LDL A phenotype in control group. Increased oxidative stress, decreased anti-oxidative defense followed with unfavorable changes in hemoglobin-cholesterol binding capacity, could have important influence on cardiovascular disease risk in renal patients regardless of LDL phenotype.

Hydroxysafflor yellow A suppresses oxidized low density lipoprotein induced proliferation of vascular smooth muscle cells

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Lin Sheng

2012-06-01

Full Text Available To investigate the relationship between the suppression of Hydroxysafflor yellow A (HSYA on the oxidized low density lipoprotein (ox-LDL induced proliferation of vascular smooth muscle cells (VSMCs and the mRNA and protein expression of extracellular signal-regulated protein kinase 1/2 (ERK1/2 and mitogen activated protein kinase phospholipase-1 (MAKP-1, VSMCs were treated with HSYA at 10 ?mol/L and/or ox-LDL at 35 mg/L for 48 h. MTT assay was done to measure cell survival rate, flow cytometry to detect cell cycle, reverse transcription PCR and Western blot to detect the expression of ERK1/2 and MAKP-1. When compared to cells treated with ox-LDL alone, the survival rate of cells treated with two reagents was reduced and the proportion of cells in G0/G1 phase significantly increased, with increased MKP-1 expression. The study suggests HSYA can inhibit VSMC proliferation via increasing MKP-1 expression, reducing p-ERK1/2 activity and suppressing cell cycle.

The Impact of Rapid Weight Loss on Oxidative Stress Markers and the Expression of the Metabolic Syndrome in Obese Individuals

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Eva Tumova

2013-01-01

Full Text Available Objective. Obesity is linked with a state of increased oxidative stress, which plays an important role in the etiology of atherosclerosis and type 2 diabetes mellitus. The aim of our study was to evaluate the effect of rapid weight loss on oxidative stress markers in obese individuals with metabolic syndrome (MetS. Design and Methods. We measured oxidative stress markers in 40 obese subjects with metabolic syndrome (MetS+, 40 obese subjects without metabolic syndrome (MetS−, and 20 lean controls (LC at baseline and after three months of very low caloric diet. Results. Oxidized low density lipoprotein (ox-LDL levels decreased by 12% in MetS+ subjects, associated with a reduction in total cholesterol (TC, even after adjustment for age and sex. Lipoprotein associated phospholipase A2 (Lp-PLA2 activity decreased by 4.7% in MetS+ subjects, associated with a drop in LDL-cholesterol (LDL-C, TC, and insulin levels. Multivariate logistic regression analysis showed that a model including ox-LDL, LpPLA2 activity, and myeloperoxidase (MPO improved prediction of MetS status among obese individuals compared to each oxidative stress marker alone. Conclusions. Oxidative stress markers were predictive of MetS in obese subjects, suggesting a higher oxidative stress. Rapid weight loss resulted in a decline in oxidative stress markers, especially in MetS+ patients.

The effect of cardioprotective diet rich with natural antioxidants on chronic inflammation and oxidized LDL during cardiac rehabilitation in patients after acute myocardial infarction

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Polona Mlakar

2015-06-01

Conclusions: The addition of cardioprotective diet, rich with natural antioxidants, to physical activity as a part of a CR program, positively modifies not just classic risk factors and exercise capacity, but also diminishes chronic inflammation markers. These effects, and oxLDL decline were most prominent in nonsmoking patients.

Oxidative Stress and Inflammation Differentially Elevated in Objective Versus Habitual Subjective Reduced Sleep Duration in Obstructive Sleep Apnea.

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DeMartino, Theresanne; Ghoul, Rawad El; Wang, Lu; Bena, James; Hazen, Stanley L; Tracy, Russel; Patel, Sanjay R; Auckley, Dennis; Mehra, Reena

2016-07-01

Data have demonstrated adverse health effects of sleep deprivation. We postulate that oxidative stress and systemic inflammation biomarkers will be elevated in relation to short-term and long-term sleep duration reduction. We analyzed data from the baseline examination of a randomized controlled trial involving participants with moderate to severe obstructive sleep apnea (OSA). Baseline polysomnography provided the total sleep time (PSG-TST, primary predictor); self-reported habitual sleep duration (SR-HSD) data was collected. Morning measures of oxidative stress and systemic inflammation included: myeloperoxidase (MPO, pmol/L), oxidized low-density lipoprotein (ox-LDL, U/L), F2-isoprostane (ng/mg), paraoxonase 1 (PON1, nmol·min(-1)·mL(-1)), and aryl esterase (μmol·min(-1)·mL(-1)). Linear models adjusted for age, sex, race, body mass index (BMI), cardiovascular disease (CVD), smoking, statin/anti-inflammatory medications, and apnea-hypopnea index were utilized (beta estimates and 95% confidence intervals). One hundred forty-seven participants comprised the final analytic sample; they were overall middle-aged (51.0 ± 11.7 y), obese (BMI = 37.3 ± 8.1 kg/m(2)), and 17% had CVD. Multivariable models demonstrated a significant inverse association of PSG-TST and MPO (β [95% CI] = -20.28 [-37.48, -3.08], P = 0.021), i.e., 20.3 pmol/L MPO reduction per hour increase PSG-TST. Alternatively, a significant inverse association with ox-LDL and SR-HSD was observed (β [95% CI] = 0.98 [0.96, 0.99], P = 0.027), i.e., 2% ox-LDL reduction per hour increase SR-HSD. Even after consideration of obesity and OSA severity, inverse significant findings were observed such that reduced PSG-TST was associated with elevated MPO levels and SR-HSD with ox-LDL, suggesting differential up-regulation of oxidative stress and pathways of inflammation in acute versus chronic sleep curtailment. NIH clinical trials registry number NCT00607893. © 2016 Associated Professional Sleep Societies, LLC.

High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1

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Chaohuan Luo

2016-11-01

Full Text Available Background/Aims: Hyperuricemia is part of the metabolic-syndrome cluster of abdominal obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, and hypertension. Monocytes/macrophages are critical in the development of metabolic syndrome, including gout, obesity and atherosclerosis. However, how high uric acid (HUA exposure affects monocyte/macrophage function remains unclear. In this study, we investigated the molecular mechanism of HUA exposure in monocytes/macrophages and its impact on oxidized low-density lipoprotein (oxLDL-induced foam-cell formation in a human monocytic cell line, THP-1. Methods: We primed THP-1 cells with phorbol-12-myristate-13-acetate (PMA for differentiation, then exposed cells to HUA and detected the production of reactive oxygen species (ROS and analyzed the level of phospho-AMPKα. THP-1 cells were pre-incubated with Compound C, an AMPK inhibitor, or N-acetyl-L-cysteine (NAC, a ROS scavenger, or HUA before PMA, to assess CD68 expression and phospho-AMPKα level. PMA-primed THP-1 cells were pre-treated with oxLDL before Compound C and HUA treatment. Western blot analysis was used to examine the levels of phospho-AMPKα, CD68, ABCG1, ABCA1, cyclooxygenase-2 (COX-2 and NF-κB (p65. Flow cytometry was used to assess ROS production and CD68 expression in live cells. Oil-red O staining was used to observe oxLDL uptake in cells. Results: HUA treatment increased ROS production in PMA-primed THP-1 cells; NAC blocked HUA-induced oxidative stress. HUA treatment time-dependently increased phospho-AMPKα level in PMA-primed THP-1 cells. The HUA-induced oxidative stress increased phospho-AMPKα levels, which was blocked by NAC. HUA treatment impaired CD68 expression during cell differentiation by activating the AMPK pathway, which was reversed by Compound C treatment. Finally, HUA treatment inhibited oxLDL uptake in the formation of foam cells in THP-1 cells, which was blocked by Compound C treatment. HUA treatment

HDL enhances oxidation of LDL in vitro in both men and women

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Lehtimäki T

2005-10-01

Full Text Available Abstract Background Oxidative modification of low-density lipoprotein (LDL is a key event in the oxidation hypothesis of atherogenesis. Some in vitro experiments have previously suggested that high-density lipoprotein (HDL co-incubated with LDL prevents Cu2+-induced oxidation of LDL, while some other studies have observed an opposite effect. To comprehensively clarify the role of HDL in this context, we isolated LDL, HDL2 and HDL3 from sera of 61 free-living individuals (33 women and 28 men. Results When the isolated LDL was subjected to Cu2+-induced oxidation, both HDL2 and HDL3 particles increased the rate of appearance and the final concentration of conjugated dienes similarly in both genders. Oxidation rate was positively associated with polyunsaturated fatty acid content of the lipoproteins in that it was positively related to the content of linoleate and negatively related to oleate. More saturated fats thus protected the lipoproteins from damage. Conclusion We conclude that in vitro HDL does not protect LDL from oxidation, but is in fact oxidized fastest of all lipoproteins due to its fatty acid composition, which is oxidation promoting.

Oxidative conditions prevail in severe IUGR with vascular disease and Doppler anomalies.

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Maisonneuve, Emeline; Delvin, Edgard; Edgard, Annie; Morin, Lucie; Dubé, Johanne; Boucoiran, Isabelle; Moutquin, Jean-Marie; Fouron, Jean-Claude; Klam, Stephanie; Levy, Emile; Leduc, Line

2015-08-01

Intrauterine growth restriction (IUGR) and prenatal exposure to oxidative stress are thought to lead to increased risks of cardiovascular disease later in life. The objective of the present study was to document whether cord blood oxidative stress biomarkers vary with the severity of IUGR and of vascular disease in the twin pregnancy model in which both fetuses share the same maternal environment. This prospective cohort study involved dichorionic twin pairs, with one co-twin with IUGR. Oxidative stress biomarkers were measured in venous cord blood samples from each neonate of 32 twin pairs, and compared, according to severity of IUGR (IUGR <5th percentile), Doppler anomalies of the umbilical artery and early onset IUGR (in the second trimester) of the growth restricted twin. Oxidized Low-Density Lipoproteins (oxLDL) and Malondialdehyde (MDA) concentrations were increased proportionally in cases of severe IUGR. OxLDL concentrations were also increased in cases of IUGR with Doppler anomaly. Our data indicate that severe IUGR, is related to a derangement in redox balance, illustrated by increased venous cord blood oxidative stress biomarkers concentrations. Severe IUGR and IUGR with abnormal Doppler can be translated into conditions with intense oxidative stress.

Bioactive components and mechanisms of Chinese poplar propolis alleviates oxidized low-density lipoprotein-induced endothelial cells injury.

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Chang, Huasong; Yuan, Wenwen; Wu, Haizhu; Yin, Xusheng; Xuan, Hongzhuan

2018-05-03

Propolis, a polyphenol-rich natural product, has been used as a functional food in anti-inflammation. However, its bioactive components and mechanisms have not been fully elucidated. To discover the bioactive components and anti-inflammatory mechanism, we prepared and separated 8 subfractions from ethyl acetate extract of Chinese propolis (EACP) and investigated the mechanism in oxidized low density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) damage. Eight subfractions were prepared and separated from ethyl acetate extract of Chinese propolis (EACP) with different concentrations of methanol-water solution, and analysed its chemical constituents by HPLC-DAD/Q-TOF-MS. Then 80% confluent HUVECs were stimulated with 40 μg/mL ox-LDL. Cell viability and apoptosis were evaluated by Sulforhodamine B (SRB) assay and Hoechst 33,258 staining, respectively. Levels of caspase 3, PARP, LC3B, p62, p-mTOR, p-p70S6K, p-PI3K, p-Akt, LOX-1 and p-p38 MAPK were assessed by western blotting and immunofluorescence assay, respectively. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Each subfraction exhibited similar protective effect although the contents of chemical constituents were different. EACP attenuated ox-LDL induced HUVECs apoptosis, depressed the ratio of LC3-II/LC3-I and enhanced the p62 level. In addition, treatment with EACP also activated the phosphorylation of PI3K/Akt/mTOR, and deactivated the level of LOX-1 and phosphorylation of p38 MAPK. The overproduction of ROS and the damage of MMP were also ameliorated after ECAP treatment. These findings indicated that the bioactive component of propolis on anti-inflammatory activity was not determined by a single constituent, but a complex interaction including flavonoids, esters and phenolic acids. EACP attenuated ox-LDL induced HUVECs injury by inhibiting LOX-1 level and depressed ROS production against oxidative stress in ox-LDL

Kinetic modeling of low density lipoprotein oxidation in arterial wall and its application in atherosclerotic lesions prediction.

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Karimi, Safoora; Dadvar, Mitra; Modarress, Hamid; Dabir, Bahram

2013-01-01

Oxidation of low-density lipoprotein (LDL) is one of the major factors in atherogenic process. Trapped oxidized LDL (Ox-LDL) in the subendothelial matrix is taken up by macrophage and leads to foam cell generation creating the first step in atherosclerosis development. Many researchers have studied LDL oxidation using in vitro cell-induced LDL oxidation model. The present study provides a kinetic model for LDL oxidation in intima layer that can be used in modeling of atherosclerotic lesions development. This is accomplished by considering lipid peroxidation kinetic in LDL through a system of elementary reactions. In comparison, characteristics of our proposed kinetic model are consistent with the results of previous experimental models from other researches. Furthermore, our proposed LDL oxidation model is added to the mass transfer equation in order to predict the LDL concentration distribution in intima layer which is usually difficult to measure experimentally. According to the results, LDL oxidation kinetic constant is an important parameter that affects LDL concentration in intima layer so that existence of antioxidants that is responsible for the reduction of initiating rates and prevention of radical formations, have increased the concentration of LDL in intima by reducing the LDL oxidation rate. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Relationship between oxidized low-density lipoprotein antibodies and obesity in different glycemic situations

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Babakr AT

2014-10-01

Full Text Available Abdullatif Taha Babakr,1 Osman Mohamed Elsheikh,2 Abdullah A Almarzouki,3 Adel Mohamed Assiri,1 Badr Eldin Elsonni Abdalla,4 Hani Yousif Zaki,5 Samir H Fatani,1 EssamEldin Mohamed NourEldin11Department of Medical Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Kingdom of Saudi Arabia; 2Department of Biochemistry, Faculty of Medicine, International University of Africa, Khartoum, Sudan; 3Department of Internal Medicine, Faculty of Medicine, Umm Al-Qura University, Makkah, 4Department of Biochemistry, Sciences Faculty for Girls, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 5Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira, Sudan Background: Autoantibodies to oxidized low-density lipoprotein (oxLDL are a heterogeneous group of antibodies that are controversially discussed to be either pathogenic or protective. Biochemical and anthropometric measurements correlated with increased levels of these antibodies are also controversial, especially in conditions of impaired glucose tolerance and type 2 diabetes mellitus. The present study was conducted to evaluate levels of oxLDL antibodies and their correlation with obesity in different glycemic situations. Methods: Two hundred and seventy-four adult males were classified into three subgroups: group 1 (n=125, comprising a control group of nondiabetic subjects; group 2 (n=77, comprising subjects with impaired glucose tolerance; and group 3 (n=72, comprising patients with type 2 diabetes mellitus. Body mass index was calculated, and measurement of oxLDL and oxLDL antibodies was performed. Results: Higher mean concentrations of oxLDL were found in the type 2 diabetes mellitus and impaired glucose tolerance groups (143.5±21.9 U/L and 108.7±23.7 U/L, respectively. The mean value for the control group was 73.5±27.5 U/L (P<0.001. Higher mean concentrations of anti-oxLDL antibodies were observed in the type 2 diabetes mellitus and impaired

Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase.

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Sukhanov, Sergiy; Snarski, Patricia; Vaughn, Charlotte; Lobelle-Rich, Patricia; Kim, Catherine; Higashi, Yusuke; Shai, Shaw-Yung; Delafontaine, Patrice

2015-02-01

We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe(-/-) mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation. We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe(-/-) mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX. Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1. Published by Elsevier Ireland Ltd.

Insulin-like Growth Factor I Reduces Lipid Oxidation and Foam Cell Formation via Downregulation of 12/15-lipoxygenase

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Sukhanov, Sergiy; Snarski, Patricia; Vaughn, Charlotte; Lobelle-Rich, Patricia; Kim, Catherine; Higashi, Yusuke; Shai, Shaw-Yung; Delafontaine, Patrice

2014-01-01

Objective We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe−/− mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation. Approach and Results We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe−/− mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX. Conclusions Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1. PMID:25549319

Oxidized low density lipoprotein induced caspase-1 mediated pyroptotic cell death in macrophages: implication in lesion instability?

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Jing Lin

Full Text Available BACKGROUND: Macrophage death in advanced lesion has been confirmed to play an important role in plaque instability. However, the mechanism underlying lesion macrophage death still remains largely unknown. METHODS AND RESULTS: Immunohistochemistry showed that caspase-1 activated in advanced lesion and co-located with macrophages and TUNEL positive reaction. In in-vitro experiments showed that ox-LDL induced caspase-1 activation and this activation was required for ox-LDL induced macrophages lysis, IL-1β and IL-18 production as well as DNA fragmentation. Mechanism experiments showed that CD36 and NLRP3/caspase-1/pathway involved in ox-LDL induced macrophage pyroptosis. CONCLUSION: Our study here identified a novel cell death, pyroptosis in ox-LDL induced human macrophage, which may be implicated in lesion macrophages death and play an important role in lesion instability.

Pitavastatin Differentially Modulates MicroRNA-Associated Cholesterol Transport Proteins in Macrophages.

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Haijun Zhang

Full Text Available There is emerging evidence identifying microRNAs (miRNAs as mediators of statin-induced cholesterol efflux, notably through the ATP-binding cassette transporter A1 (ABCA1 in macrophages. The objective of this study was to assess the impact of an HMG-CoA reductase inhibitor, pitavastatin, on macrophage miRNAs in the presence and absence of oxidized-LDL, a hallmark of a pro-atherogenic milieu. Treatment of human THP-1 cells with pitavastatin prevented the oxLDL-mediated suppression of miR-33a, -33b and -758 mRNA in these cells, an effect which was not uniquely attributable to induction of SREBP2. Induction of ABCA1 mRNA and protein by oxLDL was inhibited (30% by pitavastatin, while oxLDL or pitavastatin alone significantly induced and repressed ABCA1 expression, respectively. These findings are consistent with previous reports in macrophages. miRNA profiling was also performed using a miRNA array. We identified specific miRNAs which were up-regulated (122 and down-regulated (107 in THP-1 cells treated with oxLDL plus pitavastatin versus oxLDL alone, indicating distinct regulatory networks in these cells. Moreover, several of the differentially expressed miRNAs identified are functionally associated with cholesterol trafficking (six miRNAs in cells treated with oxLDL versus oxLDL plus pitavastatin. Our findings indicate that pitavastatin can differentially modulate miRNA in the presence of oxLDL; and, our results provide evidence that the net effect on cholesterol homeostasis is mediated by a network of miRNAs.

Aqueous extracts of Tribulus terrestris protects against oxidized low-density lipoprotein-induced endothelial dysfunction.

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Jiang, Yue-hua; Yang, Chuan-hua; Li, Wei; Wu, Sai; Meng, Xian-qing; Li, Dong-na

2016-03-01

To investigate the role of aqueous extracts of Tribulus terrestris (TT) against oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) dysfunction in vitro. HUVECs were pre-incubated for 60 min with TT (30 and 3 μg/mL respectively) or 10(-5) mol/L valsartan (as positive controls) and then the injured endothelium model was established by applying 100 μg/mL ox-LDL for 24 h. Cell viability of HUVECs was observed by real-time cell electronic sensing assay and apoptosis rate by Annexin V/PI staining. The cell migration assay was performed with a transwell insert system. Cytoskeleton remodeling was observed by immunofluorescence assay. The content of endothelial nitric oxide synthase (eNOS) was measured by enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) generation was assessed by immunofluorescence and flow cytometer. Key genes associated with the metabolism of ox-LDL were chosen for quantitative real-time polymerase chain reaction to explore the possible mechanism of TT against oxidized LDL-induced endothelial dysfunction. TT suppressed ox-LDL-induced HUVEC proliferation and apoptosis rates significantly (41.1% and 43.5% after treatment for 3 and 38 h, respectively; P<0.05). It also prolonged the HUVEC survival time and postponed the cell's decaying stage (from the 69th h to over 100 h). According to the immunofluorescence and transwell insert system assay, TT improved the endothelial cytoskeletal network, and vinculin expression and increased cell migration. Additionally, TT regulated of the synthesis of endothelial nitric oxide synthase and generation of intracellular reactive oxygen species (P<0.05). Both 30 and 3 μg/mL TT demonstrated similar efficacy to valsartan. TT normalized the increased mRNA expression of PI3Kα and Socs3. It also decreased mRNA expression of Akt1, AMPKα1, JAK2, LepR and STAT3 induced by ox-LDL. The most notable changes were JAK2, LepR, PI3Kα, Socs3 and STAT3. TT

Association between diet and polymorphisms in individuals with statin-controlled dyslipidaemia grouped according to oxidative stress biomarkers

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Patrícia Borges Botelho

2012-03-01

Full Text Available The objective of this study was to investigate whether differences in diet and in single-nucleotide polymorphisms (SNPs found in paraoxonase-1 (PON-1, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, cholesterol ester transfer protein (CETP and apolipoprotein E (APOE genes, are associated with oxidative stress biomarkers and consequently with susceptibility of low-density cholesterol (LDL to oxidation. A multivariate approach was applied to a group of 55 patients according to three biomarkers: plasma antioxidant activity, malondialdehyde and oxidized LDL (oxLDL concentrations. Individuals classified in Cluster III showed the worst prognoses in terms of antioxidant activity and oxidative status. Individuals classified in Cluster I presented the lowest oxidative status, while individuals grouped in Cluster II presented the highest levels of antioxidant activity. No difference in nutrient intake was observed among the clusters. Significantly higher γ- and δ-tocopherol concentrations were observed in those individuals with the highest levels of antioxidant activity. No single linear regression was statistically significant, suggesting that mutant alleles of the SNPs selected did not contribute to the differences observed in oxidative stress response. Although not statistically significant, the p value of the APO E coefficient for oxLDL response was 0.096, indicating that patients who carry the TT allele of the APO E gene tend to present lower plasma oxLDL concentrations. Therefore, the differences in oxidative stress levels observed in this study could not be attributed to diet or to the variant alleles of PON-1, CETP, HMGCR or APO E. This data supports the influence of γ-tocopherol and δ-tocopherol on antioxidant activity, and highlights the need for further studies investigating APO E alleles and LDL oxidation.O objetivo deste estudo foi investigar se diferenças na dieta e em polimorfismos de nucleotídeos únicos (SNPs encontrados no

The Inhibition Effect of Cell DNA Oxidative Damage and LDL Oxidation by Bovine Colostrums

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Chih-Wei Chen

2016-10-01

Full Text Available In the present study, we investigated the effect of bovine colostrums on inhibition of DNA oxidative damage and low density lipoprotein (LDL oxidation in vitro. Results showed that whey and skimmed milk exhibited not only higher inhibitory activities of oxidative damage of deoxyribose but also an inhibitory effect on the breakdown of supercoiled DNA into open circular DNA and linear DNA. The quantities of 8-OH-2′-dG formed under whey, caseins and skimmed milk treatment were 0.24, 0.24 and 1.24 μg/mL, respectively. The quantity of malondialdehyde formed through LDL oxidation induced by copprous ion was significantly decreased as colostrums protein solutions were added, in which whey and caseins led to a more significant decrease than skimmed milk. The formation of conjugated dienes could be inhibited by treatment with colostrums protein solutions. Whey exhibited the longest lag time of conjugated dienes formation among the colostrums proteins. The lag time of the whey was 2.33 times that of the control. From the results of foregoing, the bovine colostrums protein has potential value in the inhibition of DNA oxidation damage and LDL oxidation.

Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity.

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Silvia Biocca

Full Text Available The human lectin-like oxidized low density lipoprotein receptor 1 LOX-1, encoded by the ORL1 gene, is the major scavenger receptor for oxidized low density lipoprotein in endothelial cells. Here we report on the functional effects of a coding SNP, c.501G>C, which produces a single amino acid change (K>N at codon 167. Our study was aimed at elucidating whether the c.501G>C polymorphism changes the binding affinity of LOX-1 receptor altering its function. The presence of p.K167N mutation reduces ox-LDL binding and uptake. Ox-LDL activated extracellular signal-regulated kinases 1 and 2 (ERK 1/2 is inhibited. Furthermore, ox-LDL induced biosynthesis of LOX-1 receptors is dependent on the p.K167N variation. In human macrophages, derived from c.501G>C heterozygous individuals, the ox-LDL induced LOX-1 46 kDa band is markedly lower than in induced macrophages derived from c.501G>C controls. Investigation of p.K167N mutation through molecular dynamics simulation and electrostatic analysis suggests that the ox-LDL binding may be attributed to the coupling between the electrostatic potential distribution and the asymmetric flexibility of the basic spine residues. The N/N-LOX-1 mutant has either interrupted electrostatic potential and asymmetric fluctuations of the basic spine arginines.

Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-Induced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells.

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Zhang, Guo-Qiang; Tao, Yong-Kang; Bai, Yong-Ping; Yan, Sheng-Tao; Zhao, Shui-Ping

2018-04-20

Oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α-subunit (eIF2α)/CCAAT/enhancer-binding protein homologous protein (CHOP) endoplasmic reticulum (ER) stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were treated with simvastatin (0.1, 0.5, or 2.5 μmol/L) or DEVD-CHO (selective inhibitor of caspase-3, 100 μmol/L) for 1 h before the addition of ox-LDL (100 μg/ml) and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance (ANOVA) followed by post hoc pairwise comparisons using Tukey's tests. A value of P LDL resulted in a significant increase in apoptosis (31.9% vs. 4.9%, P LDL-induced apoptosis (28.0%, 24.7%, and 13.8%, F = 15.039, all P LDL significantly increased the expression of PERK (499.5%, P LDL-induced expression of PERK (407.8%, 339.1%, and 187.5%, F = 10.121, all P LDL-induced expression of PERK (486.4%) and phosphorylation of eIF2α (418.8%). Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment. This study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.

Adipokines, Oxidized Low-Density Lipoprotein, and C-Reactive Protein Levels in Lean, Overweight, and Obese Portuguese Patients with Type 2 Diabetes

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Neuparth, Maria João; Proença, Jorge Brandão; Santos-Silva, Alice; Coimbra, Susana

2013-01-01

Aim. Our aim was to study how different BMI scores may influence the levels of inflammation, oxidative stress, adipogenesis, glucose, and lipid metabolism, in lean, overweight, and obese Portuguese patients with type 2 diabetes mellitus (T2DM). Methods. We studied 28 lean, 38 overweight, and 17 obese patients with T2DM and 20 controls (gender and age matched). The circulating levels of oxLDL, CRP, and some adipokines—adiponectin, leptin, and chemerin—and the lipid profile were evaluated. Results. Obese patients presented significantly lower levels of adiponectin and higher leptin, oxLDL, and chemerin levels, as compared to the overweight, lean, and control groups. Overweight, compared to lean and control, subjects showed significantly lower adiponectin and higher leptin and chemerin levels; oxLDL values were significantly higher in overweight than in lean patients. Lean patients presented significantly higher chemerin values than the control. Obese patients presented significantly higher CRP values, as compared to lean patients and the control group. Obese and overweight patients presented significantly higher triglycerides values than lean patients. Except for CRP, all the observed significant changes between control and patients remained significant after statistical adjustment for the body mass index (BMI). Conclusion. The levels of leptin, adiponectin, oxLDL, CRP, and triglycerides in patients with T2DM seem to be more associated with obesity and less with diabetes. Chemerin levels were raised in lean, overweight, and obese patients, suggesting that, independently of BMI, an adipocyte dysfunction occurs. Moreover, chemerin may provide an important early biomarker of adipocyte dysfunction and a link between obesity and type 2 diabetes mellitus. PMID:24634792

Molecular biology based assessment of green tea effects on oxidative stress and cardiac remodelling in dialysis patients.

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Calo, Lorenzo A; Vertolli, Ugo; Davis, Paul A; Maso, Lucia Dal; Pagnin, Elisa; Ravarotto, Verdiana; Maiolino, Giuseppe; Lupia, Mario; Seccia, Teresa M; Rossi, Gian Paolo

2014-06-01

Cardiovascular disease, the most common cause for morbidity and mortality in end-stage renal disease (ESRD), has prompted the exploration of multiple approaches to improve outcomes. Cardiovascular risk factors such as oxidative stress (OxSt) and cardiac remodelling are common in ESRD and dialysis patients. Green tea (GT) is well recognized as reducing OxSt. This 6 months study evaluated in 20 ESRD patients under chronic dialysis, the effect of GT treatment (1 g/day as commercially available capsule) on cellular and plasma OxSt and proliferation related markers using a molecular biology approach. Mononuclear cell p22(phox), Haeme Oxygenase (HO)-1 protein expression, and phosphorylated ERK1/2 status were evaluated in dialysis patients at baseline, after 3 and 6 months of GT treatment by Western blot analysis and plasma oxLDL by ELISA. Cardiac remodelling was assessed by echocardiographic left ventricular (LV) mass determination at baseline and at the end of the study. GT treatment reduced p22(phox) and pERK1/2 from baseline while HO-1 increased. At baseline, LV mass correlated with both p22(phox) and oxLDL. GT treatment decreased LV mass from baseline, which correlated with oxLDL. 9 patients had LV hypertrophy at baseline, which, at 6 months, was normalized in 5 and reduced in 3, showing a parallel decrease of p22(phox), pERK1/2, oxLDL and increase of HO-1. Treatment with GT decreased the expression of OxSt-related proteins tightly associated with cardiovascular disease and decreased LV mass. It appears highly likely that the addition of GT can provide a benefit in terms of cardiovascular protection in dialysis patients. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

β-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins

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Khan Tayeba

2004-11-01

Full Text Available Abstract Background Recent studies suggest that hypercholesterolemia, an established risk factor for atherosclerosis, is also a risk factor for Alzheimer's disease. The myeloid scavenger receptor CD36 binds oxidized lipoproteins that accumulate with hypercholesterolemia and mediates their clearance from the circulation and peripheral tissues. Recently, we demonstrated that CD36 also binds fibrillar β-amyloid and initiates a signaling cascade that regulates microglial recruitment and activation. As increased lipoprotein oxidation and accumulation of lipid peroxidation products have been reported in Alzheimer's disease, we investigated whether β-amyloid altered oxidized lipoprotein clearance via CD36. Methods The availability of mice genetically deficient in class A (SRAI & II and class B (CD36 scavenger receptors has facilitated studies to discriminate their individual actions. Using primary microglia and macrophages, we assessed the impact of Aβ on: (a cholesterol ester accumulation by GC-MS and neutral lipid staining, (b binding, uptake and degradation of 125I-labeled oxidized lipoproteins via CD36, SR-A and CD36/SR-A-independent pathways, (c expression of SR-A and CD36. In addition, using mice with targeted deletions in essential kinases in the CD36-signaling cascade, we investigated whether Aβ-CD36 signaling altered metabolism of oxidized lipoproteins. Results In primary microglia and macrophages, Aβ inhibited binding, uptake and degradation of oxidized low density lipoprotein (oxLDL in a dose-dependent manner. While untreated cells accumulated abundant cholesterol ester in the presence of oxLDL, cells treated with Aβ were devoid of cholesterol ester. Pretreatment of cells with Aβ did not affect subsequent degradation of oxidized lipoproteins, indicating that lysosomal accumulation of Aβ did not disrupt this degradation pathway. Using mice with targeted deletions of the scavenger receptors, we demonstrated that Aβ inhibited oxidized

Beneficial Effects of the RESMENA Dietary Pattern on Oxidative Stress in Patients Suffering from Metabolic Syndrome with Hyperglycemia Are Associated to Dietary TAC and Fruit Consumption

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J. Alfredo Martinez

2013-03-01

Full Text Available Hyperglycemia and oxidative stress are conditions directly related to the metabolic syndrome (MetS, whose prevalence is increasing worldwide. This study aimed to evaluate the effectiveness of a new weight-loss dietary pattern on improving the oxidative stress status on patients suffering MetS with hyperglycemia. Seventy-nine volunteers were randomly assigned to two low-calorie diets (−30% Energy: the control diet based on the American Health Association criteria and the RESMENA diet based on a different macronutrient distribution (30% proteins, 30% lipids, 40% carbohydrates, which was characterized by an increase of the meal frequency (seven-times/day, low glycemic load, high antioxidant capacity (TAC and high n-3 fatty acids content. Dietary records, anthropometrical measurements, biochemical parameters and oxidative stress biomarkers were analyzed before and after the six-month-long study. The RESMENA (Metabolic Syndrome Reduction in Navarra diet specifically reduced the android fat mass and demonstrated more effectiveness on improving general oxidative stress through a greater decrease of oxidized LDL (oxLDL values and protection against arylesterase depletion. Interestingly, oxLDL values were associated with dietary TAC and fruit consumption and with changes on body mass index (BMI, waist circumference, fat mass and triacilglyceride (TG levels. In conclusion, the antioxidant properties of the RESMENA diet provide further benefits to those attributable to weight loss on patients suffering Mets with hyperglycemia.

Beneficial effects of the RESMENA dietary pattern on oxidative stress in patients suffering from metabolic syndrome with hyperglycemia are associated to dietary TAC and fruit consumption.

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de la Iglesia, Rocio; Lopez-Legarrea, Patricia; Celada, Paloma; Sánchez-Muniz, Francisco J; Martinez, J Alfredo; Zulet, M Angeles

2013-03-27

Hyperglycemia and oxidative stress are conditions directly related to the metabolic syndrome (MetS), whose prevalence is increasing worldwide. This study aimed to evaluate the effectiveness of a new weight-loss dietary pattern on improving the oxidative stress status on patients suffering MetS with hyperglycemia. Seventy-nine volunteers were randomly assigned to two low-calorie diets (-30% Energy): the control diet based on the American Health Association criteria and the RESMENA diet based on a different macronutrient distribution (30% proteins, 30% lipids, 40% carbohydrates), which was characterized by an increase of the meal frequency (seven-times/day), low glycemic load, high antioxidant capacity (TAC) and high n-3 fatty acids content. Dietary records, anthropometrical measurements, biochemical parameters and oxidative stress biomarkers were analyzed before and after the six-month-long study. The RESMENA (Metabolic Syndrome Reduction in Navarra) diet specifically reduced the android fat mass and demonstrated more effectiveness on improving general oxidative stress through a greater decrease of oxidized LDL (oxLDL) values and protection against arylesterase depletion. Interestingly, oxLDL values were associated with dietary TAC and fruit consumption and with changes on body mass index (BMI), waist circumference, fat mass and triacilglyceride (TG) levels. In conclusion, the antioxidant properties of the RESMENA diet provide further benefits to those attributable to weight loss on patients suffering Mets with hyperglycemia.

Effects of Nebivolol on Endothelial Gene Expression during Oxidative Stress in Human Umbilical Vein Endothelial Cells

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Ulisse Garbin

2008-01-01

Full Text Available The endothelium plays a key role in the development of atherogenesis and its inflammatory and proliferative status influences the progression of atherosclerosis. The aim of this study is to compare the effects of two beta blockers such as nebivolol and atenolol on gene expression in human umbilical vein endothelial cells (HUVECs following an oxidant stimulus. HUVECs were incubated with nebivolol or atenolol (10 micromol/L for 24 hours and oxidative stress was induced by the addition of oxidized (ox-LDL. Ox-LDL upregulated adhesion molecules (ICAM-1, ICAM-2, ICAM-3, E-selectin, and P-selectin; proteins linked to inflammation (IL-6 and TNFalpha, thrombotic state (tissue factor, PAI-1 and uPA, hypertension such as endothelin-1 (ET-1, and vascular remodeling such as metalloproteinases (MMP-2, MMP-9 and protease inhibitor (TIMP-1. The exposure of HUVECs to nebivolol, but not to atenolol, reduced these genes upregulated by oxidative stress both in terms of protein and RNA expression. The known antioxidant properties of the third generation beta blocker nebivolol seem to account to the observed differences seen when compared to atenolol and support the specific potential protective role of this beta blocker on the expression of a number of genes involved in the initiation and progression of atherosclerosis.

Kaempferol alleviates ox-LDL-induced apoptosis by up-regulation of autophagy via inhibiting PI3K/Akt/mTOR pathway in human endothelial cells.

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Che, Jianbo; Liang, Bing; Zhang, Yuan; Wang, Yi; Tang, Jianyu; Shi, Gongning

Oxidized low-density lipoprotein (ox-LDL) has been reported to induce apoptosis of endothelial cells (ECs) and contribute to the progression of atherosclerosis. Kaempferol has been shown to possess antiatherosclerotic effect. The aim of the present study was to evaluate the effect of kaempferol on ox-LDL-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and its possible molecular basis. The results showed that kaempferol alleviated ox-LDL-induced apoptosis. Kaempferol increased the ratio of LC3-II/I and beclin-1 level in ox-LDL-induced HUVECs. Moreover, the expression of p-Akt and p-mTOR was down-regulated after treatment with kaempferol in ox-LDL-treated HUVECs, which is similar to the effect of PI3K inhibitor (LY294002) or mTOR inhibitor [rapamycin (RAP)]. Besides, autophagy induced by kaempferol was enhanced by LY294002 or RAP, while kaempferol-induced autophagy was attenuated with insulin treatment, the activator of PI3K/Akt/mTOR pathway. Furthermore, insulin also abated the effect of kaempferol on cell viability and apoptosis in ox-LDL-induced HUVECs. The results indicated that kaempferol alleviated ox-LDL-induced cell apoptosis by up-regulation of autophagy via inhibiting PI3K/Akt/mTOR pathway in human ECs. Copyright © 2017 Elsevier Inc. All rights reserved.

B-1 cell immunoglobulin directed against oxidation-specific epitopes

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Dimitrios eTsiantoulas

2013-01-01

Full Text Available Natural antibodies (NAbs are pre-existing antibodies with germline origin that arise in the absence of previous exposure to foreign antigens. NAbs are produced by B-1 lymphocytes and are primarily of the IgM isotype. There is accumulating evidence that - in addition to their role in antimicrobial host defense - NAbs exhibit important housekeeping functions by facilitating the non-immunogenic clearance of apoptotic cells as well as the removal of (neo-self antigens. These properties are largely mediated by the ability of NAbs to recognize highly conserved and endogenously generated structures, which are exemplified by so-called oxidation-specific epitopes (OSEs that are products of lipid peroxidation. The generation of OSEs as well as their interaction with the immune system have been studied extensively in the context of atherosclerosis, a chronic inflammatory disease of the vascular wall that is characterized by the accumulation of cellular debris and oxidized low-density lipoproteins (OxLDL. Both apoptotic cells as well as OxLDL carry OSEs that are targeted by NAbs. Therefore, OSEs represent stress-induced neo-self structures that mediate recognition of metabolic waste (e.g. cellular debris by NAbs, allowing its safe disposal, which has fundamental implications in health and disease.

Are oxidized low-density lipoprotein and C-reactive protein markers of atherosclerosis in nephrotic children?

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Rybi-Szumińska, A.; Wasilewska, A.; Michaluk-Skutnik, J.; Osipiuk-Remża, B.; Fiłonowicz, R.; Zając, M.

2014-01-01

Background Lipid disorders are known to be linked to disturbance in oxidative reactions and play an important role in the progression and complications of idiopathic nephrotic syndrome (INS). Aims The aim of this study was to assess oxidized low-density lipoprotein (oxLDL), high-sensitive C-reactive protein (hs-CRP) serum concentrations and other parameters of lipid metabolism in children with INS during relapse and remission of proteinuria. Methods The examination was performed on 23 childre...

Hydrolysis of phosphatidylcholine during LDL oxidation is mediated by platelet-activating factor acetylhydrolase.

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Steinbrecher, U P; Pritchard, P H

1989-03-01

Degradation of phosphatidylcholine to lysophosphatidylcholine occurs during oxidative modification of low density lipoproteins (LDL). In this study, we have shown that this phospholipid hydrolysis is brought about by an LDL-associated phospholipase A2 that can hydrolyze oxidized but not intact LDL phosphatidylcholine. The chemical nature of the oxidized phospholipids that can act as substrates for this enzyme was not fully characterized, but we hypothesized that the specificity of the enzyme for oxidized LDL phosphatidylcholine might be explained by fragmentation of polyunsaturated sn-2 fatty acyl groups in LDL phosphatidylcholine during oxidation. To facilitate characterization of this enzyme, we therefore selected a fluorescent phosphatidylcholine substrate that had a short-chain, polar residue in the sn-2 position: 1-palmitoyl 2-(6-[7-nitrobenzoxadiazolyl]amino) caproyl phosphatidylcholine, (C6NBD PC). This substrate was efficiently hydrolyzed by LDL, but the dodecanoyl analogue of C6NBD PC, which differed only in that a 12-carbon rather than a 6-carbon acyl derivative was present in the sn-2 position, was not hydrolyzed. The phospholipase activity was heat-stable, calcium-independent, and was inhibited by the serine esterase inhibitors phenylmethylsulfonyl-fluoride and diisopropylfluorophosphate, but was resistant to p-bromophenacylbromide and dithiobisnitrobenzoic acid. The phospholipid hydrolysis could not be attributed to the action of lecithin:cholesterol acyltransferase or lipoprotein lipase. Nearly all of the activity in EDTA-anticoagulated normal plasma was physically associated with apoB-containing lipoproteins, but this apoprotein was not essential as enzyme activity was present in plasma from abetalipoproteinemic patients. These properties are very similar to those recently reported for human plasma platelet-activating factor (PAF) acetylhydrolase. In the present study, we found that acylhydrolase activity against C6NBD PC, PAF, and oxidized

Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases.

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Lingaraju M Halasiddappa

Full Text Available Oxidized phospholipids (OxPLs, including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs. These OxPLs are factors contributing to pro-atherogenic effects of oxidized LDLs (OxLDLs, including inflammation, proliferation and death of vascular cells. OxLDL also elicits formation of the lipid messenger ceramide (Cer which plays a pivotal role in apoptotic signaling pathways. Here we report that both PGPC and POVPC are cytotoxic to cultured macrophages and induce apoptosis in these cells which is associated with increased cellular ceramide levels after several hours. In addition, exposure of RAW 264.7 cells to POVPC and PGPC under the same conditions resulted in a significant increase in ceramide synthase activity, whereas, acid or neutral sphingomyelinase activities were not affected. PGPC is not only more toxic than POVPC, but also a more potent inducer of ceramide formation by activating a limited subset of CerS isoforms. The stimulated CerS activities are in line with the C16-, C22-, and C24:0-Cer species that are generated under the influence of the OxPL. Fumonisin B1, a specific inhibitor of CerS, suppressed OxPL-induced ceramide generation, demonstrating that OxPL-induced CerS activity in macrophages is responsible for the accumulation of ceramide. OxLDL elicits the same cellular ceramide and CerS effects. Thus, it is concluded that PGPC and POVPC are active components that contribute to the capacity of this lipoprotein to elevate ceramide levels in macrophages.

Pig PON1

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Larsen, Knud Erik; Farajzadeh, Leila; Kristensen, Kaja Kjaer

2018-01-01

Atherosclerosis is an inflammatory disease promoted by oxidized low density lipoprotein (LDL). High density lipoprotein (HDL) is an important antioxidant, protecting LDL and itself from oxidation and by detoxifying the hydroperoxides from oxidized LDL. Paraoxonase, encoded by the PON1 gene......, is an enzyme involved in oxidant defense by hydrolyzing oxidized lipids, including oxLDL, and in detoxification of organophosphate pesticides. Aging is the major risk factor for developing atherosclerosis and as paraoxonase is responsible for the antioxidant effect of HDL, aging might be accompanied...

Integrated analysis of long noncoding RNA and mRNA profiling ox-LDL-induced endothelial dysfunction after atorvastatin administration.

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Jiang, Ling-Yu; Jiang, Yue-Hua; Qi, Ying-Zi; Shao, Lin-Lin; Yang, Chuan-Hua

2018-06-01

Long noncoding RNAs (lncRNAs) play a key role in the development of endothelial dysfunction. However, few lncRNAs associated with endothelial dysfunction after atorvastatin administration have been reported. In the present study, differentially expressed (DE) genes in ox-LDL versus control and ox-LDL + atorvastatin versus control were detected. Bioinformatics analysis and integrated analysis of mRNAs and lncRNAs were conducted to study the mechanisms of endothelial dysfunction after atorvastatin administration and to explore the regulation functions of lncRNAs. Here, 532 DE mRNAs and 532 DE lncRNAs were identified (among them, 195 mRNAs and 298 lncRNAs were upregulated, 337 mRNAs and 234 lncRNAs were downregulated) after ox-LDL treatment for 24 hours (fold change ≥2.0, P atorvastatin administration, 750 DE mRNAs and 502 DE lncRNAs were identified (among them, 149 mRNAs and 218 lncRNAs were upregulated and 601 mRNAs and 284 lncRNAs were downregulated). After atorvastatin administration, 167 lncRNAs and 262 mRNAs were still DE. Q-PCR validated the results of microarrays. Chronic inflammatory response, nitric oxide biosynthetic process, microtubule cytoskeleton, cell proliferation and cell migration are regulated by lncRNAs, which also participated in the mainly molecular function and biological processes underlying endothelial dysfunction. Atorvastatin partly improved endothelial dysfunction, but the aspects beyond recovery were mainly concentrated in cell cycle, mitosis, and metabolism. Further exploration is required to explicit the mechanism by which lncRNAs participate in endothelial dysfunction.

Low Serum Paraoxonase-1 Lactonase and Arylesterase Activities in Obese Children and Adolescents

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Sandor Raluca

2015-12-01

Full Text Available Serum paraoxonase-1 (PON1 binds mainly to high density lipoproteins (HDLs and protects low density lipoproteins (LDLs against oxidation. While paraoxonase and arylesterase activities are traditionally assayed, lactonase activity, accounting for protection against LDL oxidation, was less investigated in obese children and adolescents. Therefore, we aimed to measure lactonase, paraoxonase and arylesterase activities, oxidized LDL (ox-LDL and malondialdehyde (MDA levels in obese children and adolescents.

Increased LDL susceptibility to oxidation accelerates future carotid artery atherosclerosis

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Aoki Toshinari

2012-01-01

Full Text Available Abstract Background We analyzed the causal relationship between LDL susceptibility to oxidation and the development of new carotid artery atherosclerosis over a period of 5 years. We previously described the determinants related to a risk of cardiovascular changes determined in a Japanese population participating in the Niigata Study, which is an ongoing epidemiological investigation of the prevention of cardiovascular diseases. Methods We selected 394 individuals (169 males and 225 females who underwent a second carotid artery ultrasonographic examination in 2001 - 2002 for the present study. The susceptibility of LDL to oxidation was determined as the photometric absorbance and electrophoretic mobility of samples that had been collected in 1996 - 1997. The measurements were compared with ultrasonographic findings obtained in 2001 - 2002. Results The multivariate-adjusted model showed that age (odds ratio (OR, 1.034; 95% confidence interval (95%CI, 1.010 - 1.059, HbA1c (OR, 1.477; 95%CI, 0.980 - 2.225, and photometric O/N (OR, 2.012; 95%CI, 1.000 - 4.051 were significant variables that could independently predict the risk of new carotid artery atherosclerosis. Conclusion The susceptibility of LDL to oxidation was a significant parameter that could predict new carotid artery atherosclerosis over a 5-year period, and higher susceptibility was associated with a higher incidence of new carotid artery atherosclerosis.

L-4F Inhibits Oxidized Low-density Lipoprotein-induced Inflammatory Adipokine Secretion via Cyclic AMP/Protein Kinase A-CCAAT/Enhancer Binding Protein β Signaling Pathway in 3T3-L1 Adipocytes

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Xiang-Zhu Xie

2016-01-01

Conclusions: OxLDL induces C/EBPβ protein synthesis in a time-dependent manner and enhances MCP-1 secretion and expression in 3T3-L1 adipocytes. L-4F dose-dependently counterbalances the pro-inflammatory effect of oxLDL, and cyclic AMP/PKA-C/EBPβ signaling pathway may participate in it.

Markers of Oxidative Stress in Dogs with Myxomatous Mitral Valve Disease are Influenced by Sex, Neuter Status, and Serum Cholesterol Concentration

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Reimann, M J; Häggström, J; Møller, J E

2017-01-01

-tocopherol [P = .003]) was associated with body condition score (BCS), but the association disappeared when cholesterol was included in the analyses. All markers of oxidative stress (MDA, oxLDL, and vitamin E) were positively associated with serum cholesterol concentration (P ≤ .04), but none were associated...... with clinical stage of MMVD. CONCLUSIONS: In conclusion, markers of oxidative stress are associated with sex, BCS, neuter status, and cholesterol. The results cannot confirm a relationship between oxidative stress and clinical stage of the disease in dogs with MMVD....

Proprietary tomato extract improves metabolic response to high-fat meal in healthy normal weight subjects

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Xavier Deplanque

2016-10-01

Full Text Available Background: Low-density lipoprotein (LDL oxidation is a risk factor for atherosclerosis. Lycopene and tomato-based products have been described as potent inhibitors of LDL oxidation. Objectives: To evaluate the effect of a 2-week supplementation with a carotenoid-rich tomato extract (CRTE standardized for a 1:1 ratio of lycopene and phytosterols, on post-prandial LDL oxidation after a high-fat meal. Design: In a randomized, double-blind, parallel-groups, placebo-controlled study, 146 healthy normal weight individuals were randomly assigned to a daily dose of CRTE standardized for tomato phytonutrients or placebo during 2 weeks. Oxidized LDL (OxLDL, glucose, insulin, and triglyceride (TG responses were measured for 8 h after ingestion of a high-fat meal before and at the end of intervention. Results: Plasma lycopene, phytofluene, and phytoene were increased throughout the study period in the CRTE group compared to placebo. CRTE ingestion significantly improved changes in OxLDL response to high-fat meal compared to placebo after 2 weeks (p<0.0001. Changes observed in glucose, insulin, and TG responses were not statistically significant after 2 weeks of supplementation, although together they may suggest a trend of favorable effect on metabolic outcomes after a high-fat meal. Conclusions: Two-week supplementation with CRTE increased carotenoids levels in plasma and improved oxidized LDL response to a high-fat meal in healthy normal weight individuals.

The pro-atherogenic effects of macrophages are reduced upon formation of a complex between C-reactive protein and lysophosphatidylcholine

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Chang Mi-Kyung

2012-10-01

Full Text Available Abstract Rationale C-reactive protein (CRP and lysophosphatidylcholine (LPC are phosphorylcholine-(PC-containing oxidized phospholipids (oxPLs found in oxidized LDL (oxLDL, which trigger pro-atherogenic activities of macrophages during the process of atherosclerosis. It has been previously reported that CRP binds to the PC head group of oxLDL in a calcium-dependent manner. The aim of this study was to investigate the importance of binding between CRP and LPC to the pro-atherogenic activities of macrophages. Objectives and findings A chemiluminescent immunoassay and HPLC showed that human recombinant CRP formed a stable complex with LPC in the presence of calcium. The Kd value of the binding of the CRP-LPC complex to the receptors FcγRIA or FcγRIIA was 3–5 fold lower than that of CRP alone. The CRP-LPC complex triggered less potent generation of reactive oxygen species and less activation of the transcription factors AP-1 and NF-kB by human monocyte-derived macrophages in comparison to CRP or LPC alone. However, CRP did not affect activities driven by components of oxLDL lacking PC, such as upregulation of PPRE, ABCA1, CD36 and PPARγ and the enhancement of cholesterol efflux by human macrophages. The presence of CRP inhibited the association of Dil-labelled oxLDL to human macrophages. Conclusions The formation of complexes between CRP and PC-containing oxPLs, such as LPC, suppresses the pro-atherogenic effects of CRP and LPC on macrophages. This effect may in part retard the progression of atherosclerosis.

Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages.

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Park, Sin-Hye; Paek, Ji Hun; Shin, Daekeun; Lee, Jae-Yong; Lim, Soon Sung; Kang, Young-Hee

2015-04-01

The cellular accumulation of cholesterol is critical in the development and progression of atherosclerosis. ATP-binding cassette (ABC) transporters play an essential role in mediating the efflux of excess cholesterol. In the current study, we investigated whether purple Perilla frutescens extracts (PPE) at a non-toxic concentration of 1-10 µg/ml stimulate the induction of the ABC transporters, ABCA1 and ABCG1, and cholesterol efflux from lipid-laden J774A.1 murine macrophages exposed to 50 ng/ml oxidized low-density lipoprotein (LDL). Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects. Our results revealed that treatment with oxidized LDL for 24 h led to the accumulation of lipid droplets in the macrophages. PPE suppressed the oxidized LDL-induced foam cell formation by blocking the induction of scavenger receptor B1. However, PPE promoted the induction of the ABC transporters, ABCA1 and ABCG1, and subsequently accelerated cholesterol efflux from the lipid-loaded macrophages. The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect. PPE did not induce LXRα and PPARγ expression per se, but enhanced their expression in the macrophages exposed to oxidized LDL. α-asarone was isolated from PPE and characterized as a major component enhancing the induction of ABCA1 and ABCG1 in macrophages exposed to oxidized LDL. α-asarone, but not β-asarone was effective in attenuating foam cell formation and enhancing cholesterol efflux, revealing an isomeric difference in their activity. The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans.

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Wan, Y; Vinson, J A; Etherton, T D; Proch, J; Lazarus, S A; Kris-Etherton, P M

2001-11-01

Flavonoids are polyphenolic compounds of plant origin with antioxidant effects. Flavonoids inhibit LDL oxidation and reduce thrombotic tendency in vitro. Little is known about how cocoa powder and dark chocolate, rich sources of polyphenols, affect these cardiovascular disease risk factors. We evaluated the effects of a diet high in cocoa powder and dark chocolate (CP-DC diet) on LDL oxidative susceptibility, serum total antioxidant capacity, and urinary prostaglandin concentrations. We conducted a randomized, 2-period, crossover study in 23 healthy subjects fed 2 diets: an average American diet (AAD) controlled for fiber, caffeine, and theobromine and an AAD supplemented with 22 g cocoa powder and 16 g dark chocolate (CP-DC diet), providing approximately 466 mg procyanidins/d. LDL oxidation lag time was approximately 8% greater (P = 0.01) after the CP-DC diet than after the AAD. Serum total antioxidant capacity measured by oxygen radical absorbance capacity was approximately 4% greater (P = 0.04) after the CP-DC diet than after the AAD and was positively correlated with LDL oxidation lag time (r = 0.32, P = 0.03). HDL cholesterol was 4% greater after the CP-DC diet (P = 0.02) than after the AAD; however, LDL-HDL ratios were not significantly different. Twenty-four-hour urinary excretion of thromboxane B(2) and 6-keto-prostaglandin F(1)(alpha) and the ratio of the 2 compounds were not significantly different between the 2 diets. Cocoa powder and dark chocolate may favorably affect cardiovascular disease risk status by modestly reducing LDL oxidation susceptibility, increasing serum total antioxidant capacity and HDL-cholesterol concentrations, and not adversely affecting prostaglandins.

Treatment of HIV infection with a raltegravir-based regimen increases LDL levels, but improves HDL cholesterol efflux capacity.

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Funderburg, Nicholas T; Xu, Dihua; Playford, Martin P; Joshi, Aditya A; Andrade, Adriana; Kuritzkes, Daniel R; Lederman, Michael M; Mehta, Nehal N

2017-01-01

Persons infected with HIV often have altered lipid profiles that may be affected by antiretroviral therapies (ART). Traditional lipid measurements may be insufficient to assess cardiovascular disease (CVD) risk in this population. We report results from 39 ART-naive participants in a substudy of A5248, a single-arm study of raltegravir, emtricitabine/tenofovir administration. Samples were collected at baseline, 12, 24 and 48 weeks after ART initiation. We performed advanced lipid phenotyping using nuclear magnetic resonance spectroscopy (Liposcience, Raleigh, NC, USA) for lipid particle size and number, and examined high-density lipoprotein (HDL) function measuring reverse cholesterol transport using J774 macrophages. We report significant increases in total cholesterol (13 mg/dl; PLDL; 8 mg/dl; P=0.03), with no change in triglycerides and without an increase in LDL particle number (P>0.1 all time points). HDL levels were increased over baseline levels at all time points (PLDL (oxLDL) levels decreased by week 12, but rose subsequently, and were not different from baseline at later time points. HDL increases were associated with increases in beneficial HDL particles and HDL cholesterol efflux capacity, which may reduce future CVD events. Persistent inflammation in these HIV+ participants, may be a cause or consequence of oxLDL levels, and may contribute to declining levels of HDL over time. Clinicaltrials.gov NCT00660972.

Antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation.

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Kostyuk, Vladimir A; Potapovich, Alla I; Suhan, Tatyana O; de Luca, Chiara; Korkina, Liudmila G

2011-05-11

Oxidized low-density lipoproteins (oxLDL) play a critical role in the initiation of atherosclerosis through activation of inflammatory signaling. In the present work we investigated the role of antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation. Significant decrease in intracellular NO level and superoxide overproduction was found in human umbilical vein endothelial cells (HUVEC) treated with oxLDL, but not with LDL. The redox imbalance was prevented by the addition of quercetin or resveratrol. Expression analysis of 14 genes associated with oxidative stress and inflammation revealed oxLDL-mediated up-regulation of genes specifically involved in leukocyte recruitment and adhesion. This up-regulation could be partially avoided by the addition of verbascoside or resveratrol, while treatment with quercetin resulted in a further increase in the expression of these genes. Lipopolysaccharide (LPS)-treated HUVEC were also used for the evaluation of anti-inflammatory potency of plant polyphenols. Significant differences between HUVEC treaded with oxLDL and LPS were found in both the expression pattern of inflammation-related genes and the effects of plant polyphenols on cellular responses. The present data indicate that plant polyphenols may affect vascular inflammation not only as antioxidants but also as modulators of inflammatory redox signaling pathways. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Elevated circulating LDL phenol levels in men who consumed virgin rather than refined olive oil are associated with less oxidation of plasma LDL.

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de la Torre-Carbot, Karina; Chávez-Servín, Jorge L; Jaúregui, Olga; Castellote, Ana I; Lamuela-Raventós, Rosa M; Nurmi, Tarja; Poulsen, Henrik E; Gaddi, Antonio V; Kaikkonen, Jari; Zunft, Hans-Franz; Kiesewetter, Holger; Fitó, Montserrat; Covas, María-Isabel; López-Sabater, M Carmen

2010-03-01

In human LDL, the bioactivity of olive oil phenols is determined by the in vivo disposition of the biological metabolites of these compounds. Here, we examined how the ingestion of 2 similar olive oils affected the content of the metabolic forms of olive oil phenols in LDL in men. The oils differed in phenol concentrations as follows: high (629 mg/L) for virgin olive oil (VOO) and null (0 mg/L) for refined olive oil (ROO). The study population consisted of a subsample from the EUROLIVE study and a randomized controlled, crossover design was used. Intervention periods lasted 3 wk and were preceded by a 2-wk washout period. The levels of LDL hydroxytyrosol monosulfate and homovanillic acid sulfate, but not of tyrosol sulfate, increased after VOO ingestion (P oil modulates the phenolic metabolite content in LDL after sustained, daily consumption. The inverse relationship of these metabolites with the degree of LDL oxidation supports the in vivo antioxidant role of olive oil phenolics compounds.

Vinpocetine attenuates lipid accumulation and atherosclerosis formation

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Cai, Yujun; Li, Jian-Dong; Yan, Chen

2013-01-01

Highlights: •Vinpocetine attenuates hyperlipidemia-induced atherosclerosis in a mouse model. •Vinpocetine antagonizes ox-LDL uptake and accumulation in macrophages. •Vinpocetine blocks the induction of ox-LDL receptor LOX-1 in vitro and in vivo. -- Abstract: Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis

Vinpocetine attenuates lipid accumulation and atherosclerosis formation

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Cai, Yujun [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642 (United States); Li, Jian-Dong [Center for Inflammation, Immunity and Infection, and Department of Biology, Georgia State University, Atlanta, GA 30303 (United States); Yan, Chen, E-mail: Chen_Yan@urmc.rochester.edu [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642 (United States)

2013-05-10

Highlights: •Vinpocetine attenuates hyperlipidemia-induced atherosclerosis in a mouse model. •Vinpocetine antagonizes ox-LDL uptake and accumulation in macrophages. •Vinpocetine blocks the induction of ox-LDL receptor LOX-1 in vitro and in vivo. -- Abstract: Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis.

Low-carbohydrate diets reduce lipid accumulation and arterial inflammation in guinea pigs fed a high-cholesterol diet.

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Leite, Jose O; DeOgburn, Ryan; Ratliff, Joseph; Su, Randy; Smyth, Joan A; Volek, Jeff S; McGrane, Mary M; Dardik, Alan; Fernandez, Maria Luz

2010-04-01

Low-carbohydrate diets (LCD) efficiently induce weight loss and favorably affect plasma lipids, however, the effect of LCD on atherosclerosis is still argued. To evaluate the effect of LCD on the prevention of atherosclerosis. Twenty guinea pigs were fed either a LCD or a low-fat diet (LFD) in combination with high-cholesterol (0.25g/100g) for 12 weeks. The percentage energy of macronutrient distribution was 10:65:25 for carbohydrate:fat:protein for the LCD, and 55:20:25 for the LFD. Plasma lipids were measured using colorimetric assays. Plasma and aortic oxidized (oxLDL) were quantified using ELISA methods. Inflammatory cytokines were measured in aortic homogenates using an immunoassay. H&E stained sections of aortic sinus and Schultz stained sections of carotid arteries were examined. LDL cholesterol was lower in the LCD compared to the LFD group (71.9+/-34.8 vs. 81.7+/-26.9mg/dL; p=0.039). Aortic cholesterol was also lower in the LCD (4.98+/-1.3mg/g) compared to the LFD group (6.68+/-2.0mg/g); p<0.05. The Schultz staining method confirmed less aortic cholesterol accumulation in the LCD group. Plasma oxLDL did not differ between groups, however, aortic oxLDL was 61% lower in the LCD compared to the LFD group (p=0.045). There was a positive correlation (r=0.63, p=0.03) between oxLDL and cholesterol concentration in the aorta of LFD group, which was not observed in LCD group (r=-0.05, p=0.96). Inflammatory markers were reduced in guinea pigs from the LCD group (p<0.05) and they were correlated with the decreases in oxLDL in aorta. These results suggest that LCD not only decreases lipid deposition, but also prevents the accumulation of oxLDL and reduces inflammatory cytokines within the arterial wall and may prevent atherosclerosis. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

The platelet activating factor acetyl hydrolase, oxidized low-density lipoprotein, paraoxonase 1 and arylesterase levels in treated and untreated patients with polycystic ovary syndrome.

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Carlioglu, Ayse; Kaygusuz, Ikbal; Karakurt, Feridun; Gumus, Ilknur Inegol; Uysal, Aysel; Kasapoglu, Benan; Armutcu, Ferah; Uysal, Sema; Keskin, Esra Aktepe; Koca, Cemile

2014-11-01

To evaluate the platelet activating factor acetyl hydrolyze (PAF-AH), oxidized low-density lipoprotein (ox-LDL), paraoxonase 1 (PON1), arylesterase (ARE) levels and the effects of metformin and Diane-35 (ethinyl oestradiol + cyproterone acetate) therapies on these parameters and to determine the PON1 polymorphisms among PCOS patients. Ninety patients with PCOS, age 30, and body mass index-matched healthy controls were included in the study. Patients were divided into three groups: metformin treatment, Diane-35 treatment and no medication groups. The treatment with metformin or Diane-35 was continued for 6 months and all subjects were evaluated with clinical and biochemical parameters 6 months later. One-way Anova test, t test and non-parametric Mann-Whitney U tests were used for statistical analysis. PAF-AH and ox-LDL levels were statistically significantly higher in untreated PCOS patients than controls, and they were statistically significantly lower in patients treated with metformin or Diane-35 than untreated PCOS patients. In contrast, there were lower PON1 (not statistically significant) and ARE (statistically significant) levels in untreated PCOS patients than the control group and they significantly increased after metformin and Diane-35 treatments. In PCOS patients serum PON1 levels for QQ, QR and RR phenotypes were statistically significantly lower than the control group. In patients with PCOS, proatherogenic markers increase. The treatment of PCOS with metformin or Diane-35 had positive effects on lipid profile, increased PON1 level, which is a protector from atherosclerosis and decreased the proatherogenic PAF-AH and ox-LDL levels.

Red Wine administration to Apolipoprotein E-deficient Mice reduces their Macrophage-derived Extracellular Matrix Atherogenic Properties

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MARIELLE KAPLAN

2004-01-01

Full Text Available Proteoglycans (PGs from the arterial extracellular matrix (ECM contribute to the trapping of LDL and oxidized LDL (Ox-LDL in the arterial wall, a phenomenon called "lipoprotein retention". Moreover, we have shown that subsequent to their binding to the matrix, LDL and Ox-LDL are taken up by macrophages. Oxidative stress significantly increases macrophage secretion of ECM-PGs, lipoprotein binding to the ECM and the uptake of ECM-retained lipoproteins by macrophages. The aim of the present study was to determine whether red wine administration to atherosclerotic mice would affect their peritoneal macrophage-derived extracellular matrix properties, such as the glycosaminoglycan content and the ability to bind LDL. In addition, we questioned the ability of LDL bound to the mice peritoneal macrophages-derived ECM to be taken up by macrophages. Red wine administration to atherosclerotic mice did not affect the mice peritoneal macrophages-derived ECM glycosaminoglycan content but it significantly reduced the mice peritoneal macrophages-derived ECM ability to bind LDL and the subsequent uptake of ECM-retained LDL by the macrophages. The present study thus clearly demonstrated the inhibitory effect of red wine consumption by E0 mice on their peritoneal macrophage-derived extracellular matrix atherogenic properties.

Elevated circulating LDL phenol levels in men who consumed virgin rather than refined olive oil are associated with less oxidation of plasma LDL

DEFF Research Database (Denmark)

de la Torre-Carbot, Karina; Chávez-Servín, Jorge L; Jaúregui, Olga

2010-01-01

In human LDL, the bioactivity of olive oil phenols is determined by the in vivo disposition of the biological metabolites of these compounds. Here, we examined how the ingestion of 2 similar olive oils affected the content of the metabolic forms of olive oil phenols in LDL in men. The oils differed...... in phenol concentrations as follows: high (629 mg/L) for virgin olive oil (VOO) and null (0 mg/L) for refined olive oil (ROO). The study population consisted of a subsample from the EUROLIVE study and a randomized controlled, crossover design was used. Intervention periods lasted 3 wk and were preceded...... acids (P phenol levels (r = -0.296; P = 0.013). Phenols in LDL were not associated with other oxidation markers. In summary, the phenol concentration of olive oil modulates the phenolic metabolite content in LDL after sustained...

Inhibition of LDL-oxidation and antioxidant properties related to polyphenol content of hydrophilic fractions from seaweed Halimeda Incrassata (Ellis Lamouroux

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Ariana Costa-Mugica

2012-03-01

Full Text Available LDL oxidation and oxidative stress are closely related to atherosclerosis. Therefore, natural antioxidants have been studied as promising candidates. In the present study, the LDL oxidation inhibition activity of bioactive compounds from Halimeda incrassata seaweed. associated to antioxidant capacity, was evaluated in vitro. Experimental work was conducted with lyophilized aqueous extract and phenolic-rich fractions of the seaweed and their effect on LDL oxidation was evaluated using heparin-precipitated LDL (hep-LDL with exposure to Cu2+ ions and AAPH as the free radical generator. H. incrassata had a protective effect for hep-LDL in both systems and the presence of phenolic compounds contributed to the activity where phenolic-rich fractions showed significant capacity for inhibition of oxidation mediated by Cu2+ ions. The observed effect could be related to the antioxidant potential of polar fractions evidenced by reducing activity and DPPH• radical scavenging. The results obtained in vitro further support the antioxidant and LDL oxidation inhibition properties of H. incrassata and further knowledge toward future phytotherapeutic application of the seaweed.A oxidação da LDL e o estresse oxidativo estão intimamente relacionados com a aterosclerose. Por isso, os antioxidantes naturais têm sido estudados como candidatos promissores. No presente trabalho foi avaliada in vitro a capacidade de inibição da oxidação da LDL pelos compostos bioativos da alga Halimeda incrassata em associação à capacidade antioxidante. O trabalho experimental foi conduzido com extratos polares (extrato aquoso liofilizado e frações ricas em fenólicos e seu efeito na oxidação da LDL foi avaliado usando LDL precipitada com heparina (hep-LDL, oxidada com íons de Cu2+ e AAPH, como geradores de radicais livres. A H. incrassata apresentou efeito protetor para hep-LDL em ambos sistemas e a presença de compostos fenólicos contribuiu para a atividade em que as

Polysaccharide from Fuzi protects against Ox-LDL-induced calcification of human vascular smooth muscle cells by increasing autophagic activity

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Liao, Lizhen; Zhuang, Xiaodong; Li, Weidong; Su, Qibiao; Zhao, Jie; Liu, Ying

2018-01-01

Polysaccharide from Fuzi (FPS) is a water-soluble polysaccharide isolated from the traditional Chinese herbal medicine Fuzi. It has been demonstrated to protect hepatocytes against ischemia-reperfusion injury through its potent antioxidant effects, and to attenuate starvation-induced cytotoxicity in H9c2 cells by increasing autophagic activity. In the present study, Alizarin Red S staining was used to detect mineral deposition and reverse transcription-quantitative polymerase chain reaction was used to detect the core binding factor α1 and smooth muscle 22α mRNA expression. To analyze autophagic activity, western blotting was used to detect microtubule-associated protein 1A/1B light chain 3 and nucleoporin P62 expression. In addition, green fluorescent protein-LC3 dots-per-cell was observed by fluorescence microscopy. It was demonstrated that oxidized low-density lipoprotein (Ox-LDL) could increase the calcification of human vascular smooth muscle cells (VSMCs) in a concentration-dependent manner, and that FPS treatment had a significant protective effect against Ox-LDL-induced calcification of human VSMCs. Furthermore, FPS treatment alleviated the Ox-LDL-induced downregulation of autophagic activity, and the protective effect of FPS on Ox-LDL-induced calcification was attenuated by the autophagy inhibitor 3-methyladenine. In conclusion, the present study demonstrated for the first time to the best of the authors' knowledge that FPS can protect against Ox-LDL-induced vascular calcification in human VSMCs, and that this likely occurs via the activation of autophagy. This supports the hypothesis that autophagy may be an endogenous protective mechanism counteracting vascular calcification, and that FPS may be used as a potential therapeutic for vascular calcification. PMID:29393437

Adding exercise training to rosuvastatin treatment: influence on serum lipids and biomarkers of muscle and liver damage.

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Coen, Paul M; Flynn, Michael G; Markofski, Melissa M; Pence, Brandt D; Hannemann, Robert E

2009-07-01

Statin treatment and exercise training can improve lipid profile when administered separately. The efficacy of exercise and statin treatment combined, and its impact on myalgia and serum creatine kinase (CK) have not been completely addressed. The purpose of this study was to determine the effect of statin treatment and the addition of exercise training on lipid profile, including oxidized low-density lipoprotein (oxLDL), and levels of CK and alanine transaminase. Thirty-one hypercholesterolemic and physically inactive subjects were randomly assigned to rosuvastatin (R) or rosuvastatin/exercise (RE) group. A third group of physically active hypercholesterolemic subjects served as an active control group (AC). The R and RE groups received rosuvastatin treatment (10 mg/d) for 20 weeks. From week 10 to week 20, the RE group also participated in a combined endurance and resistive exercise training program (3 d/wk). Lipid profile was determined for all subjects at week 0 (Pre), week 10 (Mid), and week 20 (Post). The CK and alanine transaminase levels were measured at the same time points in the RE and R groups and 48 hours after the first and fifth exercise bout in the RE group. Each RE subject was formally queried about muscle fatigue, soreness, and stiffness before each training session. Total, LDL, and oxLDL cholesterol was lower in the RE and R groups at Mid and Post time points when compared with Pre. Oxidized LDL was lower in the RE group compared with the R group at the Post time point. When treatment groups (R and RE) were combined, high-density lipoprotein levels were increased and triglycerides decreased across time. Creatine kinase increased in the RE group 48 hours after the first exercise bout, but returned to baseline levels 48 hours after the fifth exercise bout. Rosuvastatin treatment decreased total, LDL, and oxLDL cholesterol. The addition of an exercise training program resulted in a further decrease in oxLDL. There was no abnormal sustained increase

The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

International Nuclear Information System (INIS)

Steinmetz, Martin; Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain; Mallat, Ziad

2015-01-01

Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10 7 OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen

The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

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Steinmetz, Martin, E-mail: martin.steinmetz@ukb.uni-bonn.de [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Internal Medicine II, University Hospital Bonn, 53105 Bonn (Germany); Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Mallat, Ziad [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke' s Hospital, Cambridge, CB2 2QQ (United Kingdom)

2015-08-14

Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10{sup 7} OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen

Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease.

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Stein, J H; Keevil, J G; Wiebe, D A; Aeschlimann, S; Folts, J D

1999-09-07

In vitro, the flavonoid components of red wine and purple grape juice are powerful antioxidants that induce endothelium-dependent vasodilation of vascular rings derived from rat aortas and human coronary arteries. Although improved endothelial function and inhibition of LDL oxidation may be potential mechanisms by which red wine and flavonoids reduce cardiovascular risk, the in vivo effects of grape products on endothelial function and LDL oxidation have not been investigated. This study assessed the effects of ingesting purple grape juice on endothelial function and LDL susceptibility to oxidation in patients with coronary artery disease (CAD). Fifteen adults with angiographically documented CAD ingested 7.7+/-1.2 mL. kg(-1). d(-1) of purple grape juice for 14 days. Flow-mediated vasodilation (FMD) was measured using high-resolution brachial artery ultrasonography. Susceptibility of LDL particles to oxidation was determined from the rate of conjugated diene formation after exposure to copper chloride. At baseline, FMD was impaired (2.2+/-2. 9%). After ingestion of grape juice, FMD increased to 6.4+/-4.7% (P=0.003). In a linear regression model that included age, artery diameter, lipid values, and use of lipid-lowering and antioxidant therapies, the effect of grape juice on FMD remained significant (mean change 4.2+/-4.4%, PFMD and reduces LDL susceptibility to oxidation in CAD patients. Improved endothelium-dependent vasodilation and prevention of LDL oxidation are potential mechanisms by which flavonoids in purple grape products may prevent cardiovascular events, independent of alcohol content.

Umbilical blood flow ultrasound characteristics of perioperative fetal intrauterine hypoxia and their relationship with maternal and fetal oxidative stress injury

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Yu-Mei He

2017-05-01

Full Text Available Objective: To study the relationship between umbilical blood flow ultrasound characteristics of perioperative fetal intrauterine hypoxia and maternal as well as fetal oxidative stress injury. Methods: 108 puerperae giving birth in our hospital between May 2014 and October 2016 were selected and divided into normal pregnancy group with neonatal Apgar score >7 points and intrauterine hypoxia group with neonatal Apgar score ≤7 points, color Doppler diasonograph was used to determine umbilical blood flow ultrasound parameters, umbilical cord blood was collected to determine the levels of oxidative stress products, and the placenta was collected to determine the levels of oxidative stress products and related apoptosis molecules. Results: During 24–30 weeks, 31–36 weeks and 37–41 weeks of pregnancy, umbilical blood flow resistance index (RI, pulsatility index (PI and diastolic velocity/systolic velocity (S/D of intrauterine hypoxia group were significantly higher than those of normal pregnancy group (P<0.05; malondialdehyde (MDA, oxidized low-density lipoprotein (ox- LDL, 8-isoprostanes (8-iso, and heat shock protein 70 (HSP-70 levels in umbilical cord blood of intrauterine hypoxia group were significantly higher than those of normal pregnancy group (P<0.05, MDA, oxLDL, 8-ios, HSP-70, Fas, FasL and Bax levels in placenta tissue were significantly higher than those of normal pregnancy group (P<0.05, and Bcl-2 and XIAP levels were significantly lower than those of normal pregnancy group (P<0.05; RI, PI and S/ D were positively correlated with MDA, oxLDL, 8-ios and HSP-70 levels in umbilical cord blood and placenta tissue, positively correlated with Fas, FasL and Bax levels in placenta tissue, and negatively correlated with Bcl-2 and XIAP levels in placental tissue. Conclusions: The increased umbilical blood flow resistance and decreased flow volume of fetal intrauterine hypoxia are closely related to maternal, fetal and placental oxidative

Association of polymorphisms in FADS gene with age-related changes in serum phospholipid polyunsaturated fatty acids and oxidative stress markers in middle-aged nonobese men

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Hong SH

2013-05-01

Full Text Available Seul Hee Hong,1,* Jung Hyun Kwak,2,* Jean Kyung Paik,3 Jey Sook Chae,2 Jong Ho Lee1,21National Research Laboratory for Clinical Nutrigenetics/Nutrigenomics, 2Research Institute of Science for Aging, Yonsei University, Seoul, South Korea; 3Department of Food and Nutrition, Eulji University, Gyeonggi-do, South Korea *These authors contributed equally to this workBackground: To investigate the association of FADS gene polymorphisms with age-related changes in polyunsaturated fatty acids (PUFAs in serum phospholipids and oxidative stress markers.Methods: We genotyped 122 nonobese men aged 35–59 years without any known diseases at baseline for rs174537 near FADS1 (FEN1 rs174537G > T, FADS2 (rs174575, rs2727270, and FADS3 (rs1000778, and followed them for 3 years.Results: Among the four single-nucleotide polymorphisms, the minor variants of rs174537 and rs2727270 were significantly associated with lower concentrations of long-chain PUFAs. However, rs174537G > T showed stronger association. At baseline, men with the rs174537T allele had lower arachidonic acid (AA and AA/linoleic acid (LA, and higher interleukin (IL-6 levels than rs174537GG counterparts. After 3 years, rs174537GG men had significantly increased AA (P = 0.022, AA/dihomo-γ-linolenic acid (DGLA (P = 0.007, docosapentaenoic acid (DPA, low-density lipoprotein (LDL cholesterol, and oxidized LDL (ox-LDL, but decreased eicosatrienoic acid. The rs174537T group showed significantly increased γ-linolenic acid and ox-LDL, and decreased eicosadienoic acid, eicosapentaenoic acid (EPA/α-linolenic acid (ALA, and IL-6. After 3 years, the rs174537T group had lower AA (P < 0.001, AA/DGLA (P = 0.019, EPA, DPA, EPA/ALA, and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α (P = 0.011 than rs174537GG. Changes in AA (P = 0.001, AA/DGLA (P = 0.017, EPA, DPA, EPA/ALA, and urinary 8-epi-PGF2α (P < 0.001 were significantly different between the groups after adjusting for baseline values. Overall, changes in AA

Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice.

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Calpe-Berdiel, Laura; Zhao, Ying; de Graauw, Marjo; Ye, Dan; van Santbrink, Peter J; Mommaas, A Mieke; Foks, Amanda; Bot, Martine; Meurs, Illiana; Kuiper, Johan; Mack, Jody T; Van Eck, Miranda; Tew, Kenneth D; van Berkel, Theo J C

2012-08-01

The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in vivo and in modulating susceptibility to atherosclerosis. Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice. Interestingly, lack of ABCA2 in macrophages resulted in a diminished lesion size in the aortic root (-24.5%) and descending thoracic aorta (-36.6%) associated with a 3-fold increase in apoptotic cells, as measured by both caspase 3 and TUNEL. Upon oxidized LDL exposure, macrophages from wildtype (WT) transplanted animals developed filipin-positive droplets in lysosomal-like compartments, corresponding to free cholesterol (FC) accumulation. In contrast, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of FC over peripheral regions. The accumulation of neutral sterols in lipid droplets was increased in ABCA2-deficient macrophages, but primarily in cytoplasmic clusters and not in lysosomes. Importantly, apoptosis of oxLDL loaded macrophages lacking ABCA2 was increased 2.7-fold, probably as a consequence of the broad cellular distribution of FC. Lack of functional ABCA2 generates abnormalities in intracellular lipid distribution/trafficking in macrophages consistent with its lysosomal sequestering role, leading to an increased susceptibility to apoptosis in response to oxidized lipids and reduced atherosclerotic lesion development. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

No effect of consumption of green and black tea on plasma lipid and antioxidant levels and on LDL Oxidation in smokers

NARCIS (Netherlands)

Princen, H.M.G.; Duyvenvoorde, W. van; Buytenhek, R.; Blonk, C.; Tijburg, L.B.M.; Langius, J.A.E.; Meinders, A.E.; Pijl, H.

1998-01-01

Intake of flavonoids is associated with a reduced cardiovascular risk. Oxidation of LDL is a major step in atherogenesis, and antioxidants may protect LDL from oxidation. Because tea is an important source of flavonoids which are strong antioxidants, we have assessed in a randomized,

Dose-dependent dual effects of cholesterol and desmosterol on J774 macrophage proliferation

International Nuclear Information System (INIS)

Rodriguez-Acebes, Sara; Cueva, Paloma de la; Ferruelo, Antonio J.; Fernandez-Hernando, Carlos; Lasuncion, Miguel A.; Martinez-Botas, Javier; Gomez-Coronado, Diego

2008-01-01

We addressed the ability of native, oxidized and acetylated low-density lipoproteins (nLDL, oxLDL and acLDL, respectively) and desmosterol to act as sources of sterol for the proliferation of J774A.1 macrophages. Treatment with 0.5 μM lovastatin and lipoprotein-deficient serum suppressed cell proliferation. This inhibition was effectively prevented by nLDL, but only to a lesser extent by oxLDL. AcLDL, despite its ability to deliver a higher amount of cholesterol to J774 macrophages than the other LDLs, was dependent on mevalonate supply to sustain cell proliferation. Similarly, exogenous desmosterol, which is not converted into cholesterol in J774 cells, required the simultaneous addition of mevalonate to support optimal cell growth. Expression of hydroxymethyl glutaryl coenzyme A reductase mRNA was potently down-regulated by acLDL and exogenous desmosterol, but the effect was weaker with other sterol sources. We conclude that nLDL is more efficient than modified LDL in sustaining macrophage proliferation. Despite the requirement of cholesterol or desmosterol for J774 cell proliferation, excessive provision of either sterol limits mevalonate availability, thus suppressing cell proliferation.

Dose-dependent dual effects of cholesterol and desmosterol on J774 macrophage proliferation

Energy Technology Data Exchange (ETDEWEB)

Rodriguez-Acebes, Sara [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain); Cueva, Paloma de la; Ferruelo, Antonio J; Fernandez-Hernando, Carlos [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); Lasuncion, Miguel A [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain); Departamento de Bioquimica y Biologia Molecular, Universidad de Alcala, Alcala de Henares (Spain); Martinez-Botas, Javier [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain); Gomez-Coronado, Diego [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain)], E-mail: diego.gomez@hrc.es

2008-12-12

We addressed the ability of native, oxidized and acetylated low-density lipoproteins (nLDL, oxLDL and acLDL, respectively) and desmosterol to act as sources of sterol for the proliferation of J774A.1 macrophages. Treatment with 0.5 {mu}M lovastatin and lipoprotein-deficient serum suppressed cell proliferation. This inhibition was effectively prevented by nLDL, but only to a lesser extent by oxLDL. AcLDL, despite its ability to deliver a higher amount of cholesterol to J774 macrophages than the other LDLs, was dependent on mevalonate supply to sustain cell proliferation. Similarly, exogenous desmosterol, which is not converted into cholesterol in J774 cells, required the simultaneous addition of mevalonate to support optimal cell growth. Expression of hydroxymethyl glutaryl coenzyme A reductase mRNA was potently down-regulated by acLDL and exogenous desmosterol, but the effect was weaker with other sterol sources. We conclude that nLDL is more efficient than modified LDL in sustaining macrophage proliferation. Despite the requirement of cholesterol or desmosterol for J774 cell proliferation, excessive provision of either sterol limits mevalonate availability, thus suppressing cell proliferation.

Salidroside protects against foam cell formation and apoptosis, possibly via the MAPK and AKT signaling pathways.

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Ni, Jing; Li, Yuanmin; Li, Weiming; Guo, Rong

2017-10-10

Foam cell formation and apoptosis are closely associated with atherosclerosis pathogenesis. We determined the effect of salidroside on oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation and apoptosis in THP1 human acute monocytic leukemia cells and investigated the associated molecular mechanisms. THP1-derived macrophages were incubated with salidroside for 5 h and then exposed to ox-LDL for 24 h to induce foam cell formation. Cytotoxicity, lipid deposition, apoptosis, and the expression of various proteins were tested using the CCK8 kit, Oil Red O staining, flow cytometry, and western blotting, respectively. Ox-LDL treatment alone promoted macrophage-derived foam cell formation, while salidroside treatment alone inhibited it (p foam cell formation and apoptosis, partly by regulating the MAPK and Akt signaling pathways.

Endothelial cell oxidative stress and signal transduction

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ROCIO FONCEA

2000-01-01

Full Text Available Endothelial dysfunction (ED is an early event in atherosclerotic disease, preceding clinical manifestations and complications. Increased reactive oxygen species (ROS have been implicated as important mechanisms that contribute to ED, and ROS’s may function as intracellular messengers that modulate signaling pathways. Several intracellular signal events stimulated by ROS have been defined, including the identification of two members of the mitogen activated protein kinase family (ERK1/2 and big MAP kinase, BMK1, tyrosine kinases (Src and Syk and different isoenzymes of PKC as redox-sensitive kinases. ROS regulation of signal transduction components include the modification in the activity of transcriptional factors such as NFkB and others that result in changes in gene expression and modifications in cellular responses. In order to understand the intracellular mechanisms induced by ROS in endothelial cells (EC, we are studying the response of human umbilical cord vein endothelial cells to increased ROS generation by different pro-atherogenic stimuli. Our results show that Homocysteine (Hcy and oxidized LDL (oxLDL enhance the activity and expression of oxidative stress markers, such as NFkB and heme oxygenase 1. These results suggest that these pro-atherogenic stimuli increase oxidative stress in EC, and thus explain the loss of endothelial function associated with the atherogenic process

Effects of improved fat meat products consumption on emergent cardiovascular disease markers of male volunteers at cardiovascular risk.

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Celada, Paloma; Sánchez-Muniz, Francisco J; Delgado-Pando, Gonzalo; Bastida, Sara; Rodilla, Manuel Espárrago; Jiménez-Colmenero, Francisco; Olmedilla-Alonso, Begoña

2016-12-01

High meat-product consumption has been related to cardiovascular disease (CVD). However, previous results suggest the benefits of consuming improved fat meat products on lipoprotein-cholesterol and anthropometric measurements. Present study aims to assess the effect of consuming different Pâté and Frankfurter formulations on emergent CVD biomarkers in male volunteers at increased CVD risk. Eighteen male volunteers with at least two CVD risk factors were enrolled in a sequentially controlled study where different pork-products were tested: reduced-fat (RF), omega-3-enriched-RF (n-3RF), and normal-fat (NF). Pork-products were consumed during 4-week periods separated by 4-week washout. The cardiometabolic index (CI), oxidized low density lipoproteins (oxLDL), apolipoproteins (Apo) A1 and B, homocysteine (tHcys), arylesterase (AE), C-reactive Protein (CRP), tumor necrotic factor-alpha (TNFα), and lipoprotein (a) (Lp(a)) were tested and some other related ratios calculated. AE, oxLDL and Lp(a), AE/HDLc, LDLc/Apo B, and AE/oxLDL rate of change were differently affected (P<0.01) by pork-products consumption. RF increased (P < 0.05) AE, AE/HDLc and AE/oxLDL ratios and decreased TNFα, tHcys; n-3RF increased (P < 0.001) AE, AE/HDLc and AE/oxLDL ratios and decreased (P < 0.05) Lp(a); while NF increased (P<0.05) oxLDL and Lp(a) levels. In conclusion, RF and n-3RF products affected positively the level of some emergent CVD markers. The high regular consumption of NF-products should be limited as significantly increased Lp(a) and oxLDL values. The high variability in response observed for some markers suggests the need to perform more studies to identify targets for RF- and n-3RF-products. Graphical Abstract Emergent CVD markers.

Exercise-induced oxidative stress and antioxidant enzyme activity in type 2 diabetic patients with and without diastolic dysfunction and hypertension

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Kostić Nada

2009-01-01

Full Text Available Introduction. Antioxidant systems are important factors affecting the oxidation of lipoproteins and thereby the progression of atherosclerotic disease. It has been suggested that physical activity might maintain and promote the antioxidant defence capacity against the oxidative stress. Left ventricular dysfunction (LVDD and hypertension are more common in subjects with diabetes mellitus (DM type 2. Objective. To evaluate the oxidative stress in patients with DM type 2, particularly with LVDD and hypertension and to determine the influence of acute exercise training on the investigated parameters. Methods. To assess the oxidative stress of patients, we determined the following antioxidative parameters: triglycerides (TG, total cholesterol, low density cholesterol, OxLDL cholesterol, superoxide dismutase (SOD, glutathione peroxidase (GSH-Px, plasminogen activator-type 1 (PAI-1 which were measured at rest and immediately after the acute bout of the cardiopulmonary exercise cycle ergometer test. Results. In basal conditions, diabetic patients had a significant increase of TG (3.12±1.09 vs 1.74±0.9 mmol/l; p<0.01, OxLDL cholesterol (84.73±16.9 vs 79.00±29.26 mmol/l; p<0.05 and SOD enzyme activity (913.38±120.36 vs 877.14 ±153.18; p<0.05 compared to controls. During the acute exercise test, there were significantly greater levels of OxLDL (84.73±16.90 vs 92.33±23.29 mmol/l; p<0.05 in study patients. SOD significantly increased in both groups during exercise, in diabetic patients (913.38±120.36 vs 921.50±130.03 U/g Hb; p<0.05 and in controls (877.14±153.18 vs 895.00±193.49 U/g Hb; p<0.05. GSH-Px significantly increased only in diabetic patients after acute exercise (45.04±11.19 vs 51.81±15.07 U/g Hb; p<0.01, but not in controls. PAI significantly decreased during the exercise test only in healthy subjects (2.60±0.35 vs 2.22±0.65; p<0.05. Type 2 diabetic patients with cardiovascular complications (LVDD and hypertension had a significant

The monoterpene terpinolene from the oil of Pinus mugo L. in concert with alpha-tocopherol and beta-carotene effectively prevents oxidation of LDL.

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Grassmann, J; Hippeli, S; Spitzenberger, R; Elstner, E F

2005-06-01

Antioxidants from several nutrients, e.g. vitamin E, beta-carotene, or flavonoids, inhibit the oxidative modification of low-density lipoproteins. This protective effect could possibly retard atherogenesis and in consequence avoid coronary heart diseases. Some studies have shown a positive effect of those antioxidants on cardiovascular disease. Another class of naturally occurring antioxidants are terpenoids, which are found in essential oils. The essential oil of Pinus mugo and the contained monoterpene terpinolene effectively prevent low-density lipoprotein (LDL)-oxidation. In order to test the mechanism by which terpinolene protects LDL from oxidation, LDL from human blood plasma enriched in terpinolene was isolated. In this preparation not only the lipid part of LDL is protected against copper-induced oxidation--as proven by following the formation of conjugated dienes, but also the oxidation of the protein part is inhibited, since loss of tryptophan fluorescence is strongly delayed. This inhibition is due to a retarded oxidation of intrinsic carotenoids of LDL, and not, as in the case of some flavonoids, attributable to a protection of intrinsic alpha-tocopherol. These results are in agreement with our previous results, which showed the same effects for a monoterpene from lemon oil, i.e. gamma-terpinene.

Oxidized LDL but not total LDL is associated with HbA1c in individuals without diabetes.

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Spessatto, Débora; Brum, Liz Marina Bueno Dos Passos; Camargo, Joíza Lins

2017-08-01

This study investigates the association between HbA1c, LDL and oxi-LDL in individuals without diabetes (DM). One hundred and ninety-six individuals, without DM, were enrolled and divided into three groups according to HbA1c and fasting plasma glucose values. HbA1c, oxi-LDL, LDL, and other biochemical measurements of lipid profile were also carried out. oxi-LDL levels showed significant differences among all groups and group 3 presented higher values [34U/L (27-46); 44U/L (37-70); and 86U/L (49-136); pHbA1c showed moderate positive associations with oxi-LDL (r=0.431; pHbA1c and TC (r=0.142; p=0.048), triglycerides (r=0.155; p=0.030), LDL (r=0.148; p=0.039), non-HDL (r=0.192; p=0.007) and Apo B (r=0.171, pHbA1c and oxi-LDL, oxi-LDL/HDL and oxi-LDL/LDL ratios remained significant even after adjustment by multiple linear regression analysis for the variables alcohol consumption, use of medicine, BMI, and age. oxi-LDL levels are significantly associated with HbA1c in non-diabetic individuals. However, the levels of traditional atherogenic lipids only showed a weak association with HbA1c levels. Those at high risk of developing DM or cardiovascular disease have higher levels of oxi-LDL. These data favor to the use of HbA1c as a biomarker to identify individuals at risk of developing complications even in non-diabetic glycemic levels. Copyright © 2017 Elsevier B.V. All rights reserved.

Aerobic training suppresses exercise-induced lipid peroxidation and inflammation in overweight/obese adolescent girls.

Science.gov (United States)

Youssef, Hala; Groussard, Carole; Lemoine-Morel, Sophie; Pincemail, Joel; Jacob, Christophe; Moussa, Elie; Fazah, Abdallah; Cillard, Josiane; Pineau, Jean-Claude; Delamarche, Arlette

2015-02-01

This study aimed to determine whether aerobic training could reduce lipid peroxidation and inflammation at rest and after maximal exhaustive exercise in overweight/obese adolescent girls. Thirty-nine adolescent girls (14-19 years old) were classified as nonobese or overweight/obese and then randomly assigned to either the nontrained or trained group (12-week multivariate aerobic training program). Measurements at the beginning of the experiment and at 3 months consisted of body composition, aerobic fitness (VO2peak) and the following blood assays: pre- and postexercise lipid peroxidation (15F2a-isoprostanes [F2-Isop], lipid hydroperoxide [ROOH], oxidized LDL [ox-LDL]) and inflammation (myeloperoxidase [MPO]) markers. In the overweight/ obese group, the training program significantly increased their fat-free mass (FFM) and decreased their percentage of fat mass (%FM) and hip circumference but did not modify their VO2peak. Conversely, in the nontrained overweight/obese group, weight and %FM increased, and VO2peak decreased, during the same period. Training also prevented exercise-induced lipid peroxidation and/or inflammation in overweight/obese girls (F2-Isop, ROOH, ox-LDL, MPO). In addition, in the trained overweight/obese group, exercise-induced changes in ROOH, ox-LDL and F2-Isop were correlated with improvements in anthropometric parameters (waist-to-hip ratio, %FM and FFM). In conclusion aerobic training increased tolerance to exercise-induced oxidative stress in overweight/obese adolescent girls partly as a result of improved body composition.

Supplementation of plasma with olive oil phenols and extracts: Influence on LDL oxidation

NARCIS (Netherlands)

Leenen, R.; Roodenburg, A.J.C.; Vissers, M.N.; Schuurbiers, J.A.E.; Putte, van K.P.A.M.; Wiseman, S.A.; Put, van de F.H.M.M.

2002-01-01

Phenols present in olive oil may contribute to the health effects of the Mediterranean lifestyle. Olive oil antioxidants increase the resistance of low-density lipoproteins (LDL) against oxidation in vitro, but human intervention studies have failed to demonstrate similar consistent effects. To

Human low density lipoprotein (LDL) oxidation by metmyoglobin/H2O2: involvement of α-tocopheroxyl and phosphatidylcholine alkoxyl radicals

International Nuclear Information System (INIS)

Witting, P.K.; Willhite, C.A.; Stocker, R.; Davies, M.J.

1998-01-01

Full text: Metmyoglobin (metMb) and H 2 O 2 can oxidize low density lipoprotein (LDL) in vitro; formation of such oxidized LDL may be atherogenic. The role of α-tocopherol (α-TOH) in LDL oxidation by peroxidases, such as metMb is unclear. Herein we show that during metMb/H 2 O 2 -induced oxidation of native, α-TOH-containing, LDL, α-tocopheroxyl radical (α-TO) and hydroperoxides and hydroxides of cholesteryl esters (CE-O(O)H) and phosphatidylcholine (PC-O(O)H) accumulated concomitantly with α-TOH consumption. Accumulation of CE-O(O)H was dependent on, and correlated with, LDL's α-TOH content indicating that α-TO . acted as a chain-transfer agent and propagated LDL lipid peroxidation via tocopherol-mediated peroxidation (TMP). Further, the ratio of accumulating CE-O(O)H to PC-O(O)H remained constant in the presence α-TOH. Subsequent to α-TOH depletion, CE-O(O)H continued to accumulate, albeit at a lower rate than in the presence of α-TOH. This was accompanied by depletion of PC-OOH, a rapid increase in the CE-O(O)H/PC-O(O)H ratio, formation of lipid-derived alkoxyl radicals and phosphatidylcholine hydroxides (PC-OH), and accumulation of a second organic radical, characterized by a broad singlet EPR signal. The latter persisted for several hours at 37 deg C. We conclude that metMb/H 2 O 2 -induced peroxidation of LDL lipids is not inhibited by α-TOH and occurs initially via TMP. After α-TOH depletion, cholesteryl esters peroxidize at higher fractional rates than surface phospholipids, and this appears to be mediated via reactions involving alkoxyl radicals derived from the peroxidatic activity of metMb on PC-OO

EFFECT OF CRP ON SOME OF THE IN VITRO PHYSICOCHEMICAL PROPERTIES OF LDL

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Hashem Nayeri

2010-12-01

Full Text Available Abstract    BACKGROUND: Atherosclerosis is the most important underlying cause of cardiovascular diseases (CVD which recently has been classified as an inflammatory disorder. Accumulation of large amounts of oxidized LDL in the intima during local inflammation reaction led to increase several factors such as C -reactive protein (CRP. It has also been reported that CRP is able to bind with modified forms of LDL as well as oxidized LDL. These findings suggest possible positive or negative involvement of this protein in atherogenesis. The main objective of the present study was to assess the influence of CRP on LDL oxidation and the possible physical \\changes of LDL in the presence of CRP in vitro.    METHODS: In this study, the susceptibility of purified LDL to oxidation was assayed by monitoring of formation of conjugated dienes in different physiological concentrations of CRP (0 - 0.5 -2  µg/ml using a shimadzu spectrophotometer. Electrophoresis was used to determine the electrophoretic mobility of LDL in those conditions.    RESULTS: CRP significantly reduced the susceptibility of Cu++ -induced LDL oxidation through increasing the lag timeand there was positive relationship between these findings and CRP concentration (P < 0.05. CRP caused a significant reduction in the electrophotretic mobility of LDL compared to native LDL (n-LDL (P<0.05.     CONCLUSION: A considerable reduction was shown in LDL oxidation, in higher concentration of CRP, via an unknown mechanism. The electrophoretic mobility of LDL, in the oxidative condition, decreases in the presence of CRP compared to n-LDL, which can be indicative of the effect of this protein on the physical and chemical properties of LDL. It seems that, other pathway than LDL oxidation is responsible for the effect of CRP on the atherogenesis processes.      Keywords: Atherosclerosis, Creactive protein, Low-density lipoprotein, Inflammation.  

Pulsatile Hyperglycaemia Induces Vascular Oxidative Stress and GLUT 1 Expression More Potently than Sustained Hyperglycaemia in Rats on High Fat Diet

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Rakipovski, Gunaj; Lykkesfeldt, Jens; Raun, Kirsten

2016-01-01

expression of glucose transporter 1 (GLUT1), gp-91(PHOX) and super oxide dismutase (SOD), while only the PLG group showed increased accumulation of oxidative stress and oxidised low density lipoprotein (oxLDL) in aorta. Conclusion Pulsatile hyperglycaemia induced relatively higher levels of oxidative stress......Introduction Pulsatile hyperglycaemia resulting in oxidative stress may play an important role in the development of macrovascular complications. We investigated the effects of sustained vs. pulsatile hyperglycaemia in insulin resistant rats on markers of oxidative stress, enzyme expression...... and glucose metabolism in liver and aorta. We hypothesized that liver's ability to regulate the glucose homeostasis under varying states of hyperglycaemia may indirectly affect oxidative stress status in aorta despite the amount of glucose challenged with. Methods Animals were infused with sustained high (SHG...

The effect of ingestion of egg and low density lipoprotein (LDL oxidation on serum lipid profiles in hypercholesterolemic women

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Taweesak Techakriengkrai1

2012-04-01

Full Text Available Egg is a major source of dietary cholesterol. The serum lipid response to egg shows marked individual variation, beingpartly genetically determined, and influence by ethnic groups and the overall diet response. In the present investigation, weinvestigated the effect of ingestion of egg and low density lipoprotein (LDL oxidation on serum lipid profile in hypercholesterolemicwomen. Forty hypercholesterolemic women volunteers on a cholesterol-lowering diet (CLD divided into 2 groups ina randomized controlled cross-over study of one egg per day (CLD + 1 egg for 4-week and three eggs per day (CLD + 3 eggsfor 4-week, separated by 4-week period egg-free. The body weight, blood pressure, serum lipid profiles and LDL oxidationwere measured at 4-week intervals. Cholesterol-lowering diet was applied throughout the study by a dietitian using a foodexchange program and 3-day dietary recall every 4 weeks. Compared to the values obtained at baseline, the mean serum totalcholesterol and LDL cholesterol of CLD + 3 eggs was not significantly different from baseline whereas of those of 4-week ofegg-free period and CLD + 1 egg were significantly decreased (238.3±2.9 mg/dL and 228.3±4.7 mg/dL compared to thebaseline (252.2±5.9 mg/dL as was LDL cholesterol (161.2±3.0 mg/dL and 155.7±4.8 mg/dL compared to the baseline (177.5±6.0 mg/dL (p<0.05. The study showed there were no significantly difference the body weight, blood pressure, HDL cholesterol,triglycerides or LDL oxidation during the study. However, serum total cholesterol and LDL cholesterol of 1 or 3 eggsper day after 4-week of egg consumption was not significantly higher than the egg-free period. The study suggests that inhypercholesterolemic women who are on cholesterol-lowering diet, consuming one or three eggs per day did not raise serumcholesterol or LDL cholesterol levels at 4 weeks or result in any change in LDL oxidation.

Relationship among IL-6, LDL cholesterol and lipid peroxidation.

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Lubrano, Valter; Gabriele, Morena; Puntoni, Maria Rita; Longo, Vincenzo; Pucci, Laura

2015-06-01

Previous studies evidenced a significant reduction in serum cholesterol levels during an episode of acute inflammation. The aim of the present study was to verify the hypothesis of a regulatory role of cytokines through an in vitro model that simulates a situation of vascular inflammation and high levels of LDL or lipoperoxides. Human microvascular endothelial cells-1 were used in all experiments. The cells were exposed for 24 h to increasing doses of LDL, oxidized lipoprotein, and 8-isoprostane (in the absence or presence of SQ29.548, a TXA2 receptor antagonist). Moreover, LDL receptor and oxidized lipoprotein receptor expression analyzed after endothelial cells' incubation with increasing doses of interleukin-6. The ELISA test and quantitative real-time PCR were performed. Endothelial cells showed a significant increase in interleukin-6 medium levels associated with LDL, oxidized LDL and with the degree of oxidation (absence or presence of SQ29.548), while 8-isoprostane did not. Treatment of human microvascular endothelial cells-1 for 24 h with increasing doses of interleukin-6 significantly enhanced LDL receptor and oxidized lipoprotein receptor-1 mRNA expression. Our data suggest the presence of a compensatory mechanism. The induction of a significant increase of IL-6 does not seem to be caused by the presence of the biological activity of 8-isoprostane.

Mitofusin2 decreases intracellular cholesterol of oxidized LDL-induced foam cells from rat vascular smooth muscle cells.

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He, Chao; Chen, Ying; Liu, Chun; Cao, Ming; Fan, Yu-jin; Guo, Xiao-mei

2013-04-01

Mitofusin2 (Mfn2) plays a pivotal role in the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the effects of Mfn2 on the trafficking of intracellular cholesterol in the foam cells derived from rat VSMCs (rVSMCs) and also to investigate the effects of Mfn2 on the expression of adenosine triphosphate-binding cassette subfamily A member 1 (ABCA1), adenosine triphosphate-binding cassette subfamily G member 1 (ABCG1) and peroxisome proliferator-activated receptor gamma (PPARγ). The rVSMCs were co-cultured with oxidized low density lipoprotein (LDL, 80 μg/mL) to produce foam cells and cholesterol accumulation in cells. Before oxidized LDL treatment, different titers (20, 40 and 60 pfu/cell) of recombinant adenovirus containing Mfn2 gene (Adv-Mfn2) were added into the culture medium for 24 h to transfect the Mfn2 gene into the rVSMCs. Then the cells were harvested for analyses. The protein expression of Mfn2 was significantly higher in Adv-Mfn2-transfected group than in untransfected group (PLDL treatment, rVSMCs became irregular and their nuclei became larger, and their plasma abounded with red lipid droplets. However, the number of red lipid droplets was significantly decreased in Adv-Mfn2-transfected group as compared with untransfected group. At 48 h after oxidized LDL treatment, the intracellular cholesterol in rVSMCs was significantly increased (P0.05), the phosporylation levels of PPARγ were significantly decreased in Adv-Mfn2-transfected group as compared with untransfected group (Pcholesterol in oxidized LDL-induced rVSMCs possibly by decreasing PPARγ phosporylation and then increasing protein expression levels of ABCA1 and ABCG1, which may be helpful to suppress the formation of foam cells.

SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox-LDL condition.

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He, Jiangping; Zhang, Guangya; Pang, Qi; Yu, Cong; Xiong, Jie; Zhu, Jing; Chen, Fengling

2017-05-01

SIRT6 is a pivotal regulator of lipid metabolism. It is also closely connected to cardiovascular diseases, which are the main cause of death in diabetic patients. We observed a decrease in the expression of SIRT6 and key autophagy effectors (ATG5, LC3B, and LAMP1) in ox-LDL-induced foam cells, a special form of lipid-laden macrophages. In these cells, SIRT6 WT but not SIRT6 H133Y overexpression markedly reduced foam cell formation, as shown by Oil Red O staining, while inducing autophagy flux, as determined by both mRFP-GFP-LC3 labeling and transmission electron microscopy. Silencing the key autophagy initiation gene ATG5, reversed the autophagy-promoting effect of SIRT6 in ox-LDL-treated THP1 cells, as evidenced by an increase in foam cells. Cholesterol efflux assays indicated that SIRT6 overexpression in foam cells promoted cholesterol efflux, increased the levels of ABCA1 and ABCG1, and reduced miR-33 levels. By transfecting miR-33 into cells overexpressing SIRT6, we observed that reduced foam cell formation and autophagy flux induction were largely reversed. These data imply that SIRT6 plays an essential role in protecting against atherosclerosis by reducing foam cell formation through an autophagy-dependent pathway. © 2017 Federation of European Biochemical Societies.

Effects of biomarkers of oxidative stress damage on prevalence and severity of visual disability among black Central Africans.

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Longo-Mbenza, B; Muaka, M Mvitu; Yokobo, E Cibanda; Phemba, I Longo; Mokondjimobe, E; Gombet, T; Ndembe, D Kibokela; Mona, D Tulomba; Masamba, S Wayiza

2012-01-01

Because of the demographic transition, lifestyle changes, urbanization, and nutrition transition, Central Africans are at higher risk of ocular diseases associated with oxidative stress and visual disability. This study aimed to estimate the normal values of oxidant status defined by oxidized low-density lipoprotein (Ox-LDL), 8-Isoprostane and 8-hydroxy-deoxyguanosine (8-OHdG) and to determine their pathogenic role in the prevalence and the severity of visual disability among these black Africans. This was a cross-sectional study, run in a case-control study randomly selected from Kinshasa province, DR Congo. The study included 150 type 2 diabetes mellitus (T2DM) patients (cases) matched for sex and age to 50 healthy non diabetic controls. Logistic regression models were used to identify independent determinants of visual disability. The presence rates were 8.5% for blindness, 20.5% for visual impairment and 29% for visual disability including blindness and visual impairment. After adjusted for taro leaves intake, red beans intake, T2DM, aging, waist circumference, and systolic blood pressure, we identified low education level (OR=3.3 95%CI 1.5-7.2; p=0.003), rural-urban migration (OR=2.6 95% CI 1.2-5.6; p=0.017), and high Ox-LDL (OR=2.3 95% CI 1.1-4.7; p=0.029) as the important independent determinants of visual disability. After adjusted for education, intake of red beans, intake of taro leaves, triglycerides, and T2DM, we identified no intake of safou fruit (OR=50.7 95% CI 15.2-168.5; pvisual disability. After adjusted for education level, no intake of red beans, no intake of Taro leaves, triglycerides, and T2DM, we identified no intake of Safou fruit (OR=43.1 95% CI 13.7-135.4; pvisual disability. Visual disability remains a public health problem in Central Africa. Antioxidant supplement, fruit intake, nutrition education, control of migration, and blocking of oxidative stress are crucial steps for delayed development of vision loss.

In Vitro experimental model of trained innate immunity in human primary monocytes

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Bekkering, S.; Blok, B. A.; Joosten, Leo A B

2016-01-01

experimental protocol of monocyte training using three of the most commonly used training stimuli from the literature: β-glucan, the bacillus Calmette-Guérin (BCG) vaccine, and oxidized low-density lipoprotein (ox-LDL). We investigated and optimized a protocol of monocyte trained immunity induced by an initial....... All Rights Reserved....

Relation of Biochemical Parameters with Flow-mediated Dilatation in Patients with Metabolic Syndrome

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Nurver Turfaner Sipahioglu

2017-01-01

Conclusions: Increased ox-LDL, hs-CRP, and e-NOS are likely to be a result of oxidative stress, a condition in which an imbalance occurs between the production and inactivation of reactive nitrogen and oxygen species. In addition, in patients with MetS, smoking is independently related to endothelial dysfunction.

Oxidised LDL levels decreases after the consumption of ready-to-eat meals supplemented with cocoa extract within a hypocaloric diet.

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Ibero-Baraibar, I; Abete, I; Navas-Carretero, S; Massis-Zaid, A; Martinez, J A; Zulet, M A

2014-04-01

Cocoa flavanols are recognised by their favourable antioxidant and vascular effects. This study investigates the influence on health of the daily consumption of ready-to-eat meals supplemented with cocoa extract within a hypocaloric diet, on middle-aged overweight/obese subjects. Fifty healthy male and female middle-aged volunteers [57.26 ± 5.24 years and body mass index (BMI) 30.59 ± 2.33 kg/m(2)] were recruited to participate in a 4 week randomised, parallel and double-blind study. After following 3 days on a low-polyphenol diet, 25 volunteers received meals supplemented with 1.4 g of cocoa extract (645.3 mg of polyphenols) and the other 25 participants received control meals, within a 15% energy restriction diet. On the 4th week of intervention individuals in both dietary groups improved (p hypocaloric diet improved oxidative status (oxLDL) in middle-aged subjects, being most remarkable in males. Registered at www.clinicaltrials.gov (NCT01596309). Copyright © 2013 Elsevier B.V. All rights reserved.

Vitamin C and fibre consumption from fruits and vegetables improves oxidative stress markers in healthy young adults.

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Hermsdorff, Helen Hermana M; Barbosa, Kiriaque B F; Volp, Ana Carolina P; Puchau, Blanca; Bressan, Josefina; Zulet, M Ángeles; Martínez, J Alfredo

2012-04-01

The aim of the present cross-sectional study was to assess the potential relationships between fruit and vegetable (FV) consumption and some oxidative stress markers in young adults, with particular emphasis on fibre and vitamin C intake. The study enrolled 246 healthy subjects (eighty-eight men and 158 women), with a mean age of 22 (sd 3) years and a mean BMI of 21·9 (sd 2·8) kg/m2. Dietary intake, anthropometry, blood pressure, lifestyle features and blood biochemical data were assessed with validated procedures. Those subjects in the highest tertile (T) of FV consumption ( ≥ 705 g/d) had statistically lower oxidised LDL (ox-LDL) concentrations as well as higher plasma total antioxidant capacity (TAC) and glutathione peroxidase (GPx) activity (P for trend well as increased TAC and GPx activity in healthy young adults, with dietary fibre and vitamin C from FV clearly being implicated in this beneficial relationship.

Role of Rab5 in the formation of macrophage-derived foam cell.

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Chan, Lokwern; Hong, Jin; Pan, Junjie; Li, Jian; Wen, Zhichao; Shi, Haiming; Ding, Jianping; Luo, Xinping

2017-09-12

Foam cells play a key role in the occurrence and pathogenesis of atherosclerosis. Its formation starts with the ingestion of oxidized low-density lipoprotein (oxLDL). The process is associated with Ras related protein in brain 5 (Rab5) which plays a critical role in regulating endocytosis and early endosomal trafficking. Base on this, we presumed that Rab5 might participate in the maturation of foam cell. The aim of this study is to investigate the effect of Rab5 on macrophage cholesterol during the evolvement of macrophage when induced by oxLDL to the formation of foam cell. Immunohistochemistry was performed to analyze the distribution of macrophages and Rab5 in atherosclerotic plaque. RNA inteference study and transfection of inactive mutant (GFP-Rab5-S34N) and active mutant (GFP-Rab5-Q79L) in U937-derived macrophage were utilized to investigate the impact of Rab5 on the process of macrophage cholesterol, which could be detected by oil red O staining, determination of intracellular lipid content, filipin staining, nile red staining and the costaining of early endosome antigen-1 (EEA-1) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylin dicarbocyanine (Dil)-labelled oxLDL (Dil-oxLDL). Rab5 was found abundantly localized in macrophage rich areas of human atherosclerotic lesions. On the foam cell study, the expression of Rab5 was increased after the incubation of oxLDL. The inteference study indicated the depletion of Rab5 led to the decreases of oil red O staining areas, total cholesterol and cholesterol esters in U937-derived marophages. Moreover, the fluorescence intensity of filipin and nile red staining were lower in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. The confocal study demonstrated less Dil-oxLDL was internalized in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L; the result showed also the decrease in colocalization of internalized Dil-oxLDL and EEA-1 for GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. Rab5 plays an important role in modulating the

CD14 is a key mediator of both lysophosphatidic acid and lipopolysaccharide induction of foam cell formation.

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An, Dong; Hao, Feng; Zhang, Fuqiang; Kong, Wei; Chun, Jerold; Xu, Xuemin; Cui, Mei-Zhen

2017-09-01

Macrophage uptake of oxidized low-density lipoprotein (oxLDL) plays an important role in foam cell formation and the pathogenesis of atherosclerosis. We report here that lysophosphatidic acid (LPA) enhances lipopolysaccharide (LPS)-induced oxLDL uptake in macrophages. Our data revealed that both LPA and LPS highly induce the CD14 expression at messenger RNA and protein levels in macrophages. The role of CD14, one component of the LPS receptor cluster, in LPA-induced biological functions has been unknown. We took several steps to examine the role of CD14 in LPA signaling pathways. Knockdown of CD14 expression nearly completely blocked LPA/LPS-induced oxLDL uptake in macrophages, demonstrating for the first time that CD14 is a key mediator responsible for both LPA- and LPS-induced oxLDL uptake/foam cell formation. To determine the molecular mechanism mediating CD14 function, we demonstrated that both LPA and LPS significantly induce the expression of scavenger receptor class A type I (SR-AI), which has been implicated in lipid uptake process, and depletion of CD14 levels blocked LPA/LPS-induced SR-AI expression. We further showed that the SR-AI-specific antibody, which quenches SR-AI function, blocked LPA- and LPS-induced foam cell formation. Thus, SR-AI is the downstream mediator of CD14 in regulating LPA-, LPS-, and LPA/LPS-induced foam cell formation. Taken together, our results provide the first experimental evidence that CD14 is a novel connecting molecule linking both LPA and LPS pathways and is a key mediator responsible for LPA/LPS-induced foam cell formation. The LPA/LPS-CD14-SR-AI nexus might be the new convergent pathway, contributing to the worsening of atherosclerosis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The inhibition of macrophage foam cell formation by tetrahydroxystilbene glucoside is driven by suppressing vimentin cytoskeleton.

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Yao, Wenjuan; Huang, Lei; Sun, Qinju; Yang, Lifeng; Tang, Lian; Meng, Guoliang; Xu, Xiaole; Zhang, Wei

2016-10-01

Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Changes in LDL fatty acid composition as a response to olive oil treatment are inversely related to lipid oxidative damage: The EUROLIVE study

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Cicero, Arrigo F G; Nascetti, Simona; López-Sabater, Maria C

2008-01-01

The aim of our study was to assess the changes in the fatty acid composition of low density lipoproteins (LDL) after sustained consumption of olive oil at real-life doses (25 mL/day) and their relationship with lipid oxidative damage.......The aim of our study was to assess the changes in the fatty acid composition of low density lipoproteins (LDL) after sustained consumption of olive oil at real-life doses (25 mL/day) and their relationship with lipid oxidative damage....

Argan Oil Exerts an Antiatherogenic Effect by Improving Lipids and Susceptibility of LDL to Oxidation in Type 2 Diabetes Patients

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M. M. Ould Mohamedou

2011-01-01

Full Text Available In this study, we investigate the effect of argan oil consumption on serum lipids, apolipoproteins (AI and B, CRP, and LDL susceptibility to oxidation in type 2 diabetic patients which are known to have a high level of cardiovascular risk due to lipid abnormalities and lipid peroxidation. For that, 86 type 2 diabetic patients with dyslipidemia were randomized to one group consuming 25 mL/day of argan oil during 3 weeks and control group consuming 20 g/day of butter in breakfast. After argan oil intervention, serum triglycerides decreased by 11.84%, (P=0.001, total chol by 9.13%, (P=0.01, and LDL-chol by 11.81%, (P=0.02. However, HDL-chol and Apo AI increased (10.51%, P=0.01 and 9.40%,  P=0.045, resp.. Susceptibility of LDL to lipid peroxidation was significantly reduced by increasing of 20.95%, (P=0.038 in lag phase after argan oil consumption. In conclusion, we show for the first time that consumption of argan oil may have an antiatherogenic effect by improving lipids, and the susceptibility of LDL to oxidation in type 2 diabetes patients with dyslipidemia, and can therefore be recommended in the nutritional management of type 2 diabetes.

Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.

Science.gov (United States)

Toma, Laura; Sanda, Gabriela M; Niculescu, Loredan S; Deleanu, Mariana; Stancu, Camelia S; Sima, Anca V

2017-09-10

Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL). Levels of the receptor for advanced glycation end-products (RAGE), inflammatory stress markers (C reactive protein, CRP; vascular cell adhesion molecule-1, VCAM-1; monocyte chemoattractant protein-1, MCP-1), and oxidative stress and endoplasmic reticulum stress (ERS) markers were evaluated in gLDL-exposed HEC, in the presence/absence of CAF. RAGE silencing or blocking, specific inhibitors for oxidative stress (apocynin, N-acetyl-cysteine), and ERS (salubrinal) were used. The results showed that: (i) gLDL induced CRP synthesis and secretion through mechanisms involving NADPH oxidase-dependent oxidative stress and ERS in HEC; (ii) gLDL-RAGE interaction, oxidative stress, and ERS stimulated the secretion of VCAM-1 and MCP-1 in HEC; and (iii) CAF reduced the secretion of CRP, VCAM-1, and MCP-1 in gLDL-exposed HEC by inhibiting RAGE expression, oxidative stress, and ERS. In conclusion, CAF might be a promising alternative to ameliorate a wide spectrum of disorders due to its complex mechanisms of action resulting in anti-inflammatory and antioxidative properties. © 2017 BioFactors, 43(5):685-697, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Association of postalimentary lipemia with atherosclerotic manifestations

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Tentor, J. [Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP (Brazil); Nakamura, R.T. [Laboratório de Diagnóstico por Imagem, Campinas, SP (Brazil); Departamento de Radiologia, Universidade Estadual de Campinas, Campinas, SP (Brazil); Gidlund, M. [Laboratório de Imunofisiopatologia, Instituto de Ciências Biológicas, Universidade de São Paulo, São Paulo, SP (Brazil); Barros-Mazon, S. [Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP (Brazil); Harada, L.M. [Laboratório de Lípides, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Zago, V.S.; Oba, J.F.; Faria, E.C. de [Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP (Brazil)

2012-08-10

We identified different lipemic and metabolic responses after the ingestion of a standardized meal by healthy adults and related them to atherosclerotic markers. Samples from 60 normolipidemic adults were collected before and after a liquid meal (40 g fat/m{sup 2} body surface) at 0, 2, 4, 6, and 8 h for measurements of lipids, free fatty acids (FFA), insulin, cholesteryl ester transfer protein (CETP), autoantibodies to epitopes of oxidized LDL (oxLDL Ab), lipolytic activities, and apolipoprotein E polymorphism. Mean carotid intima-media thickness (cIMT) was determined by Doppler ultrasound. The volunteers were classified into early (N = 39) and late (N = 31) triacylglycerol (TAG) responders to the test meal. Late responders showed lower HDL cholesterol concentration at fasting and in the TAG peak, lower insulin and higher FFA concentrations compared to early responders. Multivariate regression analyses showed that mean cIMT was associated with gender (male) and age in early responders and by cholesterol levels at the 6th hour in late responders. oxLDL Ab were explained by lipoprotein lipase and negatively by hepatic lipase and oxLDL Ab (fasting period) by CETP (negative) and FFA (positive). This study is the first to identify a postalimentary insulin resistance state, combined with a reduced CETP response exclusively among late responders, and the identification of the regulators of postalimentary atherogenicity. Further research is required to determine the metabolic mechanisms described in the different postalimentary phenotypes observed in this study, as well as in different pathological states, as currently investigated in our laboratory.

Association of postalimentary lipemia with atherosclerotic manifestations

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J. Tentor

2012-11-01

Full Text Available We identified different lipemic and metabolic responses after the ingestion of a standardized meal by healthy adults and related them to atherosclerotic markers. Samples from 60 normolipidemic adults were collected before and after a liquid meal (40 g fat/m² body surface at 0, 2, 4, 6, and 8 h for measurements of lipids, free fatty acids (FFA, insulin, cholesteryl ester transfer protein (CETP, autoantibodies to epitopes of oxidized LDL (oxLDL Ab, lipolytic activities, and apolipoprotein E polymorphism. Mean carotid intima-media thickness (cIMT was determined by Doppler ultrasound. The volunteers were classified into early (N = 39 and late (N = 31 triacylglycerol (TAG responders to the test meal. Late responders showed lower HDL cholesterol concentration at fasting and in the TAG peak, lower insulin and higher FFA concentrations compared to early responders. Multivariate regression analyses showed that mean cIMT was associated with gender (male and age in early responders and by cholesterol levels at the 6th hour in late responders. oxLDL Ab were explained by lipoprotein lipase and negatively by hepatic lipase and oxLDL Ab (fasting period by CETP (negative and FFA (positive. This study is the first to identify a postalimentary insulin resistance state, combined with a reduced CETP response exclusively among late responders, and the identification of the regulators of postalimentary atherogenicity. Further research is required to determine the metabolic mechanisms described in the different postalimentary phenotypes observed in this study, as well as in different pathological states, as currently investigated in our laboratory.

Association of postalimentary lipemia with atherosclerotic manifestations

International Nuclear Information System (INIS)

Tentor, J.; Nakamura, R.T.; Gidlund, M.; Barros-Mazon, S.; Harada, L.M.; Zago, V.S.; Oba, J.F.; Faria, E.C. de

2012-01-01

We identified different lipemic and metabolic responses after the ingestion of a standardized meal by healthy adults and related them to atherosclerotic markers. Samples from 60 normolipidemic adults were collected before and after a liquid meal (40 g fat/m 2 body surface) at 0, 2, 4, 6, and 8 h for measurements of lipids, free fatty acids (FFA), insulin, cholesteryl ester transfer protein (CETP), autoantibodies to epitopes of oxidized LDL (oxLDL Ab), lipolytic activities, and apolipoprotein E polymorphism. Mean carotid intima-media thickness (cIMT) was determined by Doppler ultrasound. The volunteers were classified into early (N = 39) and late (N = 31) triacylglycerol (TAG) responders to the test meal. Late responders showed lower HDL cholesterol concentration at fasting and in the TAG peak, lower insulin and higher FFA concentrations compared to early responders. Multivariate regression analyses showed that mean cIMT was associated with gender (male) and age in early responders and by cholesterol levels at the 6th hour in late responders. oxLDL Ab were explained by lipoprotein lipase and negatively by hepatic lipase and oxLDL Ab (fasting period) by CETP (negative) and FFA (positive). This study is the first to identify a postalimentary insulin resistance state, combined with a reduced CETP response exclusively among late responders, and the identification of the regulators of postalimentary atherogenicity. Further research is required to determine the metabolic mechanisms described in the different postalimentary phenotypes observed in this study, as well as in different pathological states, as currently investigated in our laboratory

Association of postalimentary lipemia with atherosclerotic manifestations.

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Tentor, J; Nakamura, R T; Gidlund, M; Barros-Mazon, S; Harada, L M; Zago, V S; Oba, J F; Faria, E C de

2012-11-01

We identified different lipemic and metabolic responses after the ingestion of a standardized meal by healthy adults and related them to atherosclerotic markers. Samples from 60 normolipidemic adults were collected before and after a liquid meal (40 g fat/m² body surface) at 0, 2, 4, 6, and 8 h for measurements of lipids, free fatty acids (FFA), insulin, cholesteryl ester transfer protein (CETP), autoantibodies to epitopes of oxidized LDL (oxLDL Ab), lipolytic activities, and apolipoprotein E polymorphism. Mean carotid intima-media thickness (cIMT) was determined by Doppler ultrasound. The volunteers were classified into early (N = 39) and late (N = 31) triacylglycerol (TAG) responders to the test meal. Late responders showed lower HDL cholesterol concentration at fasting and in the TAG peak, lower insulin and higher FFA concentrations compared to early responders. Multivariate regression analyses showed that mean cIMT was associated with gender (male) and age in early responders and by cholesterol levels at the 6th hour in late responders. oxLDL Ab were explained by lipoprotein lipase and negatively by hepatic lipase and oxLDL Ab (fasting period) by CETP (negative) and FFA (positive). This study is the first to identify a postalimentary insulin resistance state, combined with a reduced CETP response exclusively among late responders, and the identification of the regulators of postalimentary atherogenicity. Further research is required to determine the metabolic mechanisms described in the different postalimentary phenotypes observed in this study, as well as in different pathological states, as currently investigated in our laboratory.

Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men

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A. Zembron-Lacny

2016-01-01

Full Text Available Regular exercise plays an important preventive and therapeutic role in heart and vascular diseases, and beneficially affects brain function. In blood, the effects of exercise appear to be very complex and could include protection of vascular endothelial cells via neurotrophic factors and decreased oxidative stress. The purpose of this study was to identify the age-related changes in peripheral brain-derived neurotrophic factor (BDNF and its relationship to oxidative damage and conventional cardiovascular disease (CVD biomarkers, such as atherogenic index, C-reactive protein (hsCRP and oxidized LDL (oxLDL, in active and inactive men. Seventeen elderly males (61-80 years and 17 young males (20-24 years participated in this study. According to the 6-min Åstrand-Rhyming bike test, the subjects were classified into active and inactive groups. The young and elderly active men had a significantly better lipoprotein profile and antioxidant status, as well as reduced oxidative damage and inflammatory state. The active young and elderly men had significantly higher plasma BDNF levels compared to their inactive peers. BDNF was correlated with VO2max (r=0.765, P<0.001. In addition, we observed a significant inverse correlation of BDNF with atherogenic index (TC/HDL, hsCRP and oxLDL. The findings demonstrate that a high level of cardiorespiratory fitness reflected in VO2max was associated with a higher level of circulating BDNF, which in turn was related to common CVD risk factors and oxidative damage markers in young and elderly men.

Lipid Biomarkers for Risk Assessment in Acute Coronary Syndromes.

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Meeusen, Jeffrey W; Donato, Leslie J; Jaffe, Allan S

2017-06-01

The objective of this review was to summarize evidence gathered for the prognostic value of routine and novel blood lipids and lipoproteins measured in patients with acute coronary syndromes (ACS). Data supports clear association with risk and actionable value for non-high-density lipoprotein (Non-HDL) cholesterol and plasma ceramides in a setting of ACS. The prognostic value and clinical actionability of apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)] in ACS have not been thoroughly tested, while the data for omega-3 fatty acids and oxidized low-density lipoprotein (Ox-LDL) are either untested or more varied. Measuring basic lipids, which should include Non-HDL cholesterol, at the time of presentation for ACS is guideline mandated. Plasma ceramides also provide useful information to guide both treatment decisions and follow-up. Additional studies targeting ACS patients are necessary for apoB, Lp(a), omega-3 fatty acids, and Ox-LDL.

Oxidative profiles of LDL and HDL isolated from women with preeclampsia.

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León-Reyes, G; Maida-Claros, R F; Urrutia-Medina, A X; Jorge-Galarza, E; Guzmán-Grenfell, A M; Fuentes-García, S; Medina-Navarro, R; Moreno-Eutimio, M A; Muñoz-Sánchez, J L; Hicks, J J; Torres-Ramos, Y D

2017-05-16

Oxidative stress causes biochemical changes in lipids and proteins; these changes can induce damage to the vascular endothelium and create maternal complications that are characteristic of preeclampsia. In this study, we evaluated the oxidative profile of lipoproteins isolated from women with preeclampsia. Thirty women diagnosed with preeclampsia and thirty women without preeclampsia were included in the study. Lipid-damage biomarkers, including conjugated dienes, lipohydroperoxides and malondialdehyde, were measured. The reduction of nitroblue tetrazolium, the formation of dityrosines, and the carbonylation of proteins were assessed as indicators of protein damage. The protective activity of HDL-c was evaluated by the paraoxonase-I activity present on the HDL-c particles. Serum lipid profiles were also quantified in both groups. Data were analysed using Student's t test and the Pearson correlation coefficient. Our results demonstrated in PE women evident oxidative changes in the lipids and proteins in HDL-c and LDL-c particles and the activity of the antioxidant enzyme PON-I decreased 59.9%. HDL-c exhibited self-defence, as demonstrated by the negative correlation between paraoxonase-I activity and the formation of lipohydroperoxides in HDL-c (r = -0.3755, p preeclampsia show oxidative damage to lipids and proteins. We propose an oxidative profile based on the oxidation levels indicated by each of the markers used. We also found that paraoxonase-I is inactivated in the presence of lipohydroperoxides. Antioxidant support might be helpful to reduce oxidative stress in patients with preeclampsia. Further investigations are necessary to define the association between antioxidant activities and preeclampsia.

Inhibitory effect on in vitro LDL oxidation and HMG Co-A reductase activity of the liquid-liquid partitioned fractions of Hericium erinaceus (Bull.) Persoon (lion's mane mushroom).

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Rahman, Mohammad Azizur; Abdullah, Noorlidah; Aminudin, Norhaniza

2014-01-01

Oxidation of low-density lipoprotein (LDL) has been strongly suggested as the key factor in the pathogenesis of atherosclerosis. Mushrooms have been implicated in having preventive effects against chronic diseases due especially to their antioxidant properties. In this study, in vitro inhibitory effect of Hericium erinaceus on LDL oxidation and the activity of the cholesterol biosynthetic key enzyme, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG Co-A) reductase, was evaluated using five liquid-liquid solvent fractions consisting of methanol : dichloromethane (M : DCM), hexane (HEX), dichloromethane (DCM), ethyl acetate (EA), and aqueous residue (AQ). The hexane fraction showed the highest inhibition of oxidation of human LDL as reflected by the increased lag time (100 mins) for the formation of conjugated diene (CD) at 1 µg/mL and decreased production (68.28%, IC50 0.73 mg/mL) of thiobarbituric acid reactive substances (TBARS) at 1 mg/mL. It also mostly inhibited (59.91%) the activity of the HMG Co-A reductase at 10 mg/mL. The GC-MS profiling of the hexane fraction identified the presence of myconutrients: inter alia, ergosterol and linoleic acid. Thus, hexane fraction of Hericium erinaceus was found to be the most potent in vitro inhibitor of both LDL oxidation and HMG Co-A reductase activity having therapeutic potential for the prevention of oxidative stress-mediated vascular diseases.

Direct effects of fatty meals and adiposity on oxidised low-density lipoprotein.

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Laguna-Camacho, Antonio; Alonso-Barreto, Arely S; Mendieta-Zerón, Hugo

2015-01-01

High-fat intake and high adiposity contribute to hyperlipaemia. In a hyperlipaemic state, lipoproteins infiltrate arterial wall where they are modified and cause an immune response characteristic of atherosclerosis. A small fraction of modified lipoproteins including oxidised low-density lipoprotein (ox-LDL) returns to circulation. The present study tracked high-fat meals during four weeks as to find effects of sustained frequency change on adiposity and ox-LDL. The findings indicated that changes in frequency of consumption of high-fat eating episodes correlated directly with changes in adiposity and ox-LDL. Hence the number of fatty meals consumed by people with overweight or obesity in few weeks could affect the atherogenic process. Copyright © 2015 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Antioxidant protection of LDL by physiological concentrations of 17 beta-estradiol. Requirement for estradiol modification.

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Shwaery, G T; Vita, J A; Keaney, J F

1997-03-18

Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17 beta-estradiol (E2) inhibit oxidative modification of LDL. Plasma incubated with E2 (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu2+ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E2 at these concentrations in buffered saline produced no effect on Cu(2+)-mediated oxidation. Incubation of plasma with E2 had no effect on LDL alpha-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [3H]E2 was associated with dose-dependent association of 3H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [3H]E2 indicated that the majority of the associated species were not detectable as authentic E2 but as nonpolar forms of E2 that were susceptible to base hydrolysis consistent with fatty acid esterification of E2. Plasma-mediated association of E2 and subsequent antioxidant protection was inhibited by 5,5'-dithiobis(2-nitrobenzoic acid), an inhibitor of plasma acyltransferase activity. Exposure of LDL to physiological levels of E2 in a plasma milieu is associated with enhanced resistance to Cu(2+)-mediated oxidation and incorporation of E2 derivatives into LDL. This antioxidant capacity may be another means by which E2 limits coronary artery disease in women.

Pemanfaatan ekstrak jintan hitam untuk menurunkan kadar enzim LPPLA2 sebagai kandidat pengobatan aterosklerosis

OpenAIRE

Retno Susilowati; Evika Sandi Savitri; Kholifah Holil

2013-01-01

Ox-LDL deposits in the sub-endothelial easily occur in individuals who have hyperlipidemia accompanied with oxidative stress. The enzyme Lp-PLA2 is an enzyme marker of three proaterogenik conditions, those are hyperlipidemia, oxidative stress and inflammation. Black cumin seeds (Nigella sativa L.) have antioxidants ingredient that can inhibit lipid peroxidation, and expected to inhibit atherosclerosis through decreased levels of the enzyme Lp-PLA2 and F2-Isp. This study used posttest only con...

Accumulation of Oxidized Low-Density Lipoprotein in Psoriatic Skin and Changes of Plasma Lipid Levels in Psoriatic Patients

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Nilgun Solak Tekin

2007-01-01

Full Text Available Background. Psoriasis is a chronic inflammatory skin disease characterized by an accelerated turnover of epidermal cells and an incomplete differentiation in epidermis with lesion. However, the exact etiology of psoriasis is unknown. Abnormalities in essential fatty acid metabolism, free radical generation, lipid peroxidation, and release of lymphokines have been proposed. Objective. Our purpose was to evaluate the plasma lipids and oxidized low-density lipoprotein accumulation in psoriatic skin lesion in order to ascertain the possible participation of oxidative stress and oxidative modification of lipids in pathogenesis of psoriasis. Methods. The study group included 84 patients with psoriasis, and 40 sex- and age-matched healthy volunteers. Blood lipid profile was determined. Psoriatic and nonlesional skin samples of psoriatic patients were evaluated for the presence of oxidized low-density lipoprotein by using an immune-fluorescent staining method. Results. The mean levels of lipids (total cholesterol, triglyceride, and LDL cholesterol in patients with psoriasis were found to be significantly higher than those of healthy subjects. Psoriatic skins were shown positive oxidized low-density lipoprotein staining. There was no staining in nonlesional skin samples of the same individuals. Conclusion. Lipid peroxidation mediated by free radicals is believed to be one of the important causes of cell membrane destruction and cell damage. This study shows for the first time the accumulation of oxidized low-density lipoprotein in psoriatic skin lesion. We believe that accumulation of ox-LDL in psoriatic skin may have an important role in the immune-inflammatory events that result in progressive skin damage.

Lectin-like oxidized low-density lipoprotein receptor-1 promotes endothelial dysfunction in LDL receptor knockout background.

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Hofmann, Anja; Brunssen, Coy; Poitz, David M; Langbein, Heike; Strasser, Ruth H; Henle, Thomas; Ravens, Ursula; Morawietz, Henning

2017-11-01

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date. Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr -/- ) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph. WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr -/- mice (Eff max : 56.7 ± 23.0%) compared to WT (Eff max : 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Eff max : 76.7 ± 12.9%, P < 0.05) and Ldlr -/- mice (Eff max : 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr -/- mice were detectable when comparing all genotypes. Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Lysophosphatidic acid directly induces macrophage-derived foam cell formation by blocking the expression of SRBI.

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Chen, Linmu; Zhang, Jun; Deng, Xiao; Liu, Yan; Yang, Xi; Wu, Qiong; Yu, Chao

2017-09-23

The leading cause of morbidity and mortality is the result of cardiovascular disease, mainly atherosclerosis. The formation of macrophage foam cells by ingesting ox-LDL and focal retention in the subendothelial space are the hallmarks of the early atherosclerotic lesion. Lysophosphatidic acid (LPA), which is a low-molecular weight lysophospholipid enriched in oxidized LDL, exerts a range of effects on the cardiovascular system. Previous reports show that LPA increases the uptake of ox-LDL to promote the formation of foam cells. However, as the most active component of ox-LDL, there is no report showing whether LPA directly affects foam cell formation. The aim of this study was to investigate the effects of LPA on foam cell formation, as well as to elucidate the underlying mechanism. Oil red O staining and a Cholesterol/cholesteryl ester quantitation assay were used to evaluate foam cell formation in Raw264.7 macrophage cells. We utilized a Western blot and RT-PCR to investigate the relationship between LPA receptors and lipid transport related proteins. We found that LPA promoted foam cell formation, using 200 μM for 24 h. Meanwhile, the expression of the Scavenger receptor BI (SRBI), which promotes the efflux of free cholesterol, was decreased. Furthermore, the LPA 1/3 receptor antagonist Ki16425 significantly abolished the LPA effects, indicating that LPA 1/3 was involved in the foam cell formation and SRBI expression induced by LPA. Additionally, the LPA-induced foam cell formation was blocked with an AKT inhibitor. Our results suggest that LPA-enhanced foam cell formation is mediated by LPA 1/3 -AKT activation and subsequent SRBI expression. Copyright © 2017. Published by Elsevier Inc.

Comparision of Inhibitory effects of Satureja Khozistanica,vitamin E and coenzyme Q10 on LDL peroxidation induced-CuSO4 in vitro

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hasan Ahmadvand

2010-02-01

Full Text Available Oxidation of low-density lipoprotein (LDL has been strongly suggested as a key factor in the pathogenesis of atherosclerosis. Thus the inclusion of some anti-oxidant compounds such as Satureja Khozistanica,vitamin E and coenzyme Q10 in daily dietary food stuff may inhibit the production of oxidized LDL and may decrease both the development and the progression of atherosclerosis. The present study investigated the inhibitory effects of Satureja Khozistanica, vitamin E and coenzyme Q10 on LDL peroxidation induced by CuSO4 quantitatively in vitro. Materials and Methods: LDL was incubated with CuSO4 and the formation of conjugated dienes and thiobarbituric acid reactive substances (TBARS of LDL were monitored as markers of LDL oxidation. Inhibition of this Cu-induced oxidation was studied in the presence of extracts of Satureja Khozistanica,vitamin E and coenzyme Q10. Results: It was demonstrated that Satureja Khozistanica like vitamin E and coenzyme Q10 is able to inhibit LDL oxidation and decrease the resistance of LDL against oxidation in vitro. Conclusion: This study showed that Satureja Khozistanica similar to vitamin E and coenzyme Q10 prevented the oxidation of LDL in vitro and it may suggest that they have the similar effect in vivo

Biomarkers of Subclinical Atherosclerosis in Patients with Autoimmune Disorders

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Elisabetta Profumo

2012-01-01

Full Text Available Atherosclerosis is accelerated in rheumatoid arthritis (RA and psoriatic arthritis (PsA. We investigated a possible association of oxidized low-density lipoproteins (ox-LDLs, nitric oxide (NO, 3-nitrotyrosine, vitamin A, vitamin E, and β-carotene serum levels with subclinical atherosclerosis in RA and PsA. By the use of ELISA, we observed higher ox-LDL levels in patients with intima-media thickness (IMT > 1 than in patients with IMT ≤ 1 and a negative correlation between NO levels and IMT values. By the use of high-performance liquid chromatography, we determined higher levels of vitamin A in patients with PsA and IMT ≤ 1 than in controls and lower levels of β-carotene in patients with RA and PsA than in controls. β-carotene concentrations were negatively correlated to the duration of disease in RA. Our study confirms that ox-LDLs and NO may be markers of accelerated atherosclerosis in RA and PsA whereas vitamins seem to be associated only to the presence of the autoimmune disorders.

Serum Lipoprotein (a Levels in Black South African Type 2 Diabetes Mellitus Patients

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Jim Joseph

2016-01-01

Full Text Available Lipoprotein (a (Lp(a which is a low-density lipoprotein-like particle containing apo(a is considered as an emergent cardiovascular risk factor. Type 2 diabetes mellitus (T2DM is associated with a two- to threefold increase in the risk of cardiovascular disease (CVD. The aim of this study was to investigate the levels of Lp(a in Black South African T2DM patients and its association with other metabolic factors. 67 T2DM patients and 48 healthy control participants were recruited for the cross-sectional study. The Lp(a level was determined by ELISA and the result was analyzed using SPSS. The Lp(a level in diabetics was found to be significantly increased (P=0.001 when compared to the normal healthy group. In the diabetic group, the Lp(a levels correlated significantly with the duration of diabetes (P=0.008 and oxidized LDL (ox-LDL levels (P=0.03 and decreased total antioxidant capacity (P=0.001. The third tertile of Lp(a was significantly correlated with increased ox-LDL, C-reactive protein, and triglycerides and decreased total antioxidant capacity.

Sida rhomboidea.Roxb aqueous extract down-regulates in vivo expression of vascular cell adhesion molecules in atherogenic rats and inhibits in vitro macrophage differentiation and foam cell formation.

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Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Salunke, Sunita P; Devkar, Ranjitsinh V; Ramachandran, A V

2012-10-01

The present study evaluates efficacy of Sida rhomboidea.Roxb (SR) leaves extract in ameliorating experimental atherosclerosis using in vitro and in vivo experimental models. Atherogenic (ATH) diet fed rats recorded significant increment in the serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), very LDL (VLDL), autoantibody against oxidized LDL (Ox-LDL), markers of LDL oxidation and decrement in high-density lipoprotein (HDL) along with increment in aortic TC and TG. The ex vivo LDL oxidation assay revealed an increased susceptibility of LDL isolated from ATH rats to undergo copper mediated oxidation. These set of changes were minimized by simultaneous co-supplementation of SR extract to ATH diet fed rats. Histopathology of aorta and immunolocalization studies recorded pronounced atheromatous plaque formation, vascular calcification, significant elastin derangements and higher expression of macrophage surface marker (F4/80), vascular cell adhesion molecule-1 (VCAM-1) and p-selectin in ATH rats. Whereas, ATH+SR rats depicted minimal evidence of atheromatous plaque formation, calcium deposition, distortion/defragmentation of elastin and accumulation of macrophages along with lowered expression of VCAM-1 and P-selectin compared to ATH rats. Further, monocyte to macrophage differentiation and in vitro foam cell formation were significantly attenuated in presence of SR extract. In conclusion, SR extract has the potency of controlling experimental atherosclerosis and can be used as promising herbal supplement in combating atherosclerosis.

Acute Effects of Apple Cider Vinegar Intake on Some Biochemical Risk Factors of Atherosclerosis in Rabbits Fed with a High Cholesterol Diet

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M Setorki

2012-05-01

Full Text Available

Background and Objectives: Metabolic changes in postprandial stage, especially after consumption of high fat meal cause atherosclerosis and increase the risk of cardiovascular diseases. Apple cider vinegar is an acidic juice with useful medicinal effects. In this research; we investigated acute effects of apple cider vinegar intake on some of the biochemical atherosclerosis risk factors in high cholesterol fed rabbits.

Methods: Thirty two male New Zealand rabbits were randomly divided into four groups: normal diet group, high cholesterol diet group (%1cholesterol, %1 cholesterol with 5ml apple cider vinegar group, %1 cholesterol with 10ml apple cider vinegar group. The C-Reactive Protein (CRP, low density lipoprotein (LDL-C, high density lipoprotein (HDL-C, total cholesterol (TC, malondialdehyde (MDA, oxidized-LDL (OxLDL, serum glutamic pyruvic transaminase (SGPT, serum glutamic oxaloacetate transaminase (SGOT, nitrite, nitrate, glucose, fibrinogen triacylglycerol (TG, apolipoprotein A (ApoA1, apolipoprotein B (ApoB100 were all measured before the experiment and three hours after feeding with these treatment diets.

Results: In high cholesterol diet fibrinogen, nitrite, glucose, OxLDL, MDA and CRP showed a significant increase compared to normal diet. Significant differences were observed between both groups of apple cider vinegar by fibrinogen in comparison with hypercholesterolemic diet. Using 10ml apple cider vinegar with cholesterolemic diet caused a significant reduction in Ox-LDL, MDA and glucose in comparison with hypercholesterolemic diet. Moreover, the consumption of 5ml apple cider vinegar with cholesterolemic diet caused a significant decrease in LDL-C and TC compared to hypercholesterolemic diet. No significant difference was found between apple cider vinegar taking groups and

Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin.

Science.gov (United States)

Rodenburg, Jessica; Vissers, Maud N; Wiegman, Albert; Miller, Elizabeth R; Ridker, Paul M; Witztum, Joseph L; Kastelein, John J P; Tsimikas, Sotirios

2006-05-02

To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin. Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The significance of OxPL markers in children is unknown. Children with FH were randomized to placebo (n = 88) or pravastatin (n = 90) after instruction on American Heart Association step II diet. Unaffected siblings (n = 78) served as controls. The OxPL content on apolipoprotein B-100 (apoB) detected by antibody E06 (OxPL/apoB ratio), immunoglobulin (Ig)G and IgM immune complexes per apoB (IC/apoB) and on all apoB particles (total apoB-IC = IC/apoB multiplied by plasma apoB levels), autoantibodies to malondialdehyde (MDA)-low-density lipoprotein (LDL), Lp(a), and apoB levels were measured at baseline and after two years of treatment. Compared with unaffected siblings, children with FH had significantly lower levels of OxPL/apoB but higher levels of IgG and IgM total apoB-IC and IgM MDA-LDL autoantibodies. From baseline to two-year follow-up, compared with placebo pravastatin treatment resulted in a greater mean percentage change in apoB (-18.7% vs. 0.3%; p = 0.001), total IgG apoB-IC (-31.9% vs. -12.2%; p vs. 13.2%; p = 0.001). Interestingly, pravastatin also resulted in higher OxPL/apoB (48.7% vs. 29.3%; p = 0.028) and Lp(a) levels (21.9% vs. 10.7%; p = 0.044). Compared with unaffected siblings, children with FH are characterized by elevated levels of apoB-IC and IgM MDA-LDL autoantibodies. Compared with placebo, pravastatin led to a greater reduction in apoB-IC but also to a greater increase in OxPL/apoB and Lp(a), which may represent a novel mechanism of mobilization and clearance of OxPL.

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts

DEFF Research Database (Denmark)

Gonen, Ayelet; Hansen, Lotte; Turner, William W

2014-01-01

as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought......Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use...... responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do...

Inhibitory Effect on In Vitro LDL Oxidation and HMG Co-A Reductase Activity of the Liquid-Liquid Partitioned Fractions of Hericium erinaceus (Bull. Persoon (Lion’s Mane Mushroom

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Mohammad Azizur Rahman

2014-01-01

Full Text Available Oxidation of low-density lipoprotein (LDL has been strongly suggested as the key factor in the pathogenesis of atherosclerosis. Mushrooms have been implicated in having preventive effects against chronic diseases due especially to their antioxidant properties. In this study, in vitro inhibitory effect of Hericium erinaceus on LDL oxidation and the activity of the cholesterol biosynthetic key enzyme, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG Co-A reductase, was evaluated using five liquid-liquid solvent fractions consisting of methanol : dichloromethane (M : DCM, hexane (HEX, dichloromethane (DCM, ethyl acetate (EA, and aqueous residue (AQ. The hexane fraction showed the highest inhibition of oxidation of human LDL as reflected by the increased lag time (100 mins for the formation of conjugated diene (CD at 1 µg/mL and decreased production (68.28%, IC50 0.73 mg/mL of thiobarbituric acid reactive substances (TBARS at 1 mg/mL. It also mostly inhibited (59.91% the activity of the HMG Co-A reductase at 10 mg/mL. The GC-MS profiling of the hexane fraction identified the presence of myconutrients: inter alia, ergosterol and linoleic acid. Thus, hexane fraction of Hericium erinaceus was found to be the most potent in vitro inhibitor of both LDL oxidation and HMG Co-A reductase activity having therapeutic potential for the prevention of oxidative stress-mediated vascular diseases.

Polyphenols and Oxidative Stress in Atherosclerosis-Related Ischemic Heart Disease and Stroke

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Yu-Chen Cheng

2017-01-01

Full Text Available Good nutrition could maintain health and life. Polyphenols are common nutrient mainly derived from fruits, vegetables, tea, coffee, cocoa, mushrooms, beverages, and traditional medicinal herbs. They are potential substances against oxidative-related diseases, for example, cardiovascular disease, specifically, atherosclerosis-related ischemic heart disease and stroke, which are health and economic problems recognized worldwide. In this study, we reviewed the risk factors for atherosclerosis, including hypertension, diabetes mellitus, hyperlipidemia, obesity, and cigarette smoking as well as the antioxidative activity of polyphenols, which could prevent the pathology of atherosclerosis, including endothelial dysfunction, low-density lipoprotein oxidation, vascular smooth muscle cell proliferation, inflammatory process by monocytes, macrophages or T lymphocytes, and platelet aggregation. The strong radical-scavenging properties of polyphenols would exhibit antioxidative and anti-inflammation effects. Polyphenols reduce ROS production by inhibiting oxidases, reducing the production of superoxide, inhibiting OxLDL formation, suppressing VSMC proliferation and migration, reducing platelet aggregation, and improving mitochondrial oxidative stress. Polyphenol consumption also inhibits the development of hypertension, diabetes mellitus, hyperlipidemia, and obesity. Despite the numerous in vivo and in vitro studies, more advanced clinical trials are necessary to confirm the efficacy of polyphenols in the treatment of atherosclerosis-related vascular diseases.

Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women

NARCIS (Netherlands)

Princen, H.M.G.; Duyvenvoorde, W. van; Buytenhek, R.; Laarse, A. van der; Poppel, G. van; Gevers Leuven, J.A.; Hinsbergh, V.W.M. van

1995-01-01

There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant D,L-α-tocopherol (vitamin E),

Anti-Atherogenic Activity of Polyphenol-Rich Extract from Bee Pollen

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Anna Rzepecka-Stojko

2017-12-01

Full Text Available The aim of this study was to determine the effect of polyphenol-rich ethanol extract of bee pollen (EEP on atherosclerosis induced by a high-fat diet in ApoE-knockout mice. EEP was given with feed in two doses of 0.1 and 1 g/kg body mass (BM. The studies have been conducted in a period of 16 weeks. The following factors were estimated: total cholesterol (TC, oxidized low density lipoproteins (ox-LDL, asymmetric dimethylarginine (ADMA, angiotensin-converting enzyme (ACE and angiotensin II (ANG II in the 5th, 10th, 12th, 14th, and 16th week of the experiment. In the last, i.e., 16th week of the studies the development of coronary artery disease (CAD was also estimated histopathologically. Supplementing diet with EEP resulted in decreasing TC level. EEP reduced oxidative stress by lowering the levels of ox-LDL, ADMA, ANG II and ACE. EEP protected coronary arteries by significantly limiting the development of atherosclerosis (the dose of 0.1 g/kg BM or completely preventing its occurrence (the dose of 1 g/kg BM. The obtained results demonstrate that EEP may be useful as a potential anti-atherogenic agent.

Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection.

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Sandler, Netanya G; Zhang, Xinyan; Bosch, Ronald J; Funderburg, Nicholas T; Choi, Andrew I; Robinson, Janet K; Fine, Derek M; Coombs, Robert W; Jacobson, Jeffrey M; Landay, Alan L; Douek, Daniel C; Tressler, Randall; Read, Sarah W; Wilson, Cara C; Deeks, Steven G; Lederman, Michael M; Gandhi, Rajesh T

2014-11-15

Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. NCT 01543958. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Trp64Arg polymorphism of the ADRB3 gene associated with maximal fat oxidation and LDL-C levels in non-obese adolescents.

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Jesus, Íncare Correa de; Alle, Lupe Furtado; Munhoz, Eva Cantalejo; Silva, Larissa Rosa da; Lopes, Wendell Arthur; Tureck, Luciane Viater; Purim, Katia Sheylla Malta; Titski, Ana Claudia Kapp; Leite, Neiva

2017-09-21

To analyze the association between the Trp64Arg polymorphism of the ADRB3 gene, maximal fat oxidation rates and the lipid profile levels in non-obese adolescents. 72 schoolchildren, of both genders, aged between 11 and 17 years, participated in the study. The anthropometric and body composition variables, in addition to total cholesterol, HDL-c, LDL-c, triglycerides, insulin, and basal glycemia, were evaluated. The sample was divided into two groups according to the presence or absence of the polymorphism: non-carriers of the Arg64 allele, i.e., homozygous (Trp64Trp: n=54), and carriers of the Arg64 allele (Trp64Arg+Arg64Arg: n=18), in which the frequency of the Arg64 allele was 15.2%. The maximal oxygen uptake and peak of oxygen uptake during exercise were obtained through the symptom-limited, submaximal treadmill test. Maximal fat oxidation was determined according to the ventilatory ratio proposed in Lusk's table. Adolescents carrying the less frequent allele (Trp64Arg and Arg64Arg) had higher LDL-c levels (p=0.031) and lower maximal fat oxidation rates (p=0.038) when compared with non-carriers (Trp64Trp). Although the physiological processes related to lipolysis and lipid metabolism are complex, the presence of the Arg 64 allele was associated with lower rates of FATMAX during aerobic exercise, as well as with higher levels of LDL-c in adolescents. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Consumption of seafood and its estimated heavy metals are associated with lipid profile and oxidative lipid damage on healthy adults from a Spanish Mediterranean area: A cross-sectional study.

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Aranda, N; Valls, R M; Romeu, M; Sánchez-Martos, V; Albaladejo, R; Fernández-Castillejo, S; Nogués, R; Catalán, Ú; Pedret, A; Espinel, A; Delgado, M A; Arija, V; Sola, R; Giralt, M

2017-07-01

The association between the consumption of seafood and its benefits on cardiovascular (CVD) risk can be challenged by its heavy metal (HM) content. This study aimed to explore the association of seafood consumption and its estimated HM contents with the lipid profile and lipid oxidation biomarkers in adults from a Spanish Mediterranean area who do not present risk factors for CVD. In this cross-sectional study, the clinical history, three-day dietary record, lipid profile (LDLc, HDLc, APOB/A, and triglyceride levels), plasma oxidised LDL (oxLDL) and 8-isoprostane levels of 81 adults without risk factors for CVD [43% men, with a mean age of 43.6 years (95%CI: 40.1-47.1)] were assessed. The HM [arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb)] contents of seafood were estimated according to data from analyses of marine species in the same Mediterranean area. Moderate adherence to the Mediterranean diet (score: 4.6 of 9) with a mean seafood consumption of 74.9g/day (95%CI: 59.9-89.9), including 22.7g of shellfish per day (95%CI: 13.5-31.9), was observed. The estimated HM contents were lower than the provisional tolerable weekly intakes (PTWIs): 21.12µg/kg/week As, 0.57µg/kg/week InAs, 0.15µg/kg/week Cd, 1.11µg/kg/week Hg and 0.28µg/kg/week Pb. After adjusting by confounder variables, an increase in shellfish consumption was associated with increases in the levels of LDLc (P=0.013), non-HDLc (P=0.015), APOB/A (P=0.02) and plasma oxLDL (P=0.002). Moreover, an increase in the estimated As and Hg levels in shellfish was associated with an increase in LDLc (P=0.015 and P=0.018, respectively), non-HDLc (Pconsumption, even by a moderate amount, could favour a pro-atherogenic lipid profile and a higher level of oxidised LDL. These associations are likely influenced by the estimated exposure to As and Hg from shellfish despite these values are lower than the PTWIs. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of Vitamin E and Selenium Supplement on Paraoxonase-1 Activity, Oxidized Low Density Lipoprotein and Antioxidant Defense in Diabetic Rats

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Mohammad-Reza Rashidi

2011-08-01

Full Text Available Introduction: The aim of the present study was to assess the effects of vitamin E and selenium supplementation on serum paraoxonase (PON1 activity, lipid peroxidation and antioxidant defense in streptozotocin-induced diabetic rats. Methods: Thirty two female Sprague Dawley rats were divided into 3 groups: the control group (n=8 received a standard diet; streptozotocin (STZ-induced diabetic rats (n=12, received corn oil and physiological solution; and vitamin E and selenium supplemented diabetic rats (n=12 were treated with oral administration of vitamin E (300 mg/kg and sodium selenite (0.5 mg/kg once a day for 4 weeks. Results: Significantly lower total antioxidant status (TAS, PON1and erythrocyte SOD activities and a higher fasting plasma glucose level were observed in the diabetic rats compared to the control. A significant increase in SOD and GPX activities in vitamin E and selenium supplemented diabetic group was observed after 5 weeks of the experiment. Compared to the normal rats, malondialdehyde (MDA and oxidized LDL (Ox-LDL levels were higher in the diabetic animals; however, these values reduced significantly following vitamin E and selenium supplementation. Conclusion: Vitamin E and selenium supplementation in diabetic rats has hypolipidemic, hypoglycemic and antioxidative effects and may slow down the progression of diabetic complications through its protective effect on PON1 activity and lipoproteins oxidation.

Mechanisms of multiple neurotransmitters in the effects of Lycopene on brain injury induced by Hyperlipidemia.

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Yang, Weichun; Shen, Ziyi; Wen, Sixian; Wang, Wei; Hu, Minyu

2018-02-07

Lycopene is a kind of carotenoid, with a strong capacity of antioxidation and regulating the bloodlipid. There has been some evidence that lycopene has protective effects on the central nervous system, but few studies have rigorously explored the role of neurotransmitters in it. Therefore, the present study was designed to investigate the effects of several neurotransmitters as lycopene exerts anti-injury effects induced by hyperlipidemia. Eighty adult SD rats, half male and half female, were randomly divided into eight groups on the basis of serum total cholesterol (TC) levels and body weight. There was a control group containing rats fed a standard laboratory rodent chow diet (CD); a hypercholesterolemic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil - this is also called a CCT diet) group; a positive group (CCT + F) fed CCT, supplemented with 10 mg·kg·bw - 1 ·d - 1 fluvastatin sodium by gastric perfusion; and lycopene groups at five dose levels (CCT + LYCO) fed with CCT and supplied lycopene at doses of 5, 25, 45, 65, and 85 mg·kg·bw - 1 ·d - 1 . The levels of TC, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), oxidized low density lipoprotein (ox-LDL), low-density lipoprotein receptor (LDLR), nerve growth factor (NGF), glutamic acid (Glu), Gamma aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), N-methyl-D-aspartate (NMDA1R), GABA A , 5-HT 1 , D 1 , and apoptosis-related proteins Caspase3, bax, and bcl-2 were measured after the experiment. Nissl staining was adopted to observe the morphological changes in neurons. At the end of the experiment, the levels of TC, TG, LDL-C, IL-1, TNF-α, and ox-LDL in the serum and brain as well as the content of Glu, DA, NMDA, and D 1 in the brain of rats in the CCT group were higher than those in the control group (Plycopene (25�

Generation of Adducts of 4-Hydroxy-2-nonenal with Heat Shock 60 kDa Protein 1 in Human Promyelocytic HL-60 and Monocytic THP-1 Cell Lines

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Alessia Arcaro

2015-01-01

Full Text Available Heat shock 60 kDa protein 1 (HSP60 is a chaperone and stress response protein responsible for protein folding and delivery of endogenous peptides to antigen-presenting cells and also a target of autoimmunity implicated in the pathogenesis of atherosclerosis. By two-dimensional electrophoresis and mass spectrometry, we found that exposure of human promyelocytic HL-60 cells to a nontoxic concentration (10 μM of 4-hydroxy-2-nonenal (HNE yielded a HSP60 modified with HNE. We also detected adducts of HNE with putative uncharacterized protein CXorf49, the product of an open reading frame identified in various cell and tissue proteomes. Moreover, exposure of human monocytic THP-1 cells differentiated with phorbol 12-myristate 13-acetate to 10 μM HNE, and to light density lipoprotein modified with HNE (HNE-LDL or by copper-catalyzed oxidation (oxLDL, but not to native LDL, stimulated the formation of HNE adducts with HSP60, as detected by immunoprecipitation and western blot, well over basal levels. The identification of HNE-HSP60 adducts outlines a framework of mutually reinforcing interactions between endothelial cell stressors, like oxLDL and HSP60, whose possible outcomes, such as the amplification of endothelial dysfunction, the spreading of lipoxidative damage to other proteins, such as CXorf49, the activation of antigen-presenting cells, and the breaking of tolerance to HSP60 are discussed.

Electronegative L5-LDL induces the production of G-CSF and GM-CSF in human macrophages through LOX-1 involving NF-κB and ERK2 activation.

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Yang, Tzu-Ching; Chang, Po-Yuan; Kuo, Tzu-Ling; Lu, Shao-Chun

2017-12-01

Circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are associated with the severity of acute myocardial infarction (AMI). However, what causes increases in G-CSF and GM-CSF is unclear. In this study, we investigated whether L5-low-density lipoprotein (LDL), a mildly oxidized LDL from AMI, can induce G-CSF and GM-CSF production in human macrophages. L1-LDL and L5-LDL were isolated through anion-exchange chromatography from AMI plasma. Human macrophages derived from THP-1 and peripheral blood mononuclear cells were treated with L1-LDL, L5-LDL, or copper-oxidized LDL (Cu-oxLDL) and G-CSF and GM-CSF protein levels in the medium were determined. In addition, the effects of L5-LDL on G-CSF and GM-CSF production were tested in lectin-type oxidized LDL receptor-1 (LOX-1), CD36, extracellular signal-regulated kinase (ERK) 1, and ERK2 knockdown THP-1 macrophages. L5-LDL but not L1-LDL or Cu-oxLDL significantly induced production of G-CSF and GM-CSF in macrophages. In vitro oxidation of L1-LDL and L5-LDL altered their ability to induce G-CSF and GM-CSF, suggesting that the degree of oxidation is critical for the effects. Knockdown and antibody neutralization experiments suggested that the effects were caused by LOX-1. In addition, nuclear factor (NF)-κB and ERK1/2 inhibition resulted in marked reductions of L5-LDL-induced G-CSF and GM-CSF production. Moreover, knockdown of ERK2, but not ERK1, hindered L5-LDL-induced G-CSF and GM-CSF production. The results indicate that L5-LDL, a naturally occurring mild oxidized LDL, induced G-CSF and GM-CSF production in human macrophages through LOX-1, ERK2, and NF-κB dependent pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Study of the influence and molecular mechanism of ticagrelor on cerebral ischemia reperfusion injury in rats

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Gui-Fa Chen

2017-06-01

Full Text Available Objective: To study the influence and molecular mechanism of ticagrelor on cerebral ischemia reperfusion injury in rats. Methods: SD rats were selected as experimental animals and divided into control group, model group, ticagrelor group and clopidogrel group, cerebral ischemic reperfusion injury models were made, then ticagrelor group were given intragastric administration of 150 mg ticagrelor, clopidogrel group were given intragastric administration of 90 mg clopidogrel. 1 week after intervention, the brain water content as well as the contents of oxidative stress molecules and inflammatory factors were measured. Results: Water content in brain, MDA, Ox-LDL, NF-kB, TNF-α, IL-1β and IL-6 contents in brain tissue as well as TNF-α, IL-1β and IL-6 contents in serum of model group were significantly higher than those of control group while SOD, GSH-Px and Prdx6 contents in brain tissue were significantly lower than those of control group; water content in brain, MDA, Ox-LDL, NFkB, TNF-α, IL-1β and IL-6 contents in brain tissue as well as TNF-α, IL-1β and IL-6 contents in serum of ticagrelor group and clopidogrel group were significantly lower than those of model group while SOD, GSH-Px and Prdx6 contents in brain tissue were significantly higher than those of model group; water content in brain, MDA, Ox-LDL, NF-kB, TNF-α, IL-1β and IL-6 contents in brain tissue as well as TNF-α, IL-1β and IL-6 contents in serum of ticagrelor group were significantly lower than those of clopidogrel group while SOD, GSHPx and Prdx6 contents in brain tissue were significantly higher than those of clopidogrel group. Conclusion: Ticagrelor can be more effective in inhibiting oxidative stress response and inflammatory response, and reducing the cerebral ischemia reperfusion injury than clopidogrel.

The LDL receptor.

Science.gov (United States)

Goldstein, Joseph L; Brown, Michael S

2009-04-01

In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

The association between adiponectin, HDL-cholesterol and α1-antitrypsin-LDL in female subjects without metabolic syndrome.

Science.gov (United States)

Kotani, Kazuhiko; Yamada, Toshiyuki; Taniguchi, Nobuyuki

2010-12-30

Oxidized low-density lipoprotein (LDL) may act as an atheroprotective (anti-atherosclerotic) agent under some conditions. While the α1-antitrypsin (AT)-LDL complex is considered a type of oxidized LDL, its clinical relevance remains unknown. The aim of the present study was to investigate the association between AT-LDL and anti-atherosclerotic variables such as HDL-cholesterol and adiponectin in subjects with and without metabolic syndrome (MetS). In asymptomatic females (n = 194; mean age, 54 years) who were divided into non-MetS (n = 108) and MetS groups (n = 86), the fasting levels of serum AT-LDL, adiponectin and glucose/lipid panels were measured, in addition to body mass index (BMI) and blood pressure. The MetS group showed significantly higher BMI, blood pressure, glucose and triglyceride levels as well as significantly lower levels of HDL-cholesterol and adiponectin than the non-MetS group. A multivariate-adjusted analysis revealed that in the non-MetS group, AT-LDL was significantly, independently and positively correlated with adiponectin (β = 0.297, P cholesterol (β = 0.217, P LDL was significantly, independently and positively correlated with LDL-cholesterol only (β = 0.342, P LDL may exert anti-atherosclerotic effects in female subjects without MetS. More studies are required to clarify the clinical roles of AT-LDL in relation to the pathophysiology of MetS.

Lipid fluidity at different regions in LDL and HDL of β-thalassemia/Hb E patients

International Nuclear Information System (INIS)

Morales, Noppawan Phumala; Charlermchoung, Chalermkhwan; Luechapudiporn, Rataya; Yamanont, Paveena; Fucharoen, Suthat; Chantharaksri, Udom

2006-01-01

Atherosclerosis-related vascular complications in β-thalassemia/hemoglobin E (β-thal/Hb E) patients may result from iron induced oxidation of lipoproteins. To identify the specific site of oxidative damage, changes in lipid fluidity at different regions in LDL and HDL particle were investigated using two fluorescence probes and two ESR spin probes. The magnitude of increased lipid fluidity in thalassemic lipoproteins was dependent on the location of the probes. In hydrophobic region, the rotational correlation times for 16-doxyl stearic acid and DPH anisotropy were markedly changed in LDL and HDL of the patients. In the surface region, there was only a slight change in the order parameter (S) for 5-doxyl stearic acid and TMA-DPH anisotropy. Lipid fluidity at the core of LDL and HDL showed good correlation with oxidative stress markers, the ratio of CL/CO, and the level of α-tocopherol, suggesting that hydrophobic region of thalassemic lipoprotein was a target site for oxidative damage

Elevated circulating LDL phenol levels in men who consumed virgin rather than refined olive oil are associated with less oxidation of plasma LDL

DEFF Research Database (Denmark)

de la Torre-Carbot, Karina; Chávez-Servín, Jorge L; Jaúregui, Olga

2010-01-01

In human LDL, the bioactivity of olive oil phenols is determined by the in vivo disposition of the biological metabolites of these compounds. Here, we examined how the ingestion of 2 similar olive oils affected the content of the metabolic forms of olive oil phenols in LDL in men. The oils differed...... in phenol concentrations as follows: high (629 mg/L) for virgin olive oil (VOO) and null (0 mg/L) for refined olive oil (ROO). The study population consisted of a subsample from the EUROLIVE study and a randomized controlled, crossover design was used. Intervention periods lasted 3 wk and were preceded...... acids (P olive oil modulates the phenolic metabolite content in LDL after sustained...

'LDL-C' = LDL-C + Lp(a)-C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering.

Science.gov (United States)

Yeang, Calvin; Witztum, Joseph L; Tsimikas, Sotirios

2015-06-01

The measurement that is termed 'LDL-cholesterol' (LDL-C) includes the cholesterol content of lipoprotein(a) [Lp(a)-C], which can contribute approximately 30-45% to measured LDL-C levels as a percentage of its mass. We review the implications of achieved very low LDL-C levels in patients treated with potent LDL-C-lowering agents in the context of varying Lp(a) levels. Combination therapy with statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can lower LDL-C to unprecedentedly low levels. Recent PCSK9 trials have shown that routine achievement of mean LDL-C less than 50 mg/dl is feasible, along with the modest reductions in Lp(a). Many patients will achieve LDL-C less than 25 mg/dl with concomitantly elevated Lp(a) levels that contribute substantially to the measured 'LDL-C'. Therefore, it is possible that some of these patients may have little to no circulating LDL-C. As the new era of ultralow LDL-C levels ensues, it is imperative to understand the contribution of Lp(a)-C to measured LDL-C and the consequences of achieving ultralow or potentially absent LDL-C in the setting of elevated Lp(a) levels and possibly free apo(a). We review this concept and suggest avenues of research, including analyses of existing datasets in current clinical trials and new research studies, to understand its pathophysiological and clinical significance.

Refolding and characterization of the functional ligand-binding domain of human lectin-like oxidized LDL receptor.

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Xie, Qiuhong; Matsunaga, Shigeru; Shi, Xiaohua; Ogawa, Setsuko; Niimi, Setsuko; Wen, Zhesheng; Tokuyasu, Ken; Machida, Sachiko

2003-11-01

Lectin-like oxidized low-density lipoprotein receptor (LOX-1), a type II membrane protein that can recognize a variety of structurally unrelated macromolecules, plays an important role in host defense and is implicated in atherogenesis. To understand the interaction between human LOX-1 and its ligands, in this study the functional C-type lectin-like domain (CTLD) of LOX-1 was reconstituted at high efficiency from inactive aggregates in Escherichia coli using a refolding technique based on an artificial chaperone. The CD spectra of the purified domain suggested that the domain has alpha-helical structure and the blue shift of Trp residues was observed on refolding of the domain. Like wild-type hLOX-1, the refolded CTLD domain was able to bind modified LDL. Thus, even though CTLD contains six Cys residues that form disulfide bonds, it recovered its specific binding ability on refolding. This suggests that the correct disulfide bonds in CTLD were formed by the artificial chaperone technique. Although the domain lacked N-glycosylation, it showed high affinity for its ligand in surface plasmon resonance experiments. Thus, unglycosylated CTLD is sufficient for binding modified LDL.

Effects of dietary cold-pressed turnip rapeseed oil and butter on serum lipids, oxidized LDL and arterial elasticity in men with metabolic syndrome

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Wallenius Marja

2010-12-01

Full Text Available Abstract Background Rapeseed oil is the principal dietary source of monounsaturated and n-3 polyunsaturated fatty acids in the Northern Europe. However, the effect of rapeseed oil on the markers of subclinical atherosclerosis is not known. The purpose of this study was to compare the effects of dietary intake of cold-pressed turnip rapeseed oil (CPTRO and butter on serum lipids, oxidized LDL and arterial elasticity in men with metabolic syndrome. Methods Thirty-seven men with metabolic syndrome completed an open and balanced crossover study. Treatment periods lasted for 6 to 8 weeks and they were separated from each other with an eight-week washout period. Subjects maintained their normal dietary habits and physical activity without major variations. The daily fat adjunct consisted either of 37.5 grams of butter or 35 mL of VirginoR CPTRO. Participants were asked to spread butter on bread on the butter period and to drink CPTRO on the oil period. The fat adjunct was used as such without heating or frying. Results Compared to butter, administration of CPTRO was followed by a reduction of total cholesterol by 8% (p Conclusion Cold-pressed turnip rapeseed oil had favourable effects on circulating LDL cholesterol and oxidized LDL, which may be important in the management of patients at high cardiovascular risk. Trial registration ClinicalTrial.gov NCT01119690

LDL: The "Bad" Cholesterol

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... There are two main types of cholesterol: LDL (bad) cholesterol and HDL (good) cholesterol: LDL stands for low-density lipoproteins. It is called the "bad" cholesterol because a high LDL level leads to ...

It has been suggested that oxidative stress, especially oxidative ...

African Journals Online (AJOL)

nabipour

2012-02-14

Feb 14, 2012 ... 1Department of Clinical Biochemistry, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. 2Department of Cardiology ... oxidative modification of low-density lipoproteins (LDL), may play a causative role in ... the oxidation of lipids in the cell membrane especially the oxidation of LDL.

Changes in inflammation, oxidative stress and adipokines following bariatric surgery among adolescents with severe obesity.

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Kelly, A S; Ryder, J R; Marlatt, K L; Rudser, K D; Jenkins, T; Inge, T H

2016-02-01

Inflammation, oxidative stress and dysregulation of adipokines are thought to be pathophysiological mechanisms linking obesity to the development of insulin resistance and atherosclerosis. In adults, bariatric surgery reduces inflammation and oxidative stress, and beneficially changes the levels of several adipokines, but little is known about the postsurgical changes among adolescents. In two separate longitudinal cohorts we evaluated change from baseline of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemo-attractant protein-1 (MCP-1), oxidized low-density lipoprotein cholesterol (oxLDL), adiponectin, leptin and resistin up to 12 months following elective laparoscopic Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) surgery in adolescents with severe obesity. In cohort 1, which consisted of 39 adolescents (mean age 16.5±1.6 years; 29 females) undergoing either RYGB or VSG, IL-6 (baseline: 2.3±3.4 pg ml(-1) vs 12 months: 0.8±0.6 pg ml(-1), Padolescents (mean age 16.5±1.6 years; 10 females) undergoing RYGB, results were similar: IL-6 (baseline: 1.7±0.9 pg ml(-1) vs 12 months: 0.4±0.9 pg ml(-1), PBariatric surgery produced robust improvements in markers of inflammation, oxidative stress and several adipokines among adolescents with severe obesity, suggesting potential reductions in risk for type 2 diabetes and cardiovascular disease.

Oxidized LDL receptor 1 (OLR1 as a possible link between obesity, dyslipidemia and cancer.

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Magomed Khaidakov

Full Text Available Recent studies have linked expression of lectin-like ox-LDL receptor 1 (OLR1 to tumorigenesis. We analyzed microarray data from Olr1 knockout (KO and wild type (WT mice for genes involved in cellular transformation and evaluated effects of OLR1 over-expression in normal mammary epithelial cells (MCF10A and breast cancer cells (HCC1143 in terms of gene expression, migration, adhesion and transendothelial migration. Twenty-six out of 238 genes were inhibited in tissues of OLR1 KO mice; the vast majority of OLR1 sensitive genes contained NF-κB binding sites in their promoters. Further studies revealed broad inhibition of NF-kB target genes outside of the transformation-associated gene pool, with enrichment themes of defense response, immune response, apoptosis, proliferation, and wound healing. Transcriptome of Olr1 KO mice also revealed inhibition of de novo lipogenesis, rate-limiting enzymes fatty acid synthase (Fasn, stearoyl-CoA desaturase (Scd1 and ELOVL family member 6 (Elovl6, as well as lipolytic phospholipase A2 group IVB (Pla2g4b. In studies comparing MCF10A and HCC1143, the latter displayed 60% higher OLR1 expression. Forced over-expression of OLR1 resulted in upregulation of NF-κB (p65 and its target pro-oncogenes involved in inhibition of apoptosis (BCL2, BCL2A1, TNFAIP3 and regulation of cell cycle (CCND2 in both cell lines. Basal expression of FASN, SCD1 and PLA2G4B, as well as lipogenesis transcription factors PPARA, SREBF2 and CREM, was higher in HCC1143 cells. Over-expression of OLR1 in HCC1143 cells also enhanced cell migration, without affecting their adherence to TNFα-activated endothelium or transendothelial migration. On the other hand, OLR1 neutralizing antibody inhibited both adhesion and transmigration of untreated HCC1143 cells. We conclude that OLR1 may act as an oncogene by activation of NF-kB target genes responsible for proliferation, migration and inhibition of apoptosis and de novo lipogenesis genes.

Comparative reactivity of the myeloperoxidase-derived oxidants HOCl and HOSCN with low-density lipoprotein (LDL)

DEFF Research Database (Denmark)

Ismael, Fahd O; Proudfoot, Julie M; Brown, Bronwyn E

2015-01-01

Atherosclerosis is characterised by the accumulation of lipids within macrophages in the artery wall. Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces ox...

Detection of atherosclerotic lesions and intimal macrophages using CD36-targeted nanovesicles.

Science.gov (United States)

Nie, Shufang; Zhang, Jia; Martinez-Zaguilan, Raul; Sennoune, Souad; Hossen, Md Nazir; Lichtenstein, Alice H; Cao, Jun; Meyerrose, Gary E; Paone, Ralph; Soontrapa, Suthipong; Fan, Zhaoyang; Wang, Shu

2015-12-28

Current approaches to the diagnosis and therapy of atherosclerosis cannot target lesion-determinant cells in the artery wall. Intimal macrophage infiltration promotes atherosclerotic lesion development by facilitating the accumulation of oxidized low-density lipoproteins (oxLDL) and increasing inflammatory responses. The presence of these cells is positively associated with lesion progression, severity and destabilization. Hence, they are an important diagnostic and therapeutic target. The objective of this study was to noninvasively assess the distribution and accumulation of intimal macrophages using CD36-targeted nanovesicles. Soy phosphatidylcholine was used to synthesize liposome-like nanovesicles. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine was incorporated on their surface to target the CD36 receptor. All in vitro data demonstrate that these targeted nanovesicles had a high binding affinity for the oxLDL binding site of the CD36 receptor and participated in CD36-mediated recognition and uptake of nanovesicles by macrophages. Intravenous administration into LDL receptor null mice of targeted compared to non-targeted nanovesicles resulted in higher uptake in aortic lesions. The nanovesicles co-localized with macrophages and their CD36 receptors in aortic lesions. This molecular target approach may facilitate the in vivo noninvasive imaging of atherosclerotic lesions in terms of intimal macrophage accumulation and distribution and disclose lesion features related to inflammation and possibly vulnerability thereby facilitate early lesion detection and targeted delivery of therapeutic compounds to intimal macrophages. Copyright © 2015 Elsevier B.V. All rights reserved.

Myeloperoxidase-Dependent LDL Modifications in Bloodstream Are Mainly Predicted by Angiotensin II, Adiponectin, and Myeloperoxidase Activity: A Cross-Sectional Study in Men

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Karim Zouaoui Boudjeltia

2013-01-01

Full Text Available The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO, an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels.

Effect of bicarbonate on iron-mediated oxidation of low-density lipoprotein

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Arai, Hirofumi; Berlett, Barbara S.; Chock, P. Boon; Stadtman, Earl R.

2005-07-01

Oxidation of low-density lipoprotein (LDL) may play an important role in atherosclerosis. We studied the effects of bicarbonate/CO2 and phosphate buffer systems on metal ion-catalyzed oxidation of LDL to malondialdehyde (MDA) and to protein carbonyl and MetO derivatives. Our results revealed that LDL oxidation in mixtures containing free iron or heme derivatives was much greater in bicarbonate/CO2 compared with phosphate buffer. However, when copper was substituted for iron in these mixtures, the rate of LDL oxidation in both buffers was similar. Iron-catalyzed oxidation of LDL was highly sensitive to inhibition by phosphate. Presence of 0.3-0.5 mM phosphate, characteristic of human serum, led to 30-40% inhibition of LDL oxidation in bicarbonate/CO2 buffer. Iron-catalyzed oxidation of LDL to MDA in phosphate buffer was inhibited by increasing concentrations of albumin (10-200 μM), whereas MDA formation in bicarbonate/CO2 buffer was stimulated by 10-50 μM albumin but inhibited by higher concentrations. However, albumin stimulated the oxidation of LDL proteins to carbonyl derivatives at all concentrations examined in both buffers. Conversion of LDL to MDA in bicarbonate/CO2 buffer was greatly stimulated by ADP, ATP, and EDTA but only when EDTA was added at a concentration equal to that of iron. At higher than stoichiometric concentrations, EDTA prevented oxidation of LDL. Results of these studies suggest that interactions between bicarbonate and iron or heme derivatives leads to complexes with redox potentials that favor the generation of reactive oxygen species and/or to the generation of highly reactive CO2 anion or bicarbonate radical that facilitates LDL oxidation. Freely available online through the PNAS open access option.Abbreviations: LDL, low-density lipoprotein; MDA, malondialdehyde; MetO, methionine sulfoxide.

Suppression of endothelial cell adhesion by XJP-1, a new phenolic compound derived from banana peel.

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Fu, Rong; Yan, Tianhua; Wang, Qiujuan; Guo, Qinglong; Yao, Hequan; Wu, Xiaoming; Li, Yang

2012-01-01

The adhesion of monocytes to activated vascular endothelial cells is a critical event in the initiation of atherosclerosis. Adhesion is mediated by oxidized low-density lipoprotein (ox-LDL) which up-regulates inflammatory markers on endothelial cells. Here we report that (±) 7, 8-dihydroxy-3-methyl-isochromanone-4 (XJP-1), an inhibitor of ox-LDL-induced adhesion of monocytes to endothelial cells blocks cellular functions which are associated with adhesion. We show that XJP-1 down-regulates ox-LDL-induced over-expression of adhesion molecules (ICAM-1 and VCAM-1) in a dose-dependent manner in human umbilical vein endothelial cells (HUVECs), attenuates ox-LDL-induced up-regulation of low-density lipoprotein receptor (LOX)-1, decreases generation of reactive oxygen species (ROS), blocks translocation of nuclear factor-kappa B (NF-κB) activity, and prevents activation of c-Jun N-terminal kinase (JNK)/p38 pathways in endothelial cells. These findings suggest that XJP-1 may attenuate ox-LDL-induced endothelial adhesion of monocytes by blocking expression of adhesion molecules through suppressing ROS/NF-κB, JNK and p38 pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

Synthetic LDL as targeted drug delivery vehicle

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Forte, Trudy M [Berkeley, CA; Nikanjam, Mina [Richmond, CA

2012-08-28

The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

Daintain/AIF-1 Plays Roles in Coronary Heart Disease via Affecting the Blood Composition and Promoting Macrophage Uptake and Foam Cell Formation

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Junhan Wang

2013-07-01

Full Text Available Background: Daintain/AIF-1 is an inflammatory polypeptide factor/allograft inflammatory factor 1 derived from macrophages. It is characterized in APOE-/- mice as a novel inflammatory factor associated with atherosclerosis. The purpose of this study was to characterize its function in human atherosclerosis. Methods: Immunohistochemistry was used to identify the expression of daintain/AIF-1 in vessel segments within and far from atherosclerotic plaques; High-performance liquid chromatography (HPLC was used to display the effects of daintain/AIF-1 on C-reactive protein (CRP, oxidative capacity and superoxide dismutase (SOD in vivo; Oil Red O Staining was used to show the effects of daintain/AIF-1 on uptake of oxidized low density lipoprotein (ox-LDL into U937 cells, a macrophage line; Western Blot was used to test scavenger receptor A (SRA expression. Results: A high density of daintain/AIF-1 was observed in the tunica intima and media of coronary artery with atherosclerotic plaque, and fewer daintain/AIF-1 in the vessels without atherosclerotic plaque; Daintain/AIF-1 injected intravenously into BALB/c mice boosted oxidative capacity, significantly impaired SOD activities and augmented the CRP level in blood. According to the oil red O test, daintain/AIF-1 profoundly facilitated the uptake of ox-LDL in U937 macrophages and formation of foam cells in the endothelium. We also found that the molecular mechanisms are effective by promoting overexpression of SRA on macrophages. Conclusion: These findings implicate that the inflammatory factor daintain/AIF-1 is closely associated with atherogenesis, and could be further characterized as a novel risk factor for atherosclerosis

The LDL-HDL profile determines the risk of atherosclerosis: a mathematical model.

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Wenrui Hao

Full Text Available Atherosclerosis, the leading death in the United State, is a disease in which a plaque builds up inside the arteries. As the plaque continues to grow, the shear force of the blood flow through the decreasing cross section of the lumen increases. This force may eventually cause rupture of the plaque, resulting in the formation of thrombus, and possibly heart attack. It has long been recognized that the formation of a plaque relates to the cholesterol concentration in the blood. For example, individuals with LDL above 190 mg/dL and HDL below 40 mg/dL are at high risk, while individuals with LDL below 100 mg/dL and HDL above 50 mg/dL are at no risk. In this paper, we developed a mathematical model of the formation of a plaque, which includes the following key variables: LDL and HDL, free radicals and oxidized LDL, MMP and TIMP, cytockines: MCP-1, IFN-γ, IL-12 and PDGF, and cells: macrophages, foam cells, T cells and smooth muscle cells. The model is given by a system of partial differential equations with in evolving plaque. Simulations of the model show how the combination of the concentrations of LDL and HDL in the blood determine whether a plaque will grow or disappear. More precisely, we create a map, showing the risk of plaque development for any pair of values (LDL,HDL.

Antioxidant effects of aqueous extracts from dried calyx of Hibiscus sabdariffa Linn. (Roselle) in vitro using rat low-density lipoprotein (LDL).

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Hirunpanich, Vilasinee; Utaipat, Anocha; Morales, Noppawan Phumala; Bunyapraphatsara, Nuntavan; Sato, Hitoshi; Herunsalee, Angkana; Suthisisang, Chuthamanee

2005-03-01

The present study quantitatively investigated the antioxidant effects of the aqueous extracts from dried calyx of Hibiscus sabdariffa LINN. (roselle) in vitro using rat low-density lipoprotein (LDL). Formations of the conjugated dienes and thiobarbituric acid reactive substances (TBARs) were monitored as markers of the early and later stages of the oxidation of LDL, respectively. Thus, we demonstrated that the dried calyx extracts of roselle exhibits strong antioxidant activity in Cu(2+)-mediated oxidation of LDL (proselle inhibited TBARs-formation with greater potency than 100 microM of vitamin E. In conclusion, this study provides a quantitative insight into the potent antioxidant effect of roselle in vitro.

Structure-function relationships in reconstituted HDL: Focus on antioxidative activity and cholesterol efflux capacity.

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Cukier, Alexandre M O; Therond, Patrice; Didichenko, Svetlana A; Guillas, Isabelle; Chapman, M John; Wright, Samuel D; Kontush, Anatol

2017-09-01

High-density lipoprotein (HDL) contains multiple components that endow it with biological activities. Apolipoprotein A-I (apoA-I) and surface phospholipids contribute to these activities; however, structure-function relationships in HDL particles remain incompletely characterised. Reconstituted HDLs (rHDLs) were prepared from apoA-I and soy phosphatidylcholine (PC) at molar ratios of 1:50, 1:100 and 1:150. Oxidative status of apoA-I was varied using controlled oxidation of Met112 residue. HDL-mediated inactivation of PC hydroperoxides (PCOOH) derived from mildly pre-oxidized low-density lipoprotein (LDL) was evaluated by HPLC with chemiluminescent detection in HDL+LDL mixtures and re-isolated LDL. Cellular cholesterol efflux was characterised in RAW264.7 macrophages. rHDL inactivated LDL-derived PCOOH in a dose- and time-dependent manner. The capacity of rHDL to both inactivate PCOOH and efflux cholesterol via ATP-binding cassette transporter A1 (ABCA1) increased with increasing apoA-I/PC ratio proportionally to the apoA-I content in rHDL. Controlled oxidation of apoA-I Met112 gradually decreased PCOOH-inactivating capacity of rHDL but increased ABCA1-mediated cellular cholesterol efflux. Increasing apoA-I content in rHDL enhanced its antioxidative activity towards oxidized LDL and cholesterol efflux capacity via ABCA1, whereas oxidation of apoA-I Met112 decreased the antioxidative activity but increased the cholesterol efflux. These findings provide important considerations in the design of future HDL therapeutics. Non-standard abbreviations and acronyms: AAPH, 2,2'-azobis(-amidinopropane) dihydrochloride; ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; BHT, butylated hydroxytoluene; CV, cardiovascular; EDTA, ethylenediaminetetraacetic acid; HDL-C, high-density lipoprotein cholesterol; LOOH, lipid hydroperoxides; Met(O), methionine sulfoxide; Met112, methionine 112 residue; Met86, methionine 86 residue; oxLDL, oxidized low

High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans.

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Jones, Peter J H; MacKay, Dylan S; Senanayake, Vijitha K; Pu, Shuaihua; Jenkins, David J A; Connelly, Philip W; Lamarche, Benoît; Couture, Patrick; Kris-Etherton, Penny M; West, Sheila G; Liu, Xiaoran; Fleming, Jennifer A; Hantgan, Roy R; Rudel, Lawrence L

2015-02-01

Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets: 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p = 0.0005 and p = 0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p = 0.0243) and DHA-enriched high oleic canola oil (p = 0.0249), although high-oleic canola oil had the lowest binding at baseline (p = 0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

LDL-Apheresis: Technical and Clinical Aspects

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Rolf Bambauer

2012-01-01

Full Text Available The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a levels, and coronary heart disease refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL apheresis is the therapeutic option. Today, there are five different LDL-apheresis systems available: cascade filtration or lipid filtration, immunoadsorption, heparin-induced LDL precipitation, dextran sulfate LDL adsorption, and the LDL hemoperfusion. There is a strong correlation between hyperlipidemia and atherosclerosis. Besides the elimination of other risk factors, in severe hyperlipidemia therapeutic strategies should focus on a drastic reduction of serum lipoproteins. Despite maximum conventional therapy with a combination of different kinds of lipid-lowering drugs, sometimes the goal of therapy cannot be reached. Hence, in such patients, treatment with LDL-apheresis is indicated. Technical and clinical aspects of these five different LDL-apheresis methods are shown here. There were no significant differences with respect to or concerning all cholesterols, or triglycerides observed. With respect to elevated lipoprotein (a levels, however, the immunoadsorption method seems to be most effective. The different published data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe hyperlipidemia refractory to maximum conservative therapy is effective and safe in long-term application.

Dietary fatty acids regulate hepatic low density lipoprotein (LDL) transport by altering LDL receptor protein and mRNA levels.

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Horton, J D; Cuthbert, J A; Spady, D K

1993-01-01

The concentration of LDL in plasma is strongly influenced by the amount and the type of lipid in the diet. Recent studies in the hamster have shown that dietary fatty acids differentially affect circulating LDL levels primarily by altering receptor-dependent LDL uptake in the liver. To investigate the mechanistic basis of this effect, rates of receptor-dependent LDL transport in the liver were correlated with LDL receptor protein and mRNA levels in hamsters fed safflower oil or coconut oil and varying amounts of cholesterol. Hepatic LDL receptor activity was significantly lower in animals fed coconut oil than in animals fed safflower oil at all levels of cholesterol intake (26, 53, and 61% lower at cholesterol intakes of 0, 0.06, and 0.12%, respectively). These fatty acid-induced changes in hepatic LDL receptor activity were accompanied by parallel changes in hepatic LDL receptor protein and mRNA levels, suggesting that dietary fatty acids regulate the LDL receptor pathway largely at the mRNA level. Images PMID:8349814

Lipid oxidation in human low-density lipoprotein induced by metmyoglobin/H2O2

DEFF Research Database (Denmark)

Witting, P K; Willhite, C A; Davies, Michael Jonathan

1999-01-01

Metmyoglobin (metMb) and H(2)O(2) can oxidize low-density lipoprotein (LDL) in vitro, and oxidized LDL may be atherogenic. The role of alpha-tocopherol (alpha-TOH) in LDL oxidation by peroxidases such as metMb is unclear. Herein, we show that during metMb/H(2)O(2)-induced oxidation of native LDL...... of CE-O(O)H is dependent on, and correlates with, LDL's alpha-TOH content, yet does not require preformed lipid hydroperoxides or H(2)O(2). This indicates that in native LDL alpha-TOH can act as a phase-transfer agent and alpha-TO(*) as a chain-transfer agent propagating LDL lipid peroxidation via...

LDLCHOLESTEROLEXAMINATION (LDL-C USINGHOMOGENEOUS ASSAY

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Made DwiAmbara Putra

2013-07-01

Full Text Available Homogeneous method describe as a method that does not require separation of free and bound label. This method has the ability tofully automate the determination of LDL-C directly small sample volume sand short examination time. In addition this method use automated pipette and control of time and temperature more accurate. There are 5 methods i.e. Solubilization homogeneous LDL-C assay (SOL from KyowaMedex, Surfactant LDL-C assay (SUR from Daiichi Pure Chemicals, Protecting LDL-assay reagent (PRO from Wako Chemicals, LDL-C assaycatalase (CAT Denka Seiken and Calixarene of LDL-C assay (CAL from International Reagents Corporation. All method is to use a variety of detergents and other chemicals that cause blocking or dissolution of specific lipoprotein classes to achieve specificity for LDL. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

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Tan, Ricardo; Giral, Philippe; Robillard, Paul; Kontush, Anatol; Chapman, M. John

2016-01-01

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (−41%) and LDL-cholesterol (−38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3. PMID:27581680

Correlation of serum homocysteine levels with nerve injury and atherosclerosis in patients with stroke

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Gai-Zhuang Liu

2017-07-01

Full Text Available Objective: To study the correlation of serum homocysteine levels with nerve injury and atherosclerosis in patients with stroke. Methods: Patients who were diagnosed with ischemic stroke in our hospital between January 2014 and December 2016 were selected and then divided into moderate-severe stenosis group (C group, mild stenosis group (B group and no stenosis group (A group according to carotid artery ultrasonography; healthy volunteers who received physical examination during the same period were chosen as control group. The serum levels of homocysteine, nerve injury indexes and atherosclerosis indexes were detected. Results: Serum Hcy, S100B, NSE, UCH-L1, GFAP, FGF23, CD36, ox-LDL, MMP8 and MMP9 levels of C group, B group and A group were significantly higher than those of control group, and the severer the carotid stenosis, the higher the serum S100B, NSE, UCHL1, GFAP, FGF23, CD36, ox-LDL, MMP8 and MMP9 levels; serum S100B, NSE, UCHL1, GFAP, FGF23, CD36, ox-LDL, MMP8 and MMP9 levels in stoke patients with high Hcy were significantly higher than those of patients with normal Hcy. Conclusions: Serum homocysteine levels increase in patients with stroke and are closely related to the nerve injury and atherosclerosis.

The Effect of a Shear Flow on the Uptake of LDL and Ac-LDL by Cultured Vascular Endothelial Cells

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Niwa, Koichi; Karino, Takeshi

The effects of a shear flow on the uptake of fluorescence-labeled low-density lipoprotein (DiI-LDL), acetylated LDL (DiI-Ac-LDL), and lucifer yellow (LY; a tracer of fluid-phase endocytosis) by cultured bovine aortic ECs were studied using a rotating-disk shearing apparatus. It was found that 2hours’ exposure of ECs to a laminar shear flow that imposed ECs an area-mean shear stress of 10dynes/cm2 caused an increase in the uptake of DiI-LDL and LY. By contrast, the uptake of DiI-Ac-LDL was decreased by exposure of the ECs to a shear flow. Addition of dextran sulfate (DS), a competitive inhibitor of scavenger receptors, reversed the effect of a shear flow on the uptake of DiI-Ac-LDL, resulting in an increase by the imposition of a shear flow, while the uptake of DiI-LDL and LY remained unaffected. It was concluded that a shear flow promotes the endocytosis of DiI-LDL and LY by ECs, but suppresses the uptake of DiI-Ac-LDL by ECs by inhibiting scavenger receptor-mediated endocytosis.

Novel genes in LDL metabolism

DEFF Research Database (Denmark)

Christoffersen, Mette; Tybjærg-Hansen, Anne

2015-01-01

PURPOSE OF REVIEW: To summarize recent findings from genome-wide association studies (GWAS), whole-exome sequencing of patients with familial hypercholesterolemia and 'exome chip' studies pointing to novel genes in LDL metabolism. RECENT FINDINGS: The genetic loci for ATP-binding cassette......-exome sequencing and 'exome chip' studies have additionally suggested several novel genes in LDL metabolism including insulin-induced gene 2, signal transducing adaptor family member 1, lysosomal acid lipase A, patatin-like phospholipase domain-containing protein 5 and transmembrane 6 superfamily member 2. Most...... of these findings still require independent replications and/or functional studies to confirm the exact role in LDL metabolism and the clinical implications for human health. SUMMARY: GWAS, exome sequencing studies, and recently 'exome chip' studies have suggested several novel genes with effects on LDL cholesterol...

Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

International Nuclear Information System (INIS)

Luo, Di-xian; Xia, Cheng-lai; Li, Jun-mu; Xiong, Yan; Yuan, Hao-yu; TANG, Zhen-Wang; Zeng, Yixin; Liao, Duan-fang

2010-01-01

Research highlights: → Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. → Static pressure induces SREBP-1 activation. → Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. → Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. → Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different static pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 ± 2.8 mg/g, 31.8 ± 0.7 mg/g, 92.3 ± 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 ± 9.4 mg/g, 235.9 ± 3.0 mg/g, 386.7 ± 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were upregulated. Conclusion: Static

Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

Energy Technology Data Exchange (ETDEWEB)

Luo, Di-xian, E-mail: luodixian_2@163.com [Department of Pharmacology, School of Pharmaceutics, Central South University, Changsha 410083, Hunan (China); Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); First People' s Hospital of Chenzhou City, Chenzhou 423000, Hunan (China); Xia, Cheng-lai [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Department of Pharmacy, Third Affiliated Hospital Medical College of Guangzhou, Guangzhou 510150, Guangdong (China); Li, Jun-mu [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Xiong, Yan [Department of Pharmacology, School of Pharmaceutics, Central South University, Changsha 410083, Hunan (China); Yuan, Hao-yu [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Lusong Center for Disease Control and Prevention, Zhuzhou 412000, Hunan (China); TANG, Zhen-Wang; Zeng, Yixin [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Liao, Duan-fang, E-mail: dfliao66@yahoo.com.cn [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Department of Traditional Chinese Diagnostics, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 420108, Hunan (China)

2010-12-03

Research highlights: {yields} Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. {yields} Static pressure induces SREBP-1 activation. {yields} Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. {yields} Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. {yields} Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different static pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 {+-} 2.8 mg/g, 31.8 {+-} 0.7 mg/g, 92.3 {+-} 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 {+-} 9.4 mg/g, 235.9 {+-} 3.0 mg/g, 386.7 {+-} 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were

Molecular imaging of atherosclerosis in mice with MRI and near-infrared fluorescence imaging

International Nuclear Information System (INIS)

Lu Tong; Wen Song; Zhou Guanhui; Ju Shenghong; Teng Gaojun

2012-01-01

Objective: To explore the feasibility of detecting atherosclerotic plaques with 7.0 T MRI and near-infrared fluorescence imaging (NIRF) using molecular imaging probes. Methods: Atherosclerotic plaques were established in male atherosclerotic apolipoprotein E knockout (ApoE-/-) mice fed with high-cholesterol diet for 20 weeks. Wild-type C57BL/6 mice were used as negative controls. 7.0 T MRI was performed before and 36 h after intravenously administration of ultrasmall superparamagnetic particle of iron oxide (USPIO). NIR 797 was conjugated with anti-mouse-oxidized modified low density lipoprotein (oxLDL) antibodies to construct an anti-oxLDL-Ab-NIR 797 probe while non-specific IgG-NIR 797 and PBS used as controls. NIRF was performed 24 h after tail vein injection of the probe. Independent sample t-test and one-way analysis of variance were used to analyze the data by SPSS 17.0. Results: In APOE-/-mice, in vivo 36 h post-USPIO T 2 WI images revealed strong focal signal loss in the abdominal aorta than that of pre-USPIO, with relative signal intensity 0.70 ± 0.04 and 1.28 ± 0.06, respectively (t=3.376, P<0.05). The percent of signal reduced was (-56.58 ± 4.25)%. The Prussian blue staining confirmed the depositions of iron particles in the plaque lesions. Significant fluorochrome accumulation in atherosclerotic plaques was demonstrated in aortic root, aortic arch and the starting of descending aorta 24 h after injection of the anti-oxLDL-Ab-NIR 797 probe. Minimal antibody uptake was observed in normal vessels from wild-type mice receiving the anti-oxLDL-Ab-NIR 797 (SNR: 2.29 ± 1.11) and in atherosclerotic vessels from ApoE-/- mice receiving the non-specific IgG-NIR 797 (19.58 ±3.06) or PBS (4.19 ±0.82), which was significantly different from the uptake of anti-oxLDL-Ab-NIR 797 group (42.51 ±5.24, F=25.104, P<0.05). Comparison between oil red O staining and NIRF 24 h after injection of NIR 797 labeled oxLDL-antibody revealed a significant correlation (r=0.738, P

Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis.

Science.gov (United States)

Navarese, Eliano P; Robinson, Jennifer G; Kowalewski, Mariusz; Kolodziejczak, Michalina; Andreotti, Felicita; Bliden, Kevin; Tantry, Udaya; Kubica, Jacek; Raggi, Paolo; Gurbel, Paul A

2018-04-17

Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)-lowering drug trials. To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions. Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies. Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as "more intensive" (more potent pharmacologic intervention) or "less intensive" (less potent, placebo, or control group). The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE). In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96]; P = .001; absolute risk difference [ARD], -1.05 incident cases per 1000 person-years [95% CI, -1.59 to -0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (P baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.86 [95% CI, 0.80 to 0.94]; P baseline LDL-C levels were 100

Effekte des oxidativen Stresses auf die Expression der Scavenger-Rezeptoren CD36 und SR-BI und des Transkriptionsfaktors PPARγ in Makrophagen

OpenAIRE

Westendorf, Thomas

2006-01-01

Ziel dieser Dissertationsschrift war es, die Effekte des oxidativen Stresses in Form von oxLDL auf die Expression der atherogenen Scavenger-Rezeptoren CD36, SR-BI, des Transkriptionsfaktors PPARγ und pro-inflammatorischer Zytokine zu untersuchen. Die durchgeführten Untersuchungen beruhen auf der Annahme, dass modifizierte LDL durch Induktion der genannten Scavenger-Rezeptoren und nachfolgende unregulierte Aufnahme in Makrophagen mit Bildung von Schaumzellen entscheidend zur Entwicklung einer ...

Description of Discordance Between LDL Cholesterol, Non-HDL Cholesterol, and LDL Particle Number Among Patients of a Lipid Clinic

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Joshua W Gaborcik

2017-09-01

Full Text Available Background: While LDL cholesterol measures the cholesterol content within an LDL particle (LDL-P, it may not reflect LDL-P concentrations. If discordance exists, LDL-P may better predict cardiovascular events compared to LDL-C and non-HDL cholesterol (non-HDL-C. In primary prevention patients, discordance has been associated with diabetes, ethnicity, gender, metabolic syndrome, and smoking history. Objective: To describe discordance in patients of a lipid clinic by exploring associations between patient characteristics and discordance among LDL-C, non-HDL-C, or LDL-P. Secondarily to compare proportion of patients with baseline concordance versus discordance who have ASCVD events, diagnoses of new onset diabetes or death. Methods: A retrospective, single-center cohort study at a large academic medical center was conducted. Patients establishing care from January 2009 through December 2012 with complete initial labs were included. Logistic regression models were used to explore associations between discordance and patient characteristics. Results: Of 603 patients screened, the final cohort included 166 patients with 104 (62.7% discordant. LDL-P was the most common discordant value. Discordance was associated with gender, smoking status, use of lipid lowering medications, and achieving patient specific LDL-C goals. In terms of any event observed after initial measurements, no significant differences were detected between discordant and concordant groups. Conclusion: Within a lipid clinic population, discordance was associated with male gender, smoking status, lipid-lowering therapy, and being at patient specific LDL-C goal. While associations were found in our population, clinicians should consider measuring LDL-P to fully assess presence or extent of discordance. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the

Differential reactivities of four homogeneous assays for LDL-cholesterol in serum to intermediate-density lipoproteins and small dense LDL: comparisons with the Friedewald equation.

Science.gov (United States)

Yamashita, Shizuya; Kawase, Ryota; Nakaoka, Hajime; Nakatani, Kazuhiro; Inagaki, Miwako; Yuasa-Kawase, Miyako; Tsubakio-Yamamoto, Kazumi; Sandoval, Jose C; Masuda, Daisaku; Ohama, Tohru; Nakagawa-Toyama, Yumiko; Matsuyama, Akifumi; Nishida, Makoto; Ishigami, Masato

2009-12-01

In routine clinical laboratory testing and numerous epidemiological studies, LDL-cholesterol (LDL-C) has been estimated commonly using the Friedewald equation. We investigated the relationship between the Friedewald equation and 4 homogeneous assays for LDL-C. LDL-C was determined by 4 homogeneous assays [liquid selective detergent method: LDL-C (L), selective solubilization method: LDL-C (S), elimination method: LDL-C (E), and enzyme selective protecting method: LDL-C (P)]. Samples with discrepancies between the Friedewald equation and the 4 homogeneous assays for LDL-C were subjected to polyacrylamide gel electrophoresis and the beta-quantification method. The correlations between the Friedewald equation and the 4 homogeneous LDL-C assays were as follows: LDL-C (L) (r=0.962), LDL-C (S) (r=0.986), LDL-C (E) (r=0.946) and LDL-C (P) (r=0.963). Discrepancies were observed in sera from type III hyperlipoproteinemia patients and in sera containing large amounts of midband and small dense LDL on polyacrylamide gel electrophoresis. LDL-C (S) was most strongly correlated with the beta-quantification method even in sera from patients with type III hyperlipoproteinemia. Of the 4 homogeneous assays for LDL-C, LDL-C (S) exhibited the closest correlation with the Friedewald equation and the beta-quantification method, thus reflecting the current clinical databases for coronary heart disease.

Arabidopsis Histone Demethylases LDL1 and LDL2 Control Primary Seed Dormancy by Regulating DELAY OF GERMINATION 1 and ABA Signaling-Related Genes

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Ming lei Zhao

2015-03-01

Full Text Available Seed dormancy controls germination and plays a critical role in regulating the beginning of the life cycle of plants. Seed dormancy is established and maintained during seed maturation and is gradually broken during dry storage (after-ripening. The plant hormone abscisic acid (ABA and DELAY OF GERMINATION1 (DOG1 protein are essential regulators of seed dormancy. Recent studies revealed that chromatin modifications are also involved in the transcription regulation of seed dormancy. Here, we showed that two Arabidopsis histone demethylases, LYSINESPECIFIC DEMETHYLASE LIKE 1 and 2 (LDL1 and LDL2 act redundantly in repressing of seed dormancy. LDL1 and LDL2 are highly expressed in the early silique developing stage. The ldl1 ldl2 double mutant displays increased seed dormancy, whereas overexpression of LDL1 or LDL2 in Arabidopsis causes reduced dormancy. Furthermore, we showed that LDL1 and LDL2 repress the expression of seed dormancy-related genes, including DOG1, ABA2 and ABI3 during seed dormancy establishment. Furthermore, genetic analysis revealed that the repression of seed dormancy by LDL1 and LDL2 requires DOG1, ABA2 and ABI3. Taken together, our findings revealed that LDL1 and LDL2 play an essential role in seed dormancy.

Effects of an anti-oxidative ACAT inhibitor on apoptosis/necrosis and cholesterol accumulation under oxidative stress in THP-1 cell-derived foam cells.

Science.gov (United States)

Miike, Tomohiro; Shirahase, Hiroaki; Jino, Hiroshi; Kunishiro, Kazuyoshi; Kanda, Mamoru; Kurahashi, Kazuyoshi

2008-01-02

THP-1 cell-derived foam cells were exposed to oxidative stress through combined treatment with acetylated LDL (acLDL) and copper ions (Cu2+). The foam cells showed caspase-dependent apoptotic changes on exposure to oxidative stress for 6 h, and necrotic changes with the leakage of LDH after 24 h. KY-455, an anti-oxidative ACAT inhibitor, and ascorbic acid (VC) but not YM-750, an ACAT inhibitor, prevented apoptotic and necrotic changes. These preventive effects of KY-455 and VC were accompanied by the inhibition of lipid peroxidation in culture medium containing acLDL and Cu2+, suggesting the involvement of oxidized acLDL in apoptosis and necrosis. Foam cells accumulated esterified cholesterol (EC) for 24 h in the presence of acLDL without Cu2+, which was suppressed by KY-455 and YM-750. Foam cells showed necrotic changes and died in the presence of acLDL and Cu2+. KY-455 but not YM-750 prevented cell death and reduced the amount of EC accumulated. The foam cells treated with VC further accumulated EC without necrotic changes for 24 h even in the presence of acLDL and Cu2+. YM-750 as well as KY-455 inhibited lipid accumulation when co-incubated with VC in foam cells exposed to oxidative stress. It is concluded that an anti-oxidative ACAT inhibitor or the combination of an antioxidant and an ACAT inhibitor protects foam cells from oxidative stress and effectively reduces cholesterol levels, which would be a promising approach in anti-atherosclerotic therapy.

Soluble CD36 and risk markers of insulin resistance and atherosclerosis are elevated in polycystic ovary syndrome and significantly reduced during pioglitazone treatment

DEFF Research Database (Denmark)

Glintborg, Dorte; Højlund, Kurt; Andersen, Marianne

2007-01-01

Objective: We investigated the relation between soluble CD36 (sCD36), risk markers of atherosclerosis and body composition, and glucose and lipid metabolism in polycystic ovary syndrome (PCOS) Research Design and Methods: Thirty PCOS patients were randomized to pioglitazone, 30 mg/day or placebo...... units), oxLDL (44.9 (26.9 - 75.1) vs. 36.1 (23.4 - 55.5) U/l), and hsCRP (0.26 (0.03 - 2.41) vs. 0.12 (0.02 - 0.81) mg/dl) were significantly increased in PCOS patients vs. controls (geometric mean (+/- 2SD)). In PCOS, positive correlations were found between central fat mass and sCD36 (r=0.43), hs......CRP (r=0.43), and IL-6 (r=0.42), all pPCOS patients and controls (n=44). sCD36 and oxLDL were significant...

Influence of a probiotic soy product on fecal microbiota and its association with cardiovascular risk factors in an animal model

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Cavallini Daniela CU

2011-07-01

Full Text Available Abstract Background Previous work showed that daily ingestion of an aqueous soy extract fermented with Enterococcus faecium CRL 183 and Lactobacillus helveticus 416, supplemented or not with isoflavones, reduced the total cholesterol and non-HDL-cholesterol levels, increased the high-density lipoprotein (HDL concentration and inhibited the raising of autoantibody against oxidized low-density lipoprotein (ox-LDL Ab and the development of atherosclerotic lesions. Objective The aim of this study was to characterize the fecal microbiota in order to investigate the possible correlation between fecal microbiota, serum lipid parameters and atherosclerotic lesion development in rabbits with induced hypercholesterolemia, that ingested the aqueous soy extract fermented with Enterococcus faecium CRL 183 and Lactobacillus helveticus 416. Methods The rabbits were randomly allocated to five experimental groups (n = 6: control (C, hypercholesterolemic (H, hypercholesterolemic plus unfermented soy product (HUF, hypercholesterolemic plus fermented soy product (HF and hypercholesterolemic plus isoflavone-supplemented fermented soy product (HIF. Lipid parameters and microbiota composition were analyzed on days 0 and 60 of the treatment and the atherosclerotic lesions were quantified at the end of the experiment. The fecal microbiota was characterized by enumerating the Lactobacillus spp., Bifidobacterium spp., Enterococcus spp., Enterobacteria and Clostridium spp. populations. Results After 60 days of the experiment, intake of the probiotic soy product was correlated with significant increases (P Lactobacillus spp., Bifidobacterium spp. and Enterococcus spp. and a decrease in the Enterobacteria population. A strong correlation was observed between microbiota composition and lipid profile. Populations of Enterococcus spp., Lactobacillus spp. and Bifidobacterium spp. were negatively correlated with total cholesterol, non-HDL-cholesterol, autoantibodies against

Effect of Dietary n-3 Polyunsaturated Fatty Acids on Oxidant/Antioxidant Status in Macrosomic Offspring of Diabetic Rats

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B. Guermouche

2014-01-01

Full Text Available The aim of this work was to determine the effect of dietary n-3 PUFA on oxidant/antioxidant status, in vitro very low and low density lipoprotein (VLDL-LDL, and VLDL-LDL-fatty acid composition in macrosomic pups of diabetic mothers. We hypothesized that n-3 PUFA would improve oxidative stress in macrosomia. Diabetes was induced in female Wistar rats fed with the ISIO diet (control or with the EPAX diet (enriched in n-3 PUFAs, by streptozotocin. The macrosomic pups were killed at birth (day 0 and at adulthood (day 90. Lipid parameters and VLDL-LDL-fatty acid composition were investigated. The oxidant/antioxidant status was determined by measuring plasma oxygen radical absorbance capacity (ORAC, hydroperoxides, carbonyl proteins, and VLDL-LDL oxidation. Macrosomic rats of ISIO fed diabetic mothers showed an increase in plasma and VLDL-LDL-triglycerides and VLDL-LDL-cholesterol levels and altered VLDL-LDL-fatty acid composition. Plasma ORAC was low with high hydroperoxide and carbonyl protein levels. The in vitro oxidizability of VLDL-LDL was enhanced in these macrosomic rats. The EPAX diet corrected lipid parameters and improved oxidant/antioxidant status but increased VLDL-LDL susceptibility to oxidation. Macrosomia is associated with lipid abnormalities and oxidative stress. n-3 PUFA exerts favorable effects on lipid metabolism and on the oxidant/antioxidant status of macrosomic rats. However, there are no evident effects on VLDL-LDL oxidation.

Prevention of LDL-suppression of HMG-CoA reductase (HMGR) activity by progesterone (PG): evidence for cytochrome P-450 involvement

International Nuclear Information System (INIS)

Sexton, R.C.; Gupta, A.; Panini, S.R.; Rudney, H.

1987-01-01

Incubation of rat intestinal epithelial cells (IEC-6) with PG has been reported by us to prevent the suppression of HMGR activity by LDL. In the present study, addition of LDL and PG to IEC-6 cells resulted in a 2 fold increase in cellular free cholesterol (CH) in 24 h, while HMGR activity remained elevated. PG did not affect the internalization and degradation of [ 125 I] LDL nor the accumulation of free [ 3 H] CH in cells incubated with [ 3 H-cholesteryl linoleate]-LDL. Also, PG did not affect the intracellular transport of LDL-derived [ 3 H] CH to the plasma membrane nor the efflux of the [ 3 H] CH into medium containing human high density lipoprotein. Addition of LDL to cells, in which the cellular CH was radiolabeled from [ 3 H] acetate, resulted in an increased formation of radiolabeled oxysterols, detected by HPLC, and a corresponding decrease in HMGR activity. PG attenuated both the LDL-induced formation of oxysterols and suppression of HMGR activity. PG inhibited cytochrome P-450 dependent oxidation of benzphetamine, aminopyrine and aniline by liver microsomes from phenobarbitol treated rats. These results suggest PG may prevent LDL suppression of HMGR activity in IEC-6 cells by inhibiting cytochrome P-450 dependent formation of regulatory oxysterols

Is sdLDL a valuable screening tool for cardiovascular disease in ...

African Journals Online (AJOL)

Radwa Momtaz Abdelsamie Zaki Khalil

Lipoprotein Cholesterol; LDL I, large buoyant LDL; LDL II, intermediate density LDL; LDL III, smaller dense LDL; .... triglycerides >_150 mg, high density lipoprotein (HDL) <40 mg/dl in men ... sion of phenotype B.4,12 For a given triglyceride level, women were .... that sdLDL /LDL ratio is a very strong predictor of CHD in men;.

Rye bran bread intake elevates urinary excretion of ferulic acid in humans, but does not affect the susceptibility of LDL to oxidation ex vivo

DEFF Research Database (Denmark)

Harder, H.; Tetens, I.; Let, Mette Bruni

2004-01-01

Background Rye bread contributes an important part of the whole grain intake in the Scandinavian diet. Ferulic acid is the major phenolic compound in rye bran and is an antioxidant in vitro and may, therefore, contribute to cardioprotective effects of whole grain consumption. Aim of study Firstly...... had no influence on lag time or propagation rate of the LDL oxidation ex vivo. Conclusions The present study demonstrated that ferulic acid from rye bran is bioavailable and that the urinary concentration of ferulic acid reflects the dietary intake of this hydroxycinnamic acid. Within the period...

Lipid accumulation in smooth muscle cells under LDL loading is independent of LDL receptor pathway and enhanced by hypoxic conditions.

Science.gov (United States)

Wada, Youichiro; Sugiyama, Akira; Yamamoto, Takashi; Naito, Makoto; Noguchi, Noriko; Yokoyama, Shinji; Tsujita, Maki; Kawabe, Yoshiki; Kobayashi, Mika; Izumi, Akashi; Kohro, Takahide; Tanaka, Toshiya; Taniguchi, Hirokazu; Koyama, Hidenori; Hirano, Ken-ichi; Yamashita, Shizuya; Matsuzawa, Yuji; Niki, Etsuo; Hamakubo, Takao; Kodama, Tatsuhiko

2002-10-01

The effect of a variety of hypoxic conditions on lipid accumulation in smooth muscle cells (SMCs) was studied in an arterial wall coculture and monocultivation model. Low density lipoprotein (LDL) was loaded under various levels of oxygen tension. Oil red O staining of rabbit and human SMCs revealed that lipid accumulation was greater under lower oxygen tension. Cholesterol esters were shown to accumulate in an oxygen tension-dependent manner by high-performance liquid chromatographic analysis. Autoradiograms using radiolabeled LDL indicated that LDL uptake was more pronounced under hypoxia. This result holds in the case of LDL receptor-deficient rabbit SMCs. However, cholesterol biosynthesis and cellular cholesterol release were unaffected by oxygen tension. Hypoxia significantly increases LDL uptake and enhances lipid accumulation in arterial SMCs, exclusive of LDL receptor activity. Although the molecular mechanism is not clear, the model is useful for studying lipid accumulation in arterial wall cells and the difficult-to-elucidate events in the initial stage of atherogenesis.

Malaysian brown seaweeds Sargassum siliquosum and Sargassum polycystum: Low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and α-glucosidase inhibition activities.

Science.gov (United States)

Nagappan, Hemlatha; Pee, Poh Ping; Kee, Sandra Hui Yin; Ow, Ji Tsong; Yan, See Wan; Chew, Lye Yee; Kong, Kin Weng

2017-09-01

Two Malaysian brown seaweeds, Sargassum siliquosum and Sargassum polycystum were first extracted using methanol to get the crude extract (CE) and further fractionated to obtain fucoxanthin-rich fraction (FRF). Samples were evaluated for their phenolic, flavonoid, and fucoxanthin contents, as well as their inhibitory activities towards low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and α-glucosidase. In LDL oxidation assay, an increasing trend in antioxidant activity was observed as the concentration of FRF (0.04-0.2mg/mL) and CE (0.2-1.0mg/mL) increased, though not statistically significant. As for serum oxidation assay, significant decrease in antioxidant activity was observed as concentration of FRF increased, while CE showed no significant difference in inhibitory activity across the concentrations used. The IC 50 values for ACE inhibitory activity of CE (0.03-0.42mg/mL) were lower than that of FRF (0.94-1.53mg/mL). When compared to reference drug Voglibose (IC 50 value of 0.61mg/mL) in the effectiveness in inhibiting α-amylase, CE (0.58mg/mL) gave significantly lower IC 50 values while FRF (0.68-0.71mg/mL) had significantly higher IC 50 values. The α-glucosidase inhibitory activity of CE (IC 50 value of 0.57-0.69mg/mL) and FRF (IC 50 value of 0.50-0.53mg/mL) were comparable to that of reference drug (IC 50 value of 0.54mg/mL). Results had shown the potential of S. siliquosum and S. polycystum in reducing cardiovascular diseases related risk factors following their inhibitory activities on ACE, α-amylase and α-glucosidase. In addition, it is likelihood that FRF possessed antioxidant activity at low concentration level. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

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Mateusz Maciejczyk

2017-04-01

Full Text Available Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T, Bloom syndrome (BS and Nijmegen breakage syndrome (NBS are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4, oxidised low-density lipoprotein (ox-LDL or Poly (ADP-ribose polymerases (PARP. Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS, and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge.

Science.gov (United States)

Mc Auley, Mark T; Mooney, Kathleen M

2017-07-01

The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our

Prickly pear induces upregulation of liver LDL binding in familial heterozygous hypercholesterolemia

International Nuclear Information System (INIS)

Palumbo, B.; Palumbo, R.; Efthimiou, Y.; Stamatopoulos, J.; Sinzinger, H.; Oguogho, A.; Budinsky, A.; Sinzinger, H.

2003-01-01

The hypoglycemic effect of prickly pear is well known by native local Indian population since a long time. Beside the beneficial effects on lipid metabolism, oxidation injury and platelet function has been claimed in experimental animals. We recently found an upregulation of apo-B/E receptor. We therefore examined 10 patients with isolated heterozygous familial hypercholesterolemia (FH) being enrolled in a dietary run-in phase of 6 weeks after dietary counselling and a further 6 weeks of prickly pear addition. Uptake of autologous 123 I-radiolabeled LDL was determined at entry as well as after 6 weeks of daily prickly pear ingestion. We found a significant (p 176.4 mg/dl; p 123 I-LDL binding by prickly pear in FH-patients in vivo and indicate that prickly pear exerts a significant hypolipidemic action via receptor upregulation. (author)

Inhibition of human low-density lipoprotein oxidation in vitro by Maharishi Ayur-Veda herbal mixtures.

Science.gov (United States)

Sharma, H M; Hanna, A N; Kauffman, E M; Newman, H A

1992-12-01

In this study, we examined the effect of the Maharishi Ayur-Veda herbal mixtures (MAHMs) Maharishi Amrit Kalash-4 and -5 (M-4 and M-5), MA-631, and Maharishi Coffee Substitute (MCS) on low-density lipoprotein (LDL) oxidation and compared the potency of these mixtures to ascorbic acid, alpha-tocopherol, and probucol. LDL was incubated in 95% air and 5% CO2, with or without 3 microM Cu(+2), in the presence or absence of MAHMs, for 6 or 24 h. In a separate experiment, LDL was incubated as above except MAHMs were added at 0, 1.5, and 3.5 h after incubation started to assess their effect on initiation and propagation of LDL oxidation. Our results demonstrate that MAHMs caused concentration-dependent inhibition of LDL oxidation as assessed by thiobarbituric acid-reactive substances and electrophoretic mobility. The MAHM showed more antioxidant potency in preventing LDL oxidation than ascorbic acid, alpha-tocopherol, or probucol. Also, MAHMs inhibited both initiation and propagation of cupric ion-catalyzed LDL oxidation. These results suggest the importance of further research on these herbal mixtures in the investigation of atherosclerosis and free radical-induced injury.

Protective effect of dietary fenugreek (Trigonella foenum-graecum) seeds and garlic (Allium sativum) on induced oxidation of low-density lipoprotein in rats.

Science.gov (United States)

Mukthamba, Puttaswamy; Srinivasan, Krishnapura

2016-01-01

Dietary fenugreek seeds (Trigonella foenum-graecum) and garlic (Allium sativum) have been previously observed to have cardioprotective influence in experimentally induced myocardial infarction in rats. Since low-density lipoprotein (LDL) oxidation is a key factor in the arteriosclerotic process, we evaluated their potential in minimizing the LDL oxidation in rats. Fenugreek seeds, garlic, and their combination were included along with a high-cholesterol diet for 8 weeks. Iron-induced oxidation of LDL in vivo was considerably lowered by dietary fenugreek and garlic. The extent of copper-induced oxidation of isolated LDL in vitro was also significantly lesser in fenugreek-fed or fenugreek+garlic-fed rats. Anodic electrophoretic mobility of the oxidized LDL on agarose gel in case of spice-fed animals was decreased and hence consistent with the observed protective influence on LDL oxidation. Dietary fenugreek, garlic, and their combination significantly lowered lipid peroxide levels in plasma, liver, and heart in iron (II)-administered rats. The results suggest that these two dietary spices have protective effect on LDL oxidation under normal situation as well as in hypercholesterolemic situation. The protective effect of the combination of dietary fenugreek and garlic on LDL oxidation both in vivo and in vitro was greater than that of the individual spices. The protective effect of dietary fenugreek and garlic on LDL oxidation both in vivo and in vitro as evidenced in the present study is suggestive of their cardioprotective potential since LDL oxidation is a key factor in the arteriosclerotic process.

Low-grade endotoxemia, gut permeability and platelet activation in patients with impaired fasting glucose.

Science.gov (United States)

Carnevale, R; Pastori, D; Nocella, C; Cammisotto, V; Baratta, F; Del Ben, M; Angelico, F; Sciarretta, S; Bartimoccia, S; Novo, M; Targher, G; Violi, F

2017-10-01

Impaired fasting glucose (IFG) is associated with an increased risk of cardiovascular disease but the underlying mechanisms are still unclear. Aim of the study was to investigate the interplay between platelet activation, lipopolysaccharides (LPS) and markers of oxidative stress in patients with IFG and control subjects. We performed a cross-sectional study including 35 patients with IFG and 35 control subjects who were well comparable for age, sex, body mass index and smoking history. Serum levels of LPS, zonulin (a marker of gut permeability), oxidized LDL and plasma levels of soluble P-selectin, were measured. Patients with IFG had significantly higher levels of sP-selectin, LPS, zonulin and oxLDL compared to control subjects. The IFG status (beta coefficient: 0.518, p zonulin (r = 0.521, p = 0.001); this association was confirmed at multivariable analysis (beta coefficient: 0.512, p = 0.007). Our study provides evidence that patients with IFG have increased platelet activation, and suggests LPS as a potential trigger for in vivo platelet activation in this patient population. Copyright © 2017. Published by Elsevier B.V.

LDL cholesterol estimation in patients with the metabolic syndrome

OpenAIRE

Gazi, Irene; Tsimihodimos, Vasilis; Filippatos, Theodosios D; Saougos, Vasilios G; Bairaktari, Eleni T; Tselepis, Alexandros D; Elisaf, Moses

2006-01-01

Abstract Background The Friedewald formula (LDL-F) for the estimation of low-density lipoprotein (LDL) cholesterol concentrations is the most often used formula in clinical trials and clinical practice. However, much concern has been raised as to whether this formula is applicable in all patient populations such as the presence of chylomicronaemia and/or hypertriglyceridaemia. The aim of the present study was to evaluate various LDL cholesterol calculation formulas as well as LDL cholesterol ...

The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease

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M. W Twigg

2012-01-01

Full Text Available Cardiovascular disease is the leading cause of death. The disease is due to atherosclerosis which is characterized by lipid and fat accumulation in arterial blood vessel walls. A key causative event is the accumulation of oxidised low density lipoprotein particles within vascular cells, and this is mediated by scavenger receptors. One such molecule is the LOX-1 scavenger receptor that is expressed on endothelial, vascular smooth muscle, and lymphoid cells including macrophages. LOX-1 interaction with OxLDL particles stimulates atherosclerosis. LOX-1 mediates OxLDL endocytosis via a clathrin-independent internalization pathway. Transgenic animal model studies show that LOX-1 plays a significant role in atherosclerotic plaque initiation and progression. Administration of LOX-1 antibodies in cellular and animal models suggest that such intervention inhibits atherosclerosis. Antiatherogenic strategies that target LOX-1 function using gene therapy or small molecule inhibitors would be new ways to address the increasing incidence of vascular disease in many countries.

Non-HDL Cholesterol is a More Superior Predictor of Small-Dense LDL Cholesterol than LDL Cholesterol in Japanese Subjects with TG Levels ＜400 mg/dL.

Science.gov (United States)

Moriyama, Kengo; Takahashi, Eiko

2016-09-01

The Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and treatment of hyperlipidemia in Japanese adults recommend using low-density lipoprotein cholesterol (LDL-C) calculated by Friedewald formula (F_LDL-C) for subjects with triglyceride (TG) levels ＜400 mg/dL and non-high-density lipoprotein cholesterol (non-HDL-C) levels for subjects with TG levels ≥400 mg/dL. Because small-dense LDL particles are more atherogenic than large LDL particles, we sought the better lipid parameter which was more reflective of the high small-dense LDL-C (sdLDL-C) levels in subjects with TG levels ＜400 mg/dL. This study included 769 Japanese subjects who met our inclusion criteria and underwent an annual health examination, including sdLDL-C analyses. The correlation coefficient of non-HDL-C for sdLDL-C (r=0.760) was significantly higher than that of F_LDL-C (r=0.601). The area under the curve (95% confidence interval) was 0.771 (0.731, 0.811) for F_LDL-C and 0.871 (0.842, 0.901) for non HDL-C, which showed significantly higher predictive value for more than fourth quartile value of sdLDL-C (46 mg/dL). The optimal cut-off point of non-HDL-C was 158 mg/dL. Even in subjects stratified by waist circumstance, homeostasis model assessment of insulin resistance, TG, and F_LDL-C levels and non-HDL-C showed stronger relationships with sdLDL-C than F_LDL-C. Moreover, non-HDL-C showed a better relationship with sdLDL-C than total cholesterol (TC), TC/HDL-C, and non-HDL-C/HDL-C. Our data suggested that non-HDL-C is superior to F_LDL-C and one of the reliable surrogate lipid markers of sdLDL-C in Japanese subjects with TG levels ＜400 mg/dL.

Role of alpha-lipoic acid in the management of anemia in patients with chronic renal failure undergoing hemodialysis

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El-Nakib GA

2013-08-01

Full Text Available Gehad A El-Nakib,1 Tarek M Mostafa,2 Tarek M Abbas,4 Mamdouh M El-Shishtawy,3 Mokhtar M Mabrouk,2 Mohammed A Sobh41Mansoura University Hospitals, Mansoura, Egypt; 2Faculty of Pharmacy, Tanta University, Tanta, Egypt; 3Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 4Urology and Nephrology Centre, Faculty of Medicine, Mansoura University, Mansoura, EgyptIntroduction: Anemia associated with chronic kidney disease is a serious complication necessitating expenditure of huge medical efforts and resources. This study investigates the role of alpha-lipoic acid (ALA in end stage renal disease patients undergoing hemodialysis. By the virtue of its antioxidative effects, ALA is expected to act as an erythropoietin (EPO adjuvant, and also has extended beneficial effects on endothelial dysfunction.Methods: Forty-four patients undergoing hemodialysis and receiving EPO were randomized into two groups: the first group received ALA 600 mg once daily for 3 months; while the other group represented the control group. Parameters measured at baseline and at end of study were hemoglobin, EPO doses, EPO resistance index (ERI, iron store indices, malondialdehyde, oxidized low-density lipoprotein (ox-LDL, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and asymmetric dimethylarginine (ADMA, as well as routine laboratory follow-up.Results: EPO doses and ERI were significantly decreased in the treatment group, while they did not change in the control group. Hemoglobin, iron store indices, malondialdehyde, oxidized ox-LDL, IL-6, TNF-α, and ADMA were similar in both treatment and control groups at baseline, and did not change by the end of study period. Likewise, routine laboratory measures were not affected by the treatment.Conclusion: ALA could be used in hemodialysis patients to reduce requirements for EPO. However, larger and longer term studies are required to clarify the exact role of ALA in hemodialysis as well as in pre-hemodialysis patients

LDL oxidation, antioxidant capacity and growth of cultured grey mullet ( Mugil cephalus ) fed dietary sorghum distillery residue pretreated with polyethylene glycol.

Science.gov (United States)

Lee, Shin Mei; Cheng, Hui Ling; Pan, Bonnie Sun

2009-09-09

Dietary sorghum distillery residue (SDR) showed antioxidant and blood thinning effects on grey mullet during winter, but inhibited their growth. The objective of this study was to establish a preliminary treatment of the dietary SDR with polyethylene glycol (PEG), a tannin-binding agent, to enhance growth and blood antioxidant capacity of grey mullet ( Mugil cephalus ) feed. The feeding trial was carried out from June to November. The water temperature was between 25 and 30 degrees C; the specific growth rate of mullet was reduced significantly by feeding diet containing 20% SDR in comparison to fish fed the control diet or diet containing 20% SDR and PEG. In the period of October-November, the water temperature decreased to 19-25 degrees C; the specific growth rates of the 20% SDR-PEG group and the 20% SDR group were 0.13 and 0.19% day(-1), respectively, significantly higher than those fed the control diet (0.07% day(-1)). Feeding with 20% SDR or 20% SDR-PEG diets resulted in prolonged lag phase of low-density lipoprotein (LDL) oxidation compared to fish fed the control diet. The total antioxidant capacity of the plasma of the grey mullet fed 20% SDR-PEG was 1.24 mmol/L, significantly higher than those in the fish fed 20% SDR diet (0.84 mmol/L) or the control (0.72 mmol/L). In vivo observations found that preliminary treatment of SDR with PEG eliminated the endogenous undesirable growth inhibitory factors but maintained its protective effects against LDL oxidation in blood and improved the total antioxidant capacity and cold adaptation of grey mullet. The ethanol extract of SDR contained 31.9 +/- 7.8 mg/g gallic acids equivalent. The concentration needed to scavenge 50% of the DPPH radicals (IC(50)) was 0.86 mg/mL. Increased gallic acid equivalent and decreased IC(50) of DPPH scavenging activity of SDR fed to fish increased the total antioxidant capacity in blood plasma of grey mullet significantly.

Altered lipoproteins in patients with systemic lupus erythematosus are associated with augmented oxidative stress: a potential role in atherosclerosis.

Science.gov (United States)

Park, Jin Kyun; Kim, Jae-Yong; Moon, Jin Young; Ahn, Eun Young; Lee, Eun Young; Lee, Eun Bong; Cho, Kyung-Hyun; Song, Yeong Wook

2016-12-30

To examine the structural and oxidative properties of lipoproteins from patients with systemic lupus erythematosus (SLE). The lipid profiles of 35 SLE patients and 15 healthy controls (HCs) were compared. Oxidation status, susceptibility to oxidation, and structural integrity of low-density lipoprotein (LDL) were determined by measuring malondialdehyde (MDA), de novo formation of conjugated dienes in the presence of CuSO 4 , and mobility on gel electrophoresis, respectively. In vitro foam cell formation and the oxidative potential in zebrafish embryos were examined. LDL levels in SLE patients and HCs were similar (p = 0.277). LDL from SLE patients was more fragmented than that from HCs. In addition, LDL from SLE patients was more oxidized than LDL from HCs (p Lipoproteins from SLE patients exhibited greater oxidative potential, which might contribute to accelerated atherosclerosis in SLE.

Mechanism of edaravone combined with urinary kallidinogenase for acute cerebral infarction patients

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Chun-Yan Du

2017-03-01

Full Text Available Objective: To observe the effects of edaravone combined with urinary kallidinogenase on serum ox-LDL, PCT, hs-CRP, TNF-α and T cell subsets in patients with acute cerebral infarction, so as to explore the mechanisms of combination therapy on patients with acute cerebral infarction. Methods: 86 cases of patients with acute cerebral infarction in our hospital from March 2014 to May 2016 were randomly divided into two groups: control group and observation group, 43 cases in each group. All patients were given general treatment according to their own specific conditions, including hypoglycemic, pressure adjustment, prevention and treatment of complications, symptomatic support therapy, etc. The control group were given 30 mg Edaravone Injection on this basis with once per day for 14 d; The observation group was treated with 0. 15 PNA urinary kallidinogenase intravenous drip with once per day for 14 d on the basis of the control group. The levels of serum x-LDL, PCT, hs-CRP, TNF-α and CD3+, CD4+, CD8+, CD4+/CD8+ were detected and compared between the two groups. Results: (1 Before treatment, there was no significant difference between the two groups on the levels of serum ox-LDL, PCT, hs-CRP, and TNF-α; after treatment, the serum levels of ox-LDL, PCT, hs-CRP and TNF-α in the two groups were significantly lower than that before treatment, and the difference was significant (P<0.05; (2 Before treatment, there was no significant difference between the two groups on the levels of serum CD3+, CD4+, CD8+, CD4+/CD8+; after treatment, the serum levels of CD3+, CD4+ and CD4+/CD8+ were significantly increased in the two groups, and the level of CD8+ was significantly decreased compared with the same group before treatment, and the difference was significant (P<0.05; and the levels of serum CD3+, CD4+, CD8+ and CD4+/CD8+ in the observation group were significantly better than those in the control group, and the difference was significant (P<0

In silico design of anti-atherogenic biomaterials.

Science.gov (United States)

Lewis, Daniel R; Kholodovych, Vladyslav; Tomasini, Michael D; Abdelhamid, Dalia; Petersen, Latrisha K; Welsh, William J; Uhrich, Kathryn E; Moghe, Prabhas V

2013-10-01

Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

Extracts of human atherosclerotic lesions modify LDL inducing enhanced macrophage uptake

International Nuclear Information System (INIS)

Hoff, H.F.; O'Neill, J.

1986-01-01

Both an LDL-like fraction isolated from human aortic plaques and LDL incubated with cultured aortic endothelial or smooth muscle cells have been shown to be internalized by macrophages in vitro in an unregulated fashion leading to foam cell formation. Lipid peroxidation induced by free radicals released from cells was shown to be responsible for cell-modified LDL. The authors incubated LDL with a supernatant fraction of leached, i.e. non-homogenized, extracts of aortic plaques for one hour at 37 0 C, to determine whether extracellular components present in arteries were also capable of modifying LDL. Extract-treated LDL showed the following changes relative to untreated LDL: 1) increased electrophretic mobility, 2) altered pattern of B-100 on SDS-PAGE, i.e. presence of a doublet with higher M/sub r/ than B-100, and 3) enhanced uptake by cultured mouse peritoneal macrophages as measured by increased degradation of 125 I-LDL, and increased stimulation of cholesterol esterification using 14 C-oleate. Extracts from homogenized plaques and grossly normal intima induced similar changes. The modification was tissue specific in that extracts of arteries but not of liver, muscle or skin modified LDL. Protease degradation of LDL during incubation was probably not responsible since inhibitors did not prevent modification. It is possible that products of lipid peroxidation present in extracellular lipid of arteries may propagate free radicals or be incorporated into LDL, leading to modifications similar to those found in cell-modified LDL

Altered Metabolism of LDL in the Arterial Wall Precedes Atherosclerosis Regression

DEFF Research Database (Denmark)

Bartels, Emil D.; Christoffersen, Christina; Lindholm, Marie W.

2015-01-01

and degradation of LDL particles in atherosclerotic aortas of mice by measuring the accumulation of iodinated LDL particles in the arterial wall. Methods and Results: Cholesterol-fed, LDL receptor–deficient mice were treated with either an anti-Apob antisense oligonucleotide or a mismatch control antisense...... oligonucleotide once a week for 1 or 4 weeks before injection with preparations of iodinated LDL particles. The anti-Apob antisense oligonucleotide reduced plasma cholesterol by ≈90%. The aortic LDL permeability and degradation rates of newly entered LDL particles were reduced by ≈50% and ≈85% already after 1...... week of treatment despite an unchanged pool size of aortic iodinated LDL particles. In contrast, the size, foam cell content, and aortic pool size of iodinated LDL particles of aortic atherosclerotic plaques were not reduced until after 4 weeks of treatment with the anti-Apob antisense oligonucleotide...

One-Year Conservative Care Using Sodium Bicarbonate Supplementation Is Associated with a Decrease in Electronegative LDL in Chronic Kidney Disease Patients: A Pilot Study.

Science.gov (United States)

Rizzetto, Felipe; Mafra, Denise; Barra, Ana Beatriz; Pires de Melo, Gisella; Abdalla, Dulcinéia Saes Parra; Leite, Maurilo

2017-10-01

Chronic kidney disease (CKD) patients develop metabolic acidosis when approaching stages 3 and 4, a period in which accelerated atherogenesis may ensue. Studies in vitro show that low pH may increase low-density lipoprotein (LDL) oxidation, suggesting a role for chronic metabolic acidosis in atherosclerosis. The present study attempted to evaluate the effects of conservative care using oral sodium bicarbonate (NaHCO 3 ) supplementation on the electronegative LDL [LDL(-)], a minimally oxidized LDL, plasma levels in CKD patients. Thirty-one CKD patients were followed by a multidisciplinary team during 15 months of care in which 1.0 mmol/kg/day oral NaHCO 3 supplementation was first given in the third month. Blood samples were collected 3 months before the initiation of oral NaHCO 3 supplementation (T1), at the time of the beginning of supplementation (T2), and thereafter, each 4 months (T3, T4 and T5) until month 15 of care. Blood parameters and LDL(-) were measured from these collections. After 12 months of conservative care, creatinine clearance (MDRD) was kept stable, and serum bicarbonate (HCO 3 - ) increased from 20.5 ± 2.9 to 22.6 ± 1.1 mM ( p < 0.003). LDL(-) plasma levels declined from 4.5 ± 3.3 to 2.1 ± 0.9 U/L ( p < 0.007) after reaching mean serum HCO 3 - levels of 22.6 ± 1.1 mM. Conservative care using oral NaHCO 3 supplementation was able to stabilize renal function and decrease serum levels of LDL(-), a modified proatherogenic lipoprotein, only when mean serum HCO 3 - levels approached 22 mM. This study constitutes evidence that alkali therapy, in addition to its beneficial effect on renal disease progression, might serve as a preventive strategy to attenuate atherogenesis in CKD patients.

LDL receptor-GFP fusion proteins: new tools for the characterization of disease-causing mutations in the LDL receptor gene

DEFF Research Database (Denmark)

Holst, Henrik Uffe; Dagnæs-Hansen, Frederik; Corydon, Thomas Juhl

2001-01-01

. In cultured liver cells this mutation was found to inhibit the transport of LDL receptor GFP fusion protein to the cell surface, thus leading to impaired internalisation of fluorescent labelled LDL. Co-locallisation studies confirmed the retention of the mutant protein in the endoplasmic reticulum....

Daily Nutritional Dose Supplementation with Antioxidant Nutrients and Phytochemicals Improves DNA and LDL Stability: A Double-Blind, Randomized, and Placebo-Controlled Trial

Directory of Open Access Journals (Sweden)

You Jin Kim

2013-12-01

Full Text Available Reactive oxygen species are important risk factors for age-related diseases, but they also act as signaling factors for endogenous antioxidative defense. The hypothesis that a multi-micronutrient supplement with nutritional doses of antioxidant nutrients and phytochemicals (MP may provide protection against oxidative damage and maintain the endogenous antioxidant defense capacity was assessed in subjects with a habitually low intake of fruits and vegetables. In a randomized, placebo-controlled, and parallel designed trial, 89 eligible subjects were assigned to either placebo or MP for eight weeks. Eighty subjects have completed the protocol and included for the analysis. MP treatment was superior at increasing serum folate (p < 0.0001 and resistance to DNA damage (p = 0.006, tail intensity; p = 0.030, tail moment by comet assay, and LDL oxidation (p = 0.009 compared with the placebo. Moreover, the endogenous oxidative defense capacity was not weakened after MP supplementation, as determined by the levels of glutathione peroxidase (p = 0.442, catalase (p = 0.686, and superoxide dismutase (p = 0.804. The serum folate level was negatively correlated with DNA damage (r = −0.376, p = 0.001 for tail density; r = −0.329, p = 0.003 for tail moment, but no correlation was found with LDL oxidation (r = −0.123, p = 0.275. These results suggest that MP use in healthy subjects with habitually low dietary fruit and vegetable intake may be beneficial in providing resistance to oxidative damage to DNA and LDL without suppressing the endogenous defense mechanisms.

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

Energy Technology Data Exchange (ETDEWEB)

Moyer, Benjamin J. [Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Rojas, Itzel Y. [Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Kerley-Hamilton, Joanna S. [Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Hazlett, Haley F. [Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Department of Immunology & Microbiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Nemani, Krishnamurthy V. [Department of Radiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Trask, Heidi W.; West, Rachel J. [Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Lupien, Leslie E. [Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Collins, Alan J. [Department of Immunology & Microbiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); and others

2016-06-01

specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications. - Highlights: • The AHR acts as a hub in Western diet-based obesity. • Inhibition of AHR signaling by antagonists prevents obesity and liver steatosis. • ox-LDL stimulates AHR activity via a TLR2/4, NF-kB, IDO1, kynurenine axis. • TGFβ stimulates AHR activity in Hepa-1c1c7 cells via PI3K and NF-kB. • The AHR offers a simple and promising approach for treating obesity.

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

International Nuclear Information System (INIS)

Moyer, Benjamin J.; Rojas, Itzel Y.; Kerley-Hamilton, Joanna S.; Hazlett, Haley F.; Nemani, Krishnamurthy V.; Trask, Heidi W.; West, Rachel J.; Lupien, Leslie E.; Collins, Alan J.

2016-01-01

specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications. - Highlights: • The AHR acts as a hub in Western diet-based obesity. • Inhibition of AHR signaling by antagonists prevents obesity and liver steatosis. • ox-LDL stimulates AHR activity via a TLR2/4, NF-kB, IDO1, kynurenine axis. • TGFβ stimulates AHR activity in Hepa-1c1c7 cells via PI3K and NF-kB. • The AHR offers a simple and promising approach for treating obesity.

Estradiol protective role in atherogenesis through LDL structure modification

International Nuclear Information System (INIS)

Papi, Massimiliano; Ciasca, Gabriele; Maiorana, Alessandro; Maulucci, Giuseppe; Palmieri, Valentina; De Spirito, Marco; Brunelli, Roberto; Parasassi, Tiziana

2016-01-01

Relevant physiological functions are exerted by circulating low density lipoprotein (LDL) as well as eventual pathological processes triggering atherogenesis. Modulation of these functions can well be founded on modifications of LDL structure. Given its large dimension, multicomponent organization and strong interactions between the protein apoB-100 and lipids, determining LDL 3D structure remains a challenge. We propose a novel quantitative physical approach to this complex biological problem. We introduce a three-component model, fitted to small angle x-ray scattering data on LDL maintained in physiological conditions, able to achieve a consistent 3D structure. Unexpected features include three distinct protein domains protruding out of a sphere, quite rough in its surface, where several core lipid areas are exposed. All LDL components are affected by 17- β -estradiol (E2) binding to apoB-100. Mostly one of the three protruding protein domains, dramatically reducing its presence on the surface and with a consequent increase of core lipids’ exposure. This result suggests a structural basis for some E2 protecting roles and LDL physiological modifications. (paper)

Lipid profiles of non-diabetic healthy and ischaemic heart disease patients

International Nuclear Information System (INIS)

Shahzad, F.; Tawwab, S.; Ahsan, U.

2013-01-01

Objective: To find any difference in the fasting lipid profile in patients with history of ischaemic heart disease (IHD) and established atherosclerotic plaques on angiography and in subjects with no known history of IHD. Study Design: Observational, cross-sectional study. Place and Duration of Study: Immunology Department of University of Health Sciences, Lahore, from January 2007 to January 2009. Methodology: In this study, 200 male subjects, between 40 and 60 years of age were recruited. Serum cholesterol and triglycerides were determined by enzymatic CHOD-PAP and GPO-PAP calorimetric method, HDL-C by accelerator selective detergent method and LDL-C by direct homogeneous enzymatic method. Serum ox-LDL contents were determined by using quantitative sandwich enzyme immuno-assay kits. Results: The total serum cholesterol, triglyceride and LDL-C levels were within the normal range in control and patient groups whereas HDL-C levels were significantly higher in the control group compared to the patient group (p = 0.001). A significant difference (p = 0.001) for HDL-C levels was observed between smokers and non-smokers. Serum ox-LDL levels were higher in patient group as compared to the control group but the difference was not statistically significant. Conclusion: The significantly lower HDL levels in patient group with normal cholesterol, LDL and triglyceride levels may suggest low HDL-C has a greater role in IHD. Raising plasma HDL-cholesterol through weight loss, healthy diet, increased physical activity and by proper pharmacotherapy is, therefore, a legitimate therapeutic target for the optimal prevention of CHD in native population. (author)

Oxidative markers, nitric oxide and homocysteine alteration in hypercholesterolimic rats: role of atorvastatine and cinnamon.

Science.gov (United States)

Amin, Kamal A; Abd El-Twab, Thanaa M

2009-10-05

To investigate the effects of atorvastatin and cinnamon on serum lipid profile, oxidative stress, antioxidant capacity, hepatic enzymes activities, nitric oxide (NO) as well as homocysteine (Hcy) in hypercholesterolemic rats, 48 male albino rats, weighing 130-190 gm were divided into 2 groups, normal group fed on basal rat chow diet (n=12) and high cholesterol group (HCD) were fed on 1% cholesterol-enriched diet for 15 day (n=36). Hypercholesterolemic rats were divided into 3 subgroups (n=12 for each) fed the same diet and treated with atorvastatine (HCD+Atorvastatin) or cinnamon extract (HCD+cinnamon) or none treated (HCD) for 3&6 weeks. Serum triglycerides (TG), Total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), ALT, AST, NO, Hcy, hepatic reduced glutathione (GSH), Malondialdehyde (MDA) and antioxidant enzymes, Superoxide dismutase (SOD) and catalase activity were measured. Results showed that HCD increased significantly TG, TC, LDL-C, ALT, AST, Hcy and hepatic MDA, while lowered significantly antioxidant enzyme activities and NO levels. Atorvastatin therapy significantly increased HDL-C, NO and antioxidant activity while decreased LDL-C, MDA and Hcy concentrations. Serum TG, TC, LDL-C, ALT, AST and hepatic MDA levels were significantly lowered meanwhile, serum HDL, NO values and hepatic antioxidant activities were significantly, higher in cinnamon-treated than untreated group. These results indicate that lipid abnormalities, oxidative injury and hyperhomocystienemia were induced by HCD and this study recommend that administration of atorvastatine or cinnamon provided protection against the lipemic-oxidative disorder and act as hypocholesterolemic, hepatoprotective agent and improve cardiovascular function through modulation of oxidative stress, NO and Hcy.

PPARγ Ligand-Induced Unfolded Protein Responses in Monocytes

African Journals Online (AJOL)

High levels of oxLDL lead to cell dysfunction and apoptosis, a phenomenon known as lipotoxicity. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response (UPR), which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. In the present study the ...

Oxidative Damage to the Salivary Glands of Rats with Streptozotocin-Induced Diabetes-Temporal Study: Oxidative Stress and Diabetic Salivary Glands

OpenAIRE

Kna?, M.; Maciejczyk, M.; Daniszewska, I.; Klimiuk, A.; Matczuk, J.; Ko?odziej, U.; Waszkiel, D.; ?adny, J. R.; ?endzian-Piotrowska, M.; Zalewska, A.

2016-01-01

Objective. This study evaluated oxidative damage caused to the salivary glands in streptozotocin-induced diabetes (DM). Materials and Methods. Rats were divided into 4 groups: groups 1 and 2, control rats, and groups 3 and 4, DM rats. 8-Hydroxy-2′-deoxyguanosine (8-OHdG), protein carbonyl (PC), 4-hydroxynonenal protein adduct (4-HNE), oxidized and/or MDA-modified LDL-cholesterol (oxy-LDL/MDA), 8-isoprostanes (8-isoP), and oxidative stress index (OSI) were measured at 7 (groups 1 and 3) and 14...

Increased fluidity and oxidation of malarial lipoproteins: relation with severity and induction of endothelial expression of adhesion molecules

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Looareesuwan Sornchai

2004-06-01

Full Text Available Abstract Introduction Oxidative stress has been demonstrated in malaria. The potential oxidative modification of lipoproteins derived from malaria patients was studied. These oxidized lipids may have role in pathogenesis of malaria. Method The plasma lipid profile and existence of oxidized forms of very low density lipoprotein (VLDL, low density lipoprotein (LDL and high density lipoprotein (HDL were investigated in malaria (17 mild and 24 severe patients and 37 control subjects. Thiobarbituric acid reactive substances (TBARs, conjugated dienes, tryptophan fluorescence and fluidity of lipoproteins were determined as markers of oxidation. The biological effect of malarial lipoproteins was assessed by the expression of adhesion molecules on endothelial cells. Results Malarial lipoproteins had decreased cholesterol (except in VLDL and phospholipid. The triglyceride levels were unchanged. The cholesterol/phospholipid ratio of LDL was decreased in malaria, but increased in VLDL and HDL. TBARs and conjugate dienes were increased in malarial lipoproteins, while the tryptophan fluorescence was decreased. The fluidity of lipoproteins was increased in malaria. These indicated the presence of oxidized lipoproteins in malaria by which the degree of oxidation was correlated with severity. Of three lipoproteins from malarial patients, LDL displayed the most pronounced oxidative modification. In addition, oxidized LDL from malaria patients increased endothelial expression of adhesion molecules. Conclusion In malaria, the lipoproteins are oxidatively modified, and the degree of oxidation is related with severity. Oxidized LDL from malarial patients increases the endothelial expression of adhesion molecules. These suggest the role of oxidized lipoproteins, especially LDL, on the pathogenesis of disease.

The effect of lowering LDL cholesterol on vascular access patency

DEFF Research Database (Denmark)

Herrington, William; Emberson, Jonathan; Staplin, Natalie

2014-01-01

BACKGROUND AND OBJECTIVES: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering LDL-C on vascular access patency is unclear. DESIGN, SETTING, PARTICIPANTS...

Antioxidant effects of 14 Chinese traditional medicinal herbs against human low-density lipoprotein oxidation

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Hsin-Hung Lin

2015-01-01

Full Text Available The relationship between the antioxidant activities and inhibitory effect of 14 Chinese medicinal herbs against oxidized low-density lipoprotein (LDL formation was evaluated. Prolongation of the lag phase of LDL oxidation depended on the concentration of the herbs. The concentration of each herb that was able to prolong the lag time by about two-fold was calculated and expressed as doubling-time concentration. The lower the doubling-time concentration, the stronger the inhibitory effect exhibited toward LDL oxidation. Among them, Chrysanthemi Flos (Chrysanthemum morifolium ramat; 甘菊花 gān jú huā, Crataegi Fructus (Crataegus pinnatifida Bge. var. major N.E.Br.; 山楂 shān zhā, and Roselle (Hibiscus sabdariffa Linn.; 洛神 luò shén showed significant inhibitory effects. Correlation coefficients between doubling-time concentration and radical-scavenging activities were high; the total phenolic content was also high. In conclusion, phenolic compounds contributed not only to antioxidant activities, but also to the inhibitory effect against LDL oxidation. Chrysanthemi Flos, Crataegi Fructus, and H. sabdariffa, with lower doubling-time concentrations, could be potent phytochemical agents to reduce LDL oxidation and prevent the progression of atherosclerosis.

Acute effects of vinegar intake on some biochemical risk factors of atherosclerosis in hypercholesterolemic rabbits

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rohani Ali

2010-01-01

Full Text Available Abstract Background Exaggerated postprandial spikes in blood glucose and lipids induce proportional increases in oxidative stress, which acutely trigger impairment endothelial, inflammation and increased risk of future cardiovascular events. In this research, we have investigated acute effects of vinegar intake on some of the biochemical atherosclerosis risk factors in high cholesterol fed rabbits to see if we can find a probable protective value for it. Methods The rabbits were randomly divided into four groups: normal diet, high cholesterol diet (%1cholesterol, %1 cholesterol with 5 ml vinegar (low dose, %1 cholesterol with 10 ml vinegar (high dose. After fasting for 12-15 hours, blood samples were taken to determine baseline values. Three hours after feeding, blood samples were collected again to investigate acute effects of vinegar intake on the measured factors. Results Using high-dose vinegar with cholesterolemic diet caused significant reduce in LDL-cholesterol (LDL-C, oxidized-LDL (ox-LDL, malondialdehyde (MDA, total cholesterol (TC and apolipoprotein B (ApoB in comparison with hypercholesterolemic diet. Consumption low-dose vinegar with cholesterolemic diet induced a significant decrease in fibrinogen and glucose compared to hypercholesterolemic diet. Level of serum nitrite, nitrate, triacylglycerol (TAG, HDL-cholesterol (HDL-C, apolipoprotein A (ApoA, serum glutamic pyruvic transaminase (SGPT, serum glutamic oxaloacetate transaminase (SGOT and C-reactive protein (CRP were not significantly difference in low and high doses vinegar with cholesterolemic diet compared to hypercholesterolemic diet. A significant difference was observed for LDL-C, ApoB100 and TC between low and high doses vinegar. Conclusion This study suggest that vinegar, might have some acute effects on biochemical risk factors of atherosclerosis and a probable protective value can be considered for its postprandial use.

Multimeric and trimeric subunit SP-D are interconvertible structures with distinct ligand interaction

DEFF Research Database (Denmark)

Sørensen, Grith Lykke; Hoegh, Silje V; Leth-Larsen, Rikke

2009-01-01

-D compared to Met11 SP-D. Multimerization has proven important for enhancement of microbial phagocytosis. In the present study defined multimeric forms of Met11Thr SP-D were isolated from human amniotic fluid. Implementation of ManNAc-affinity chromatography allowed high recovery of natural trimeric SP......-D multimers. Trimeric SP-D subunits also showed greater binding to endogenous lipoproteins: LDL, oxLDL, and HDL, than multimeric SP-D. In conclusion, purified trimeric and multimeric SP-D represent separate and only partly interconvertible molecular populations with distinct biochemical properties....

Effects of the duration of hyperlipidemia on cerebral lipids, vessels and neurons in rats.

Science.gov (United States)

Yang, Weichun; Shi, He; Zhang, Jianfen; Shen, Ziyi; Zhou, Guangyu; Hu, Minyu

2017-01-31

The present study was designed to investigate the effects of hyperlipidemia on the cerebral lipids, vessels and neurons of rats, and to provide experimental evidence for subsequent intervention. One hundred adult SD rats, half of which were male and half of which were female, were randomly divided into five groups on the basis of serum total cholesterol (TC) levels. Four groups were fed a hypercholesterolemic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil - this is also called a CCT diet) for periods of 1 week, 2 weeks, 3 weeks and 4 weeks, respectively. A control group was included. The levels of serum lipids, cerebral lipids, free fatty acids (FFA), interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), oxidized low density lipoprotein (ox-LDL), A-beta precursor proteins (APP), amyloid beta (Aβ), glial fibrillary acidic protein (GFAP) and tight junction protein Claudin-5 were measured after the experiment. The pathologic changes and apoptosis of the rat brains were evaluated. Compared with the control group, after 1 week of a CCT diet, the levels of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and brain triglycerides had increased by 2.40, 1.29 and 1.75 and 0.3 times, respectively. The serum high density lipoprotein cholesterol (HDL-C) had decreased by 0.74 times (P neurons, had increased (P neurons had increased (P neuronal apoptosis in the rat brains, and they all were negatively correlated with Claudin-5 (P neurons by causing the secretion of TNF-α and IL-1 in the brains of rats. In the metabolic procession, brain tissue was shown to generate FFA that aggravated the biosynthesis of ox-LDL. With the extension of the duration of hyperlipidemia, high levels of cerebral TC and LDL-C were shown to aggravate the deposition of Aβ, induce the secretion of VEGF, reduce the expression of tight

Regulation of plasma LDL: the apoB paradigm.

NARCIS (Netherlands)

Sniderman, A.D.; Graaf, J. de; Couture, P.; Williams, K.; Kiss, R.S.; Watts, G.F.

2010-01-01

The objectives of this analysis are to re-examine the foundational studies of the in vivo metabolism of plasma LDL (low-density lipoprotein) particles in humans and, based on them, to reconstruct our understanding of the governance of the concentration of plasma LDL and the maintenance of

Pemanfaatan ekstrak jintan hitam untuk menurunkan kadar enzim LPPLA2 sebagai kandidat pengobatan aterosklerosis

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Retno Susilowati

2013-10-01

Full Text Available Ox-LDL deposits in the sub-endothelial easily occur in individuals who have hyperlipidemia accompanied with oxidative stress. The enzyme Lp-PLA2 is an enzyme marker of three proaterogenik conditions, those are hyperlipidemia, oxidative stress and inflammation. Black cumin seeds (Nigella sativa L. have antioxidants ingredient that can inhibit lipid peroxidation, and expected to inhibit atherosclerosis through decreased levels of the enzyme Lp-PLA2 and F2-Isp. This study used posttest only control group design using experimental animals Rattus norvegicus Wistar males. The study analysied the number of foam cells, lipid profi le, Lp-PLA2 and F2-Isp plasma levels in hyperlipidemia rats were given extracts of black cumin seeds with 3 different doses (0; 3.6 and 7.2 mg / kg. The results showed that the extract of black cumin seeds can decrease serum levels of Lp-PLA2, tend to reduce the formation of foam cells, but not signifi cant to decreasing levels of F2-Isp. Black cumin seeds extract can decrease cholesterol, TG, LDL and increase HDL in the blood serum. The extract of black cumin seeds is anti atherogenic by reducing the enzyme Lp-PLA2 and improve lipid profiles

Hypolipidemic therapy modulates expression of apolipoprotein B (APOB) epitopes on low density lipoproteins (LDL)

International Nuclear Information System (INIS)

Kleinman, Y.; Schonfeld, g.; Oshry, Y.; Gevish, d.; Eisenberg, S.

1986-01-01

LDL of untreated hypertriglyceridemic (HTG) patients are smaller and enriched in triglycerides and proteins compared with normal LDL. HTG-LDL also bind defectively to the LDL receptor of cultured human fibroblasts. These defects are reversible by hypolipidemic therapy. The authors tested the hypothesis that LDL binding to cells may be altered by modulation of apoB epitopes on the surface of LDL. Fasting plasma samples were obtained from 5 HTG patients before and three weeks after bezafibrate therapy when mean triglyceride levels were 436 and 157 mg/dl, respectively (p 50 values of LDL with Mab B1B3 fell from 6.0 to 3.2 μg LDL protein (p 50 did not change with Mab D7.1. Thus, the improved interaction of LDL is related to the altered disposition of apoB on LDL

Effects of atorvastatin on biomarkers of immune activation, inflammation, and lipids in virologically suppressed, human immunodeficiency virus-1-infected individuals with low-density lipoprotein cholesterol <130 mg/dL (AIDS Clinical Trials Group Study A5275).

Science.gov (United States)

Nixon, Daniel E; Bosch, Ronald J; Chan, Ellen S; Funderburg, Nicholas T; Hodder, Sally; Lake, Jordan E; Lederman, Michael M; Klingman, Karin L; Aberg, Judith A

Persistent immune activation and inflammation in virologically suppressed human immunodeficiency virus (HIV) infection are linked to excess cardiovascular risk. To evaluate atorvastatin as a strategy to reduce cardiovascular risk. A5275 was a multicenter, prospective, randomized, double-blind, placebo-controlled, cross-over pilot study of atorvastatin (10 mg/day for 4 weeks then 20 mg/day for 16 weeks) with a planned enrollment of 97 HIV-infected participants ≥18 years old, receiving boosted protease inhibitor-based antiretroviral therapy for ≥6 months, with plasma HIV-1 RNAs below limits of quantification ≥180 days, and fasting low-density lipoprotein (LDL) cholesterol ≥70 and atorvastatin treatment. Analyses were as-treated. Ninety-eight participants were enrolled at 31 U S sites and 73 completed study treatment. Atorvastatin treatment did not decrease T-lymphocyte or monocyte activation, circulating biomarker levels (interleukin-6, D-dimer, soluble CD14, soluble CD163, monocyte chemoattractant protein-1, interferon-gamma-induced protein-10, high-sensitivity C-reactive protein, CD40L, and P-selectin) or white blood cell Krüppel-like Factor 2/4 messenger RNA levels. Pre-to-post atorvastatin reductions in calculated LDL (-38%), oxidized-LDL (-33%), and lipoprotein-associated phospholipase A2 (-31%) were significant (P atorvastatin did not significantly decrease levels of soluble or cellular biomarkers of immune activation and inflammation but resulted in robust reductions in LDL cholesterol, oxLDL, and lipoprotein-associated phospholipase A 2 , biomarkers associated with cardiovascular risk. Copyright © 2016 National Lipid Association. All rights reserved.

Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters.

Science.gov (United States)

Briand, François; Thieblemont, Quentin; Muzotte, Elodie; Sulpice, Thierry

2013-01-01

This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters. In vivo reverse cholesterol transport was measured after an intravenous injection of (3)H-cholesteryl-oleate-labeled/oxidized low density lipoprotein particles ((3)H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further (3)H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E-rich HDL levels and significantly increased (3)H-tracer appearance in HDL by 30% over 72 hours after (3)H-oxLDL injection. However, TOR did not change (3)H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After (3)H-oxLDL injection, TOR+berberine significantly increased (3)H-tracer appearance in fecal cholesterol by 109%. Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process.

Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

International Nuclear Information System (INIS)

Pires, L.A.; Hegg, R.; Freitas, F.R.; Tavares, E.R.; Almeida, C.P.; Baracat, E.C.; Maranhão, R.C.

2012-01-01

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy

Enhanced susceptibility of low-density lipoproteins to oxidation in coronary bypass patients with progression of atherosclerosis

NARCIS (Netherlands)

Rijke, Y.B. de; Verwey, H.F.; Vogelezang, C.J.M.; Velde, E.A. van der; Princen, H.M.G.; Laarse, A. van der; Bruschke, A.V.G.; Berkel, T.J.C. van

1995-01-01

Oxidation of low-density lipoprotein (LDL) may play a causal role in atherosclerosis. In this study we analyzed whether the severity of progression of coronary atherosclerosis is related to the susceptibility of LDL to oxidative modification. On the basis of repeated coronary angiography, 28

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

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Ray, Kausik K; Landmesser, Ulf; Leiter, Lawrence A; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P T; Turner, Traci; Visseren, Frank L J; Wijngaard, Peter; Wright, R Scott; Kastelein, John J P

2017-04-13

In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (PLDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company

Yoghurt kedelai hitam (black soyghurt dapat menurunkan kadar LDL tikus hiperkolesterolemia

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Slamet Riyanto

2016-08-01

Full Text Available ABSTRACTBackground: Hypercholesterolemia is a main risk factor of cardiovascular disease that remains the higher cause of deaths in the world. Black soy bean containing protein, fiber, vitamin, isoflavon, and flavonoid can decrease serum cholesterol level. Yoghurt contains lactic acid bacteria that decrease total and LDL cholesterol, triglyceride, and increase the HDL cholesterol. Processing of black soy bean into black soyghurt can increase its isoflavon’s activity by forming aglicone, which has higher activity to decrease cholesterol.Objectives: To know the effect of black soyghurt feeding to LDL, HDL, and HDL ratio of hypercholesterolemic rats.Methods: This research was true-experimental using post test only with control group design. Subjects were 20 male Sprague dawley rats, 2 months old, inducted hypercholesterolemia, given black soyghurt diet using 2 mL, 3 mL, and 4 mL dosage for 21 days. Serum lipid profile were measured by CHOD-PAPand GPO-PAP methods respectively. Normality of the data were tested by Shapiro Wilks test. Data were analyzed by paired t test and Anova continued by LSD test using computer program.Results: The study revealed that black soyghurt 4 mL/day decreased LDL (p=0.02 at the most significant level. The other doses did not significantly influence the levels of LDL (p>0.05 . There was also no effect of black soyghurt feeding on serum HDL cholesterol levels (p=0.11 and the ratio of LDL /HDL (p=0.087.Conclusions: The feeding of black soyghurt at the dosage of 4 mL/day to hypercholesterolemic rats could decrease the serum LDL, but could decrease the ratio of LDL / HDL significantly.KEYWORDS: black soyghurt, LDL/HDL ratio, hypercholesterolemicABSTRAKLatar belakang: Hiperkolesterolemia merupakan faktor risiko penyakit kardiovaskuler yang menjadi penyebab kematian utama di dunia. Kedelai hitam mengandung protein, vitamin, serat, isoflavon, dan flavonoid yang mampu menurunkan kadar kolesterol. Yoghurt

Associations of serum LDL particle concentration with carotid intima-media thickness and coronary artery calcification.

Science.gov (United States)

Zaid, Maryam; Miura, Katsuyuki; Fujiyoshi, Akira; Abbott, Robert D; Hisamatsu, Takashi; Kadota, Aya; Arima, Hisatomi; Kadowaki, Sayaka; Torii, Sayuki; Miyagawa, Naoko; Suzuki, Sentaro; Takashima, Naoyuki; Ohkubo, Takayoshi; Sekikawa, Akira; Maegawa, Hiroshi; Horie, Minoru; Nakamura, Yasuyuki; Okamura, Tomonori; Ueshima, Hirotsugu

2016-01-01

Low-density lipoprotein particle (LDL-P) has recently been found to be a stronger predictor of cardiovascular disease (CVD) than LDL-cholesterol (LDL-C). Whether LDL-P is associated with subclinical atherosclerosis, independent of LDL-C, as well as other lipid measures has not been fully examined. We aimed to analyze LDL-P associations with measures of subclinical atherosclerosis. We examined 870 Japanese men randomly selected from Kusatsu City, Shiga, Japan, aged 40-79 years from 2006-2008, free of clinical CVD and not using lipid-lowering medication. Cross-sectional associations of lipid measures with carotid intima-media thickness (cIMT) and coronary artery calcification (CAC; >0 Agatston score) were examined. LDL-P was significantly positively associated with cIMT and maintained this association after adjustments for LDL-C and other lipid measures. Although these lipid measures were positively associated with cIMT, model adjustment for LDL-P removed any significant relationships. Higher LDL-P was associated with a significantly higher odds ratio of CAC and further adjustment for LDL-C did not affect this relationship. In contrast, the LDL-C association with CAC was no longer significant after adjustment for LDL-P. Other lipid measures attenuated associations of LDL-P with CAC. Likewise, associations of these measures with CAC were attenuated when model adjustments for LDL-P were made. In a community-based sample of Japanese men, free of clinical CVD, LDL-P was a robust marker for subclinical atherosclerosis, independent of LDL-C and other lipid measures. Associations of LDL-C and other lipid measures with either cIMT or CAC were generally not independent of LDL-P. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Göttingen minipig model of diet-induced atherosclerosis: influence of mild streptozotocin-induced diabetes on lesion severity and markers of inflammation evaluated in obese, obese and diabetic, and lean control animals

DEFF Research Database (Denmark)

Ludvigsen, Trine Pagh; Kirk, Rikke Kaae; Christoffersen, Berit Østergaard

2015-01-01

in human patients, inclusion of this disease aspect in the characterization of a such model, is highly relevant. The objective of this study was to evaluate the effect of mild streptozotocin-induced diabetes on ex- and in vivo end-points in a diet-induced atherosclerotic minipig model. Castrated male...... Göttingen minipigs were fed standard chow (CD), atherogenic diet alone (HFD) or with superimposed mild streptozotocin-induced diabetes (HFD-D). Circulating markers of inflammation (C-reactive protein (CRP), oxidized low-density lipoprotein (oxLDL), plasminogen activator inhibitor-1, lipid and glucose......From a pharmacological perspective, readily-available, well-characterized animal models of cardiovascular disease, including relevant in vivo markers of atherosclerosis are important for evaluation of novel drug candidates. Furthermore, considering the impact of diabetes mellitus on atherosclerosis...

Atorvastatin treatment lowers fasting remnant-like particle cholesterol and LDL subfraction cholesterol without affecting LDL size in type 2 diabetes mellitus: Relevance for non-HDL cholesterol and apolipoprotein B guideline targets

NARCIS (Netherlands)

Kappelle, Paul J. W. H.; Dallinga-Thie, Geesje M.; Dullaart, Robin P. F.

2010-01-01

The extent to which atorvastatin treatment affects LDL size, LDL subfraction levels and remnant-like particle cholesterol (RLP-C) was determined in type 2 diabetes. We also compared LDL size and RLP-C in relation to guideline cut-off values for LDL cholesterol, non-HDL cholesterol and apolipoprotein

Atorvastatin treatment lowers fasting remnant-like particle cholesterol and LDL subfraction cholesterol without affecting LDL size in type 2 diabetes mellitus : Relevance for non-HDL cholesterol and apolipoprotein B guideline targets

NARCIS (Netherlands)

Kappelle, Paul J.W.H.; Dallinga-Thie, Geesje M.; Dullaart, Robin P. F.

The extent to which atorvastatin treatment affects LDL size, LDL subfraction levels and remnant-like particle cholesterol (RLP-C) was determined in type 2 diabetes. We also compared LDL size and RLP-C in relation to guideline cut-off values for LDL cholesterol, non-HDL cholesterol and apolipoprotein

Rhynchophylla total alkaloid rescues autophagy, decreases oxidative stress and improves endothelial vasodilation in spontaneous hypertensive rats.

Science.gov (United States)

Li, Chao; Jiang, Feng; Li, Yun-Lun; Jiang, Yue-Hua; Yang, Wen-Qing; Sheng, Jie; Xu, Wen-Juan; Zhu, Qing-Jun

2018-03-01

Autophagy plays an important role in alleviating oxidative stress and stabilizing atherosclerotic plaques. However, the potential role of autophagy in endothelial vasodilation function has rarely been studied. This study aimed to investigate whether rhynchophylla total alkaloid (RTA) has a positive role in enhancing autophagy through decreasing oxidative stress, and improving endothelial vasodilation. In oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs), RTA (200 mg/L) significantly suppressed ox-LDL-induced oxidative stress through rescuing autophagy, and decreased cell apoptosis. In spontaneous hypertensive rats (SHR), administration of RTA (50 mg·kg -1 ·d -1 , ip, for 6 weeks) improved endothelin-dependent vasodilation of thoracic aorta rings. Furthermore, RTA administration significantly increased the antioxidant capacity and alleviated oxidative stress through enhancing autophagy in SHR. In ox-LDL-treated HUVECs, we found that the promotion of autophagy by RTA resulted in activation of the AMP-activated protein kinase (AMPK) signaling pathway. Our results show that RTA treatment rescues the ox-LDL-induced autophagy impairment in HUVECs and improves endothelium-dependent vasodilation function in SHR.

LDL cholesterol lowering beyond statins

NARCIS (Netherlands)

Akdim, F.

2010-01-01

Fatima Akdim beschrijft drie nieuwe LDL-cholesterolverlagende medicijnen die elk via een ander mechanisme hun doel bereiken: mipomersen (een antisense-remmer), ezetemibe (een cholesterolabsorbtieremmer) en implitapide (een middel dat de transfer van triglyceridetransferproteines (MTP) remt).

Elevated Atherosclerosis-Related Gene Expression, Monocyte Activation and Microparticle-Release Are Related to Increased Lipoprotein-Associated Oxidative Stress in Familial Hypercholesterolemia

DEFF Research Database (Denmark)

Hjuler Nielsen, Morten; Irvine, Helle; Vedel, Simon

2015-01-01

OBJECTIVE: Animal and in vitro studies have suggested that hypercholesterolemia and increased oxidative stress predisposes to monocyte activation and enhanced accumulation of oxidized LDL cholesterol (oxLDL-C) through a CD36-dependent mechanism. The aim of this study was to investigate the hypoth......OBJECTIVE: Animal and in vitro studies have suggested that hypercholesterolemia and increased oxidative stress predisposes to monocyte activation and enhanced accumulation of oxidized LDL cholesterol (oxLDL-C) through a CD36-dependent mechanism. The aim of this study was to investigate...... in subjects with heterozygous familial hypercholesterolemia (FH), in particular in the presence of Achilles tendon xanthomas (ATX). APPROACH AND RESULTS: We studied thirty FH subjects with and without ATX and twenty-three healthy control subjects. Intima-media thickness (IMT) and Achilles tendon (AT......LDL-C-CD36 interaction was increased in FH, especially in ATX+ subjects. Monocyte chemokine receptor CX3CR1 was identified as an independent contributor to IMT. CONCLUSIONS: Our data support that lipoprotein-associated oxidative stress is involved in accelerated atherosclerosis in FH, particularly...

Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

DEFF Research Database (Denmark)

Elsøe, Sara; Ahnström, Josefin; Christoffersen, Christina

2012-01-01

Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lip...... a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL....

Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

Science.gov (United States)

Kraehling, Jan R.; Chidlow, John H.; Rajagopal, Chitra; Sugiyama, Michael G.; Fowler, Joseph W.; Lee, Monica Y.; Zhang, Xinbo; Ramírez, Cristina M.; Park, Eon Joo; Tao, Bo; Chen, Keyang; Kuruvilla, Leena; Larriveé, Bruno; Folta-Stogniew, Ewa; Ola, Roxana; Rotllan, Noemi; Zhou, Wenping; Nagle, Michael W.; Herz, Joachim; Williams, Kevin Jon; Eichmann, Anne; Lee, Warren L.; Fernández-Hernando, Carlos; Sessa, William C.

2016-01-01

In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL. PMID:27869117

Oxidative Stress Is Differentially Present in Multiple Sclerosis Courses, Early Evident, and Unrelated to Treatment

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Maira Gironi

2014-01-01

Full Text Available Background. Oxidative stress is well documented in multiple sclerosis (MS lesions, but its correspondence at peripheral level is still controversial. Objective. To evaluate peripheral oxidative stress markers in MS patients. Methods. We studied total blood levels of Coenzyme Q10 (CoQ10, oxidized and reduced forms of glutathione, malondialdehyde, reactive oxygen species (ROS, anti-oxidized-low-density lipoproteins (anti-oxLDL antibodies, and antioxidant power (PAO in 87 patients with different MS clinical phenotypes and in 77 controls. Results. CoQ10 was lower whereas anti-oxLDL antibodies titer was higher in MS patients than in controls. The benign variant of MS displayed both higher CoQ10 and higher anti-oxLDL than other MS clinical variants. Female patients had lower CoQ10 and PAO and higher ROS than male patients. Differences were greater in younger patients with shorter disease duration. Surprisingly, there was no difference for these markers between treated and untreated patients. Conclusion. We found lower antioxidant agents and higher anti-oxLDL antibodies in MS, and the highest antibody titers occurred in the benign form. We suggest that natural anti-oxLDL antibodies can be protective against MS, saving blood brain barrier integrity. Our findings also suggest that milder MS is associated with a distinct oxidative stress pattern, which may provide a useful biomarker of disease prognosis.

Oxidative Damage to the Salivary Glands of Rats with Streptozotocin-Induced Diabetes-Temporal Study: Oxidative Stress and Diabetic Salivary Glands.

Science.gov (United States)

Knaś, M; Maciejczyk, M; Daniszewska, I; Klimiuk, A; Matczuk, J; Kołodziej, U; Waszkiel, D; Ładny, J R; Żendzian-Piotrowska, M; Zalewska, A

2016-01-01

Objective. This study evaluated oxidative damage caused to the salivary glands in streptozotocin-induced diabetes (DM). Materials and Methods. Rats were divided into 4 groups: groups 1 and 2, control rats, and groups 3 and 4, DM rats. 8-Hydroxy-2'-deoxyguanosine (8-OHdG), protein carbonyl (PC), 4-hydroxynonenal protein adduct (4-HNE), oxidized and/or MDA-modified LDL-cholesterol (oxy-LDL/MDA), 8-isoprostanes (8-isoP), and oxidative stress index (OSI) were measured at 7 (groups 1 and 3) and 14 (groups 2 and 4) days of experiment. Results. The unstimulated salivary flow in DM rats was reduced in the 2nd week, while the stimulated flow was decreased throughout the duration of the experiment versus control. OSI was elevated in both diabetic glands in the 1st and 2nd week, whereas 8-isoP and 8-OHdG were higher only in the parotid gland in the second week. PC and 4-HNE were increased in the 1st and 2nd week, whereas oxy-LDL/MDA was increased in the 2nd week in the diabetic parotid glands. Conclusions. Diabetes induces oxidative damage of the salivary glands, which seems to be caused by processes taking place in the salivary glands, independently of general oxidative stress. The parotid glands are more vulnerable to oxidative damage in these conditions.

Oxidative Damage to the Salivary Glands of Rats with Streptozotocin-Induced Diabetes-Temporal Study: Oxidative Stress and Diabetic Salivary Glands

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M. Knaś

2016-01-01

Full Text Available Objective. This study evaluated oxidative damage caused to the salivary glands in streptozotocin-induced diabetes (DM. Materials and Methods. Rats were divided into 4 groups: groups 1 and 2, control rats, and groups 3 and 4, DM rats. 8-Hydroxy-2′-deoxyguanosine (8-OHdG, protein carbonyl (PC, 4-hydroxynonenal protein adduct (4-HNE, oxidized and/or MDA-modified LDL-cholesterol (oxy-LDL/MDA, 8-isoprostanes (8-isoP, and oxidative stress index (OSI were measured at 7 (groups 1 and 3 and 14 (groups 2 and 4 days of experiment. Results. The unstimulated salivary flow in DM rats was reduced in the 2nd week, while the stimulated flow was decreased throughout the duration of the experiment versus control. OSI was elevated in both diabetic glands in the 1st and 2nd week, whereas 8-isoP and 8-OHdG were higher only in the parotid gland in the second week. PC and 4-HNE were increased in the 1st and 2nd week, whereas oxy-LDL/MDA was increased in the 2nd week in the diabetic parotid glands. Conclusions. Diabetes induces oxidative damage of the salivary glands, which seems to be caused by processes taking place in the salivary glands, independently of general oxidative stress. The parotid glands are more vulnerable to oxidative damage in these conditions.

A decrease in total bilirubin predicted hyper-LDL cholesterolemia in a health screening population.

Science.gov (United States)

Oda, Eiji

2014-08-01

To investigate cross-sectional and longitudinal associations between serum total bilirubin (TB) and LDL cholesterol. It is a retrospective observational study. Cross-sectional and longitudinal associations between TB and hyper-LDL cholesterolemia were investigated in a health screening population. Odds ratios (ORs) of coexisting hyper-LDL cholesterolemia for TB were calculated in 3,866 subjects, Spearman's correlation coefficients between baseline TB and LDL cholesterol at baseline and after 4 years were calculated in 1,735 subjects who did not use antihyperlipidemic drugs and hazard ratios (HRs) of incident hyper-LDL cholesterolemia for TB were calculated in 1,992 followed subjects. The ORs (p values) of coexisting hyper-LDL cholesterolemia for each 1 SD increase in TB was 1.04 (0.998) adjusted for sex, age, smoking, LDL cholesterol and other confounders. Spearman's correlation coefficients (p values) between baseline TB and LDL cholesterol at baseline and after 4 years and changes in LDL cholesterol were -0.026 (0.271), -0.078 (0.001) and -0.062 (0.010), respectively. Among 1,992 followed subjects, 481 developed hyper-LDL cholesterolemia during 4 years (60.4 per 1,000 person-years). The HRs (95% confidence intervals; p values) of incident hyper-LDL cholesterolemia for each 1 SD increase in TB was 0.86 (0.77-0.96; 0.006) adjusted for sex, age, smoking, LDL cholesterol, body mass index, triglycerides, HDL cholesterol, fasting glucose and other confounders. The quintiles of TB were significantly associated with the incident hyper-LDL cholesterolemia adjusted for the above covariates (p for trend = 0.008). A decrease in TB predicted incident hyper-LDL cholesterolemia in a health screening population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Hepatic apo B-100 lipoproteins and plasma LDL heterogeneity in African green monkeys

International Nuclear Information System (INIS)

Murthy, V.N.; Marzetta, C.A.; Rudel, L.L.; Zech, L.A.; Foster, D.M.

1990-01-01

The contribution of hepatic apolipoprotein (apo) B-100 lipoproteins to plasma low-density lipoprotein (LDL) metabolic heterogeneity was examined in African green monkeys. Hepatic 3H-labeled very low-density lipoproteins (VLDL) (d less than 1.006, where d is density in g/ml) or hepatic 131I-labeled LDL (1.030 less than d less than 1.063) were isolated from perfused livers and injected simultaneously with autologous plasma 125I-LDL into African green monkeys. Serial blood samples were taken, and the distribution of radioactivity among various subfractions of apo B-100 lipoproteins was determined using density-gradient ultracentrifugation. Compartmental models were developed to describe simultaneously the kinetics of hepatic lipoproteins and plasma LDL. In five of seven studies, the metabolic behavior of LDL derived from radiolabeled hepatic lipoprotein precursors differed from the metabolic behavior of radiolabeled autologous plasma LDL. These differences could be described by different models supporting two hypotheses with different physiological interpretations: (1) lipoproteins of donor and recipient animals are kinetically distinct, and/or (2) plasma LDL derived from various potential sources are kinetically distinct. Compartmental modeling was used to test these hypotheses, which were not accessible to testing by conventional experimental methodologies. The kinetic analyses of these studies suggest that plasma LDL may be derived from a variety of precursors, including hepatic VLDL and hepatic LDL, with each source giving rise to metabolically distinct plasma LDL

Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.

Directory of Open Access Journals (Sweden)

Antoneta Granic

Full Text Available Elevated low-density lipoprotein (LDL-cholesterol is a risk factor for both Alzheimer's disease (AD and Atherosclerosis (CVD, suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1 high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2 Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3 oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL, induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4 LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5 cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6 ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

LDL-Cholesterol Increases the Transcytosis of Molecules through Endothelial Monolayers.

Science.gov (United States)

Magalhaes, Ana; Matias, Inês; Palmela, Inês; Brito, Maria Alexandra; Dias, Sérgio

2016-01-01

Cholesterol has been identified as a causative factor in numerous pathologies including atherosclerosis and cancer. One of the frequent effects of elevated cholesterol levels in humans is the compromise of endothelial function due to activation of pro-inflammatory signalling pathways. While the mechanisms involved in endothelial activation by cholesterol during an inflammatory response are well established, less is known about the mechanisms by which cholesterol may affect endothelial barrier function, which were the subject of the present study. Here we show that low density lipoprotein (LDL) increases the permeability of endothelial monolayers to high molecular weight dextrans in an LDL receptor and cholesterol-dependent manner. The increased permeability seen upon LDL treatment was not caused by disruption of cell-to-cell junctions as determined by a normal localization of VE-Cadherin and ZO-1 proteins, and no major alterations in transendothelial electrical resistance or permeability to fluorescein. We show instead that LDL increases the level of high molecular weight transcytosis and that this occurs in an LDL receptor, cholesterol and caveolae-dependent way. Our findings contribute to our understanding of the systemic pathological effects of elevated cholesterol and the transport of cargo through endothelial monolayers.

Seasonal mercury exposure and oxidant-antioxidant status of James Bay sport fishermen.

Science.gov (United States)

Bélanger, Marie-Claire; Mirault, Marc-Edouard; Dewailly, Eric; Plante, Michel; Berthiaume, Line; Noël, Micheline; Julien, Pierre

2008-05-01

The effects of a moderate seasonal exposure to methylmercury on plasma low-density lipoprotein (LDL) oxidation and cardiovascular risk indices are not known. The objective of the study was to assess the effects of a seasonal exposure to mercury at similar dose reported to increase cardiovascular risk through fish consumption. Effects on lipoprotein cholesterol and fatty acid profiles, LDL oxidation, and blood oxidant-antioxidant balance were to be assessed in sport fishermen presenting normal blood selenium and omega-3 fatty acid contents. Thirty-one healthy James Bay sport fishermen were assessed for within-subject longitudinal seasonal variations in hair and blood mercury, plasma oxidized LDL, lipophilic antioxidants, homocysteine, blood selenium, and glutathione peroxidase and reductase activities determined before and after the fishing season and compared by matched-pair tests. Hair mercury doubled during the fishing season (2.8+/-0.4 microg/g, P<.0001). Baseline blood selenium, homocysteine, and erythrocyte fatty acid profiles did not change. Plasma high-density lipoprotein cholesterol increased (+5%, P=.05), whereas very low-density lipoprotein cholesterol and oxidized LDL decreased (-8%, P=.05; -18%, P=.008). Blood glutathione peroxidase (+9.7%, P=.001), glutathione reductase (+7.2%, P<.0001), and total glutathione (+45% P<.0001) increased during the fishing season. Plasma total coenzyme Q10 (+13%, P=.02), ubiquinone-10 (+67%, P=.03), and beta-carotene (+46%, P=.01) also increased, whereas vitamin E status was unaffected. Pairwise correlations revealed no association between mercury exposure and any of the biomarkers investigated. In contrast, strong predictors of cardiovascular risk such as high-density lipoprotein cholesterol, oxidized LDL, and glutathione peroxidase improved during the fishing season despite elevated methylmercury exposure. The beneficial effects of seasonal fishing activity and fish consumption on cardiovascular health may suppress

ApoB100-LDL acts as a metabolic signal from liver to peripheral fat causing inhibition of lipolysis in adipocytes.

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Josefin Skogsberg

Full Text Available BACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-Apob(100/100. CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome.

miRNA regulation of LDL-cholesterol metabolism.

Science.gov (United States)

Goedeke, Leigh; Wagschal, Alexandre; Fernández-Hernando, Carlos; Näär, Anders M

2016-12-01

In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non-coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez. Copyright © 2016 Elsevier B.V. All rights reserved.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.

Science.gov (United States)

Ren, Kun; Lu, Yan-Ju; Mo, Zhong-Cheng; -Liu, Xing; Tang, Zhen-Li; Jiang, Yue; Peng, Xiao-Shan; Li, Li; Zhang, Qing-Hai; Yi, Guang-Hui

2017-05-01

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.

Associations between CD36 gene polymorphisms and susceptibility to coronary artery heart disease

International Nuclear Information System (INIS)

Zhang, Y.; Ling, Z.Y.; Deng, S.B.; Du, H.A.; Yin, Y.H.; Yuan, J.; She, Q.; Chen, Y.Q.

2014-01-01

Associations between polymorphisms of the CD36 gene and susceptibility to coronary artery heart disease (CHD) are not clear. We assessed allele frequencies and genotype distributions of CD36 gene polymorphisms in 112 CHD patients and 129 control patients using semi-quantitative polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Additionally, we detected CD36 mRNA expression by real-time quantitative PCR, and we quantified plasma levels of oxidized low-density lipoprotein (ox-LDL) using an enzyme-linked immunosorbent assay (ELISA). There were no significant differences between the two groups (P>0.05) in allele frequencies of rs1761667 or in genotype distribution and allele frequencies of rs3173798. The genotype distribution of rs1761667 significantly differed between CHD patients and controls (P=0.034), with a significantly higher frequency of the AG genotype in the CHD group compared to the control group (P=0.011). The plasma levels of ox-LDL in patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.010). In a randomized sample taken from patients in the two groups, the CD36 mRNA expression of the CHD patients was higher than that of the controls. In CHD patients, the CD36 mRNA expression in AG genotype patients was remarkably higher than in those with an AA genotype (P=0.005). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CHD (OR=2.337, 95% CI=1.336-4.087, P=0.003). In conclusion, the rs1761667 polymorphism may be closely associated with developing CHD in the Chongqing Han population of China, and an AG genotype may be a genetic susceptibility factor for CHD

PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS.

Science.gov (United States)

Vignozzi, Linda; Gacci, Mauro; Cellai, Ilaria; Morelli, Annamaria; Maneschi, Elena; Comeglio, Paolo; Santi, Raffaella; Filippi, Sandra; Sebastianelli, Arcangelo; Nesi, Gabriella; Serni, Sergio; Carini, Marco; Maggi, Mario

2013-09-01

Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one. © 2013 Wiley Periodicals, Inc.

Associations between CD36 gene polymorphisms and susceptibility to coronary artery heart disease

Energy Technology Data Exchange (ETDEWEB)

Zhang, Y.; Ling, Z.Y.; Deng, S.B.; Du, H.A.; Yin, Y.H.; Yuan, J.; She, Q.; Chen, Y.Q. [Department of Cardiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China)

2014-08-08

Associations between polymorphisms of the CD36 gene and susceptibility to coronary artery heart disease (CHD) are not clear. We assessed allele frequencies and genotype distributions of CD36 gene polymorphisms in 112 CHD patients and 129 control patients using semi-quantitative polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Additionally, we detected CD36 mRNA expression by real-time quantitative PCR, and we quantified plasma levels of oxidized low-density lipoprotein (ox-LDL) using an enzyme-linked immunosorbent assay (ELISA). There were no significant differences between the two groups (P>0.05) in allele frequencies of rs1761667 or in genotype distribution and allele frequencies of rs3173798. The genotype distribution of rs1761667 significantly differed between CHD patients and controls (P=0.034), with a significantly higher frequency of the AG genotype in the CHD group compared to the control group (P=0.011). The plasma levels of ox-LDL in patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.010). In a randomized sample taken from patients in the two groups, the CD36 mRNA expression of the CHD patients was higher than that of the controls. In CHD patients, the CD36 mRNA expression in AG genotype patients was remarkably higher than in those with an AA genotype (P=0.005). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CHD (OR=2.337, 95% CI=1.336-4.087, P=0.003). In conclusion, the rs1761667 polymorphism may be closely associated with developing CHD in the Chongqing Han population of China, and an AG genotype may be a genetic susceptibility factor for CHD.

Recurrent LDL-receptor mutation causes familial ...

African Journals Online (AJOL)

1995-05-05

May 5, 1995 ... 3. eaudet . New. Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in ... amplification refractory mutation system (ARMS)" and single- strand conformation .... Location. Afrikaner. Mixed race. ApaLl.

EGG YOLK AND LDL: POSSIBILITIES FOR ARTIFICIAL INSEMINATION IN EQUINES

Directory of Open Access Journals (Sweden)

Igor F. Canisso

2008-12-01

Full Text Available The world horse industry exerts an important role as a job and income generation source. Reproductive technologies arises as an important tool in the service of world equine growth. Artificial insemination (AI is perhaps the biotechnology with greater impact on equine breeding; a stallion can leave hundreds of offsprings over his reproductive life if AI is efficiently used. In some countries, egg yolk is frequently used as part of equine seminal extenders. The egg yolk provides the spermatozoa “resistance factors’’ when it is added. The protective fraction of the egg yolk probably is the low density lipoproteins (LDL. Several studies have reported successful results with the addition and replacement of egg yolk by LDL. There are many citations about the use of egg yolk in seminal extenders for stallion’s cooled and frozen semen, and in the equine reproduction practice. The egg yolk dilutors are used with good fertility results. New research is needed for the better understanding of the protective effects of egg yolk and the LDL for stallion semen. The LDL would be a great solution for dilutors to artificial insemination in horse. This review discusses the use and the advantages of egg yolk and LDL as constituents of equine semen extenders.

Additional consumption of one egg per day increases serum lutein plus zeaxanthin concentration and lowers oxidized low-density lipoprotein in moderately hypercholesterolemic males.

Science.gov (United States)

Kishimoto, Yoshimi; Taguchi, Chie; Saita, Emi; Suzuki-Sugihara, Norie; Nishiyama, Hiroshi; Wang, Wei; Masuda, Yasunobu; Kondo, Kazuo

2017-09-01

The egg is a nutrient-dense food and contains antioxidative carotenoids, lutein and zeaxanthin, but its impact on serum cholesterol levels has been a matter of concern, especially for individuals who have high serum cholesterol levels. We conducted this study to determine whether and how the daily additional consumption of one egg affects serum lipid profiles and parameters of LDL oxidation in moderately hypercholesterolemic males. Nineteen male Japanese adults (total cholesterol [TC]>5.2mmol/L) participated, consuming one soft boiled egg per day for 4weeks in addition to their habitual diet. Despite the significant increase in their intake of dietary cholesterol during the intervention period, the subjects' serum concentrations of TC and low-density lipoprotein cholesterol (LDL-C) did not increase. Their serum malondialdehyde modified low-density lipoprotein (MDA-LDL) concentrations were significantly decreased and their LDL oxidation lag times, reflecting the resistance of free-radical-induced LDL lipid peroxidation (ex vivo), was prolonged after 2 and 4weeks. At weeks 2 and 4, the subjects' serum lutein+zeaxanthin concentrations were significantly higher than their baseline values and showed both an inverse relation with MDA-LDL and a positive relationship with the LDL oxidation lag time. These data showed that in moderately hypercholesterolemic males, the additional consumption of one egg per day for 4weeks did not have adverse effects on serum TC or LDL-C, and it might reduce the susceptibility of LDL to oxidation through an increase in the serum lutein and zeaxanthin concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effect of increasing body mass index on cardio-metabolic risk and biomarkers of oxidative stress and inflammation in nascent metabolic syndrome.

Science.gov (United States)

Pahwa, Roma; Adams-Huet, Beverley; Jialal, Ishwarlal

2017-05-01

The effect of BMI defined obesity on cardio-metabolic features and biomarkers of oxidative stress and inflammation in patients with nascent metabolic Syndrome (MetS) is poorly defined. Hence the aim of this study was to examine the effect of increasing obesity on the cardio metabolic risk profile, pro-oxidant state and pro-inflammatory features in nascent MetS patients without Diabetes or CVD. MetS was diagnosed by ATPIII criteria using waist circumference (WC) as the measure of adiposity. Patients (n=58) were stratified into overweight, obese and extreme obesity groups using BMI cut offs of 25-29.9, 30-39.9kg/m 2 and ≥40kg/m 2 and cardio-metabolic features, circulating and cellular biomarkers of oxidative stress and inflammation were determined and correlated with BMI. None of the main cardio-metabolic features including blood pressure, blood glucose, HDL-cholesterol, triglycerides, HOMA-IR, free fatty acids were increased with increasing BMI. Also none of the biomarkers of oxidative stress (ox-LDL, nitrotyrosine and monocyte superoxide anion release) were increased with increasing BMI. However, significant increase in hsCRP, the soluble TNFR1 and sTNFR2 and leptin, were observed with increasing adiposity. Other inflammatory bio-mediators (IL-1β, IL-6, IL-8, MCP-1, Toll-like receptors 2-4), endotoxin, LBP, sCD14 and HMGB1, adiponectin, and chemerin did not show significant increases with increasing BMI. Leptin, hsCRP, sTNFR1, and sTNFR2 correlated significantly with BMI. In conclusion, capturing the cardio-metabolic cluster of MetS that predisposed to both increased risk of diabetes and CVD, using waist circumference, as one of the 5 diagnostic criteria is sufficient and BMI does not appear to afford any major incremental benefit on the cardio-metabolic risk factors, increased oxidative stress and the majority of both cellular and circulating biomarkers of inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

INHIBITION OF HUMAN LOW-DENSITY LIPOPROTEINS OXIDATION BY Hibiscus radiatus CUV. CALYCES EXTRACT

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Hernawan Hernawan

2010-06-01

Full Text Available Hibiscus radiatus Cuv calyces extracts rich in polyphenols was screened for their potential to inhibit oxidation of human low-density lipoproteins-cholesterol (LDL-C in vitro. The inhibition of LDL-C oxidation (antioxidant activity was determined by measuring the formation of conjugated dienes and thiobarbituric acid reagent substances (TBARS. LDL-C oxidation was carried out in the presence of H. radiatus Cuv calyces extract (20 and 50 μM. CuSO4 (10 μM was used as the oxidation initiator and  butylated hydroxytoluene (BHT at 50 μM was used as standard antioxidant. The protective effect of H. radiatus Cuv. calyces extract toward human low-density lipoproteins, complex lipid system was  demonstrated by significant increase lag time (> 103 min, diminished of the propagation rate (44 %, and diminution of conjugated dienes formation 59.42 % (50 μM compared to control.   Keywords: antioxidant, conjugated dienes, Hibiscus radiatus Cuv, low-density lipoproteins-cholesterol

Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction

DEFF Research Database (Denmark)

Abdo, Adrian; Rayner, B.S.; van Reyk, D.M.

2017-01-01

Low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase (MPO) is present in atherosclerotic lesions, where it is implicated in the propagation of inflammation and acceleration of lesion development by multiple pathways, including the induction of endothelial......, although emerging evidence suggests that these particles have distinct biological properties. This is important because elevated plasma SCN- is linked with both the propagation and prevention of atherosclerosis. In this study, we demonstrate that both HOSCN- and HOCl-modified LDL inhibit endothelium......-mediated vasorelaxation ex vivo in rat aortic ring segments. In vitro experiments with human coronary artery endothelial cells show that HOSCN-modified LDL decreases in the production of nitric oxide (NO•) and induces the loss of endothelial nitric oxide synthase (eNOS) activity. This occurs to a similar extent...

Low density lipoprotein for oxidation and metabolic studies. Isolation from small volumes of plasma using a tabletop ultracentrifuge.

Science.gov (United States)

Himber, J; Bühler, E; Moll, D; Moser, U K

1995-01-01

A rapid method is described for the isolation of small volumes of plasma low density lipoprotein (LDL) free of plasma protein contaminants using the TL-100 Tabletop Ultracentrifuge (Beckman). The isolation of LDL was achieved by a 25 min discontinuous gradient density centrifugation between the density range of 1.006 and 1.21 g/ml, recovery of LDL by tube slicing followed by a 90 min flotation step (d = 1.12 g/ml). The purity of LDL and apolipoprotein B100 (apo B100) were monitored by agarose electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), radial immunodiffusion and micropreparative fast protein liquid chromatography (FPLC). The ability of LDL oxidation was assessed by following absorbance at 234 nm after addition of copper ions. The functional integrity of the isolated LDL was checked by clearance kinetics after injection of [125I]-labelled LDL in estrogen-treated rats. The additional purification step led to LDL fractions free of protein contamination and left apo B100, alpha-tocopherol and beta-carotene intact. The LDL prepared in this way was free of albumin, as evident from analytic tests and from its enhanced oxidative modification by copper ions. Used for analytical purposes, this method allows LDL preparations from plasma volumes up to 570 microliters. This method is also convenient for metabolic studies in small animals, especially those relating to the determination of kinetic parameters of LDL in which LDL-apo B100 has to be specifically radiolabelled.

Development of a new LDL-based transport system for hydrophobic/amphiphilic drug delivery to cancer cells.

Science.gov (United States)

Huntosova, Veronika; Buzova, Diana; Petrovajova, Dana; Kasak, Peter; Nadova, Zuzana; Jancura, Daniel; Sureau, Franck; Miskovsky, Pavol

2012-10-15

Low-density lipoproteins (LDL), a natural in vivo carrier of cholesterol in the vascular system, play a key role in the delivery of hydrophobic/amphiphilic photosensitizers to tumor cells in photodynamic therapy of cancer. To make this delivery system even more efficient, we have constructed a nano-delivery system by coating of LDL surface by dextran. Fluorescence spectroscopy, confocal fluorescence imaging, stopped-flow experiments and flow-cytometry were used to characterize redistribution of hypericin (Hyp), a natural occurring potent photosensitizer, loaded in LDL/dextran complex to free LDL molecules as well as to monitor cellular uptake of Hyp by U87-MG cells. It is shown that the redistribution process of Hyp between LDL molecules is significantly suppressed by dextran coating of LDL surface. The modification of LDL molecules by dextran does not inhibit their recognition by cellular LDL receptors and U-87 MG cellular uptake of Hyp loaded in LDL/dextran complex appears to be similar to that one observed for Hyp transported by unmodified LDL particles. Thus, it is proposed that dextran modified LDL molecules could be used as a basis for construction of a drug transport system for targeted delivery of hydrophobic/amphiphilic drugs to cancer cells expressing high level of LDL receptors. Copyright © 2012 Elsevier B.V. All rights reserved.

Oriented immobilized anti-LDL antibody carrying poly(hydroxyethyl methacrylate) cryogel for cholesterol removal from human plasma

International Nuclear Information System (INIS)

Bereli, Nilay; Sener, Guelsu; Yavuz, Handan; Denizli, Adil

2011-01-01

Low density lipoprotein (LDL) cholesterol is a major ingredient of the plaque that collects in the coronary arteries and causes coronary heart diseases. Among the methods used for the extracorporeal elimination of LDL from intravasal volume, immunoaffinity technique using anti-LDL antibody as a ligand offers superior selectivity and specificity. Proper orientation of the immobilized antibody is the main issue in immunoaffinity techniques. In this study, anti-human β-lipoprotein antibody (anti-LDL antibody) molecules were immobilized and oriented through protein A onto poly(2-hydroxyethyl methacrylate) (PHEMA) cryogel in order to remove LDL from hypercholesterolemic human plasma. PHEMA cryogel was prepared by free radical polymerization initiated with N,N,N',N'-tetramethylene diamine (TEMED). PHEMA cryogel with a swelling degree of 8.89 g H 2 O/g and 67% macro-porosity was characterized by swelling studies, scanning electron microscope (SEM) and blood compatibility tests. All the clotting times were increased when compared with control plasma. The maximum immobilized anti-LDL antibody amount was 63.2 mg/g in the case of random antibody immobilization and 19.6 mg/g in the case of oriented antibody immobilization (protein A loading was 57.0 mg/g). Random and oriented anti-LDL antibody immobilized PHEMA cryogels adsorbed 111 and 129 mg LDL/g cryogel from hypercholesterolemic human plasma, respectively. Up to 80% of the adsorbed LDL was desorbed. The adsorption-desorption cycle was repeated 6 times using the same cryogel. There was no significant loss of LDL adsorption capacity. - Research highlights: → LDL cholesterol is a risk factor in the development of coronary heart diseases. → Antibodies against LDL are used for the selective extracorporeal removal of LDL. → Protein A is used for the oriented immobilization of anti LDL onto PHEMA cryogel. → PHEMA cryogels are biocompatible, exhibit a low pressure drop, lack diffusion resistance and viscous samples can be

Oriented immobilized anti-LDL antibody carrying poly(hydroxyethyl methacrylate) cryogel for cholesterol removal from human plasma

Energy Technology Data Exchange (ETDEWEB)

Bereli, Nilay [Department of Chemistry, Hacettepe University, Beytepe, Ankara (Turkey); Sener, Guelsu [Nanotechnology and Nanomedicine Division, Hacettepe University, Ankara (Turkey); Yavuz, Handan, E-mail: handany@hacettepe.edu.tr [Department of Chemistry, Hacettepe University, Beytepe, Ankara (Turkey); Denizli, Adil [Department of Chemistry, Hacettepe University, Beytepe, Ankara (Turkey)

2011-07-20

Low density lipoprotein (LDL) cholesterol is a major ingredient of the plaque that collects in the coronary arteries and causes coronary heart diseases. Among the methods used for the extracorporeal elimination of LDL from intravasal volume, immunoaffinity technique using anti-LDL antibody as a ligand offers superior selectivity and specificity. Proper orientation of the immobilized antibody is the main issue in immunoaffinity techniques. In this study, anti-human {beta}-lipoprotein antibody (anti-LDL antibody) molecules were immobilized and oriented through protein A onto poly(2-hydroxyethyl methacrylate) (PHEMA) cryogel in order to remove LDL from hypercholesterolemic human plasma. PHEMA cryogel was prepared by free radical polymerization initiated with N,N,N',N'-tetramethylene diamine (TEMED). PHEMA cryogel with a swelling degree of 8.89 g H{sub 2}O/g and 67% macro-porosity was characterized by swelling studies, scanning electron microscope (SEM) and blood compatibility tests. All the clotting times were increased when compared with control plasma. The maximum immobilized anti-LDL antibody amount was 63.2 mg/g in the case of random antibody immobilization and 19.6 mg/g in the case of oriented antibody immobilization (protein A loading was 57.0 mg/g). Random and oriented anti-LDL antibody immobilized PHEMA cryogels adsorbed 111 and 129 mg LDL/g cryogel from hypercholesterolemic human plasma, respectively. Up to 80% of the adsorbed LDL was desorbed. The adsorption-desorption cycle was repeated 6 times using the same cryogel. There was no significant loss of LDL adsorption capacity. - Research highlights: {yields} LDL cholesterol is a risk factor in the development of coronary heart diseases. {yields} Antibodies against LDL are used for the selective extracorporeal removal of LDL. {yields} Protein A is used for the oriented immobilization of anti LDL onto PHEMA cryogel. {yields} PHEMA cryogels are biocompatible, exhibit a low pressure drop, lack diffusion

HDL-LDL Ratio: A Significant Predisposition to the Onset of ...

African Journals Online (AJOL)

The significance of high-density lipoprotein/low density lipoprotein (HDL-LDL) ratio as a predisposing factor to the onset of atherogenesis has been studied. Standard enzymatic method using Cholesterol kit to extract cholesterol was used. HDL was analysed using standard HDL Kit and LDL concentration was derived by a ...

Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding.

Science.gov (United States)

Maaninka, Katariina; Nguyen, Su Duy; Mäyränpää, Mikko I; Plihtari, Riia; Rajamäki, Kristiina; Lindsberg, Perttu J; Kovanen, Petri T; Öörni, Katariina

2018-04-13

Subendothelial interaction of LDL with extracellular matrix drives atherogenesis. This interaction can be strengthened by proteolytic modification of LDL. Mast cells (MCs) are present in atherosclerotic lesions, and upon activation, they degranulate and release a variety of neutral proteases. Here we studied the ability of MC proteases to cleave apoB-100 of LDL and affect the binding of LDL to proteoglycans. Mature human MCs were differentiated from human peripheral blood-derived CD34 + progenitors in vitro and activated with calcium ionophore to generate MC-conditioned medium. LDL was incubated in the MC-conditioned medium or with individual MC proteases, and the binding of native and modified LDL to isolated human aortic proteoglycans or to human atherosclerotic plaques ex vivo was determined. MC proteases in atherosclerotic human coronary artery lesions were detected by immunofluorescence and qPCR. Activated human MCs released the neutral proteases tryptase, chymase, carboxypeptidase A3, cathepsin G, and granzyme B. Of these, cathepsin G degraded most efficiently apoB-100, induced LDL fusion, and enhanced binding of LDL to isolated human aortic proteoglycans and human atherosclerotic lesions ex vivo. Double immunofluoresence staining of human atherosclerotic coronary arteries for tryptase and cathepsin G indicated that lesional MCs contain cathepsin G. In the lesions, expression of cathepsin G correlated with the expression of tryptase and chymase, but not with that of neutrophil proteinase 3. The present study suggests that cathepsin G in human atherosclerotic lesions is largely derived from MCs and that activated MCs may contribute to atherogenesis by enhancing LDL retention. Copyright © 2018 Elsevier B.V. All rights reserved.

Plant-derived phenolics inhibit the accrual of structurally characterised protein and lipid oxidative modifications.

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Arantza Soler-Cantero

Full Text Available Epidemiological data suggest that plant-derived phenolics beneficial effects include an inhibition of LDL oxidation. After applying a screening method based on 2,4-dinitrophenyl hydrazine-protein carbonyl reaction to 21 different plant-derived phenolic acids, we selected the most antioxidant ones. Their effect was assessed in 5 different oxidation systems, as well as in other model proteins. Mass-spectrometry was then used, evidencing a heterogeneous effect on the accumulation of the structurally characterized protein carbonyl glutamic and aminoadipic semialdehydes as well as for malondialdehyde-lysine in LDL apoprotein. After TOF based lipidomics, we identified the most abundant differential lipids in Cu(++-incubated LDL as 1-palmitoyllysophosphatidylcholine and 1-stearoyl-sn-glycero-3-phosphocholine. Most of selected phenolic compounds prevented the accumulation of those phospholipids and the cellular impairment induced by oxidized LDL. Finally, to validate these effects in vivo, we evaluated the effect of the intake of a phenolic-enriched extract in plasma protein and lipid modifications in a well-established model of atherosclerosis (diet-induced hypercholesterolemia in hamsters. This showed that a dietary supplement with a phenolic-enriched extract diminished plasma protein oxidative and lipid damage. Globally, these data show structural basis of antioxidant properties of plant-derived phenolic acids in protein oxidation that may be relevant for the health-promoting effects of its dietary intake.

Apple juice inhibits human low density lipoprotein oxidation.

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Pearson, D A; Tan, C H; German, J B; Davis, P A; Gershwin, M E

1999-01-01

Dietary phenolic compounds, ubiquitous in vegetables and fruits and their juices possess antioxidant activity that may have beneficial effects on human health. The phenolic composition of six commercial apple juices, and of the peel (RP), flesh (RF) and whole fresh Red Delicious apples (RW), was determined by high performance liquid chromatography (HPLC), and total phenols were determined by the Folin-Ciocalteau method. HPLC analysis identified and quantified several classes of phenolic compounds: cinnamates, anthocyanins, flavan-3-ols and flavonols. Phloridzin and hydroxy methyl furfural were also identified. The profile of phenolic compounds varied among the juices. The range of concentrations as a percentage of total phenolic concentration was: hydroxy methyl furfural, 4-30%; phloridzin, 22-36%; cinnamates, 25-36%; anthocyanins, n.d.; flavan-3-ols, 8-27%; flavonols, 2-10%. The phenolic profile of the Red Delicious apple extracts differed from those of the juices. The range of concentrations of phenolic classes in fresh apple extracts was: hydroxy methyl furfural, n.d.; phloridzin, 11-17%; cinnamates, 3-27%; anthocyanins, n.d.-42%; flavan-3-ols, 31-54%; flavonols, 1-10%. The ability of compounds in apple juices and extracts from fresh apple to protect LDL was assessed using an in vitro copper catalyzed human LDL oxidation system. The extent of LDL oxidation was determined as hexanal production using static headspace gas chromatography. The apple juices and extracts, tested at 5 microM gallic acid equivalents (GAE), all inhibited LDL oxidation. The inhibition by the juices ranged from 9 to 34%, and inhibition by RF, RW and RP was 21, 34 and 38%, respectively. Regression analyses revealed no significant correlation between antioxidant activity and either total phenolic concentration or any specific class of phenolics. Although the specific components in the apple juices and extracts that contributed to antioxidant activity have yet to be identified, this study

Protection capacity against low-density lipoprotein oxidation and antioxidant potential of some organic and non-organic wines.

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Kalkan Yildirim, Hatice; Delen Akçay, Yasemin; Güvenç, Ulgar; Yildirim Sözmen, Eser

2004-08-01

Current research suggests that phenolics from wine may play a positive role against oxidation of low-density lipoprotein (LDL), which is a key step in the development of atherosclerosis. Considering the effects of different wine-making techniques on phenols and the wine consumption preference influencing the benefical effects of the product, organically and non-organically produced wines were obtained from the grapes of Vitis vinifera origin var: Carignan, Cabernet Sauvignon, Merlot, Grenache, Columbard and Semillon. Levels of total phenols [mg/l gallic acid equivalents (GAE)], antioxidant activity (%) and inhibition of LDL oxidation [%, inhibition of diene and malondialdehyde (MDA) formation] were determined. Some phenolic acids (gallic acid, p-hydroxybenzoic acid, syringic acid, 2,3-dihydroxybenzoic acid, ferulic acid, p-coumaric acid and vanillic acid) were quantified by high-performance liquid chromatography equipped with an electrochemical detection carried at +0.65 V (versus Ag/AgCl, 0.5 microA full scale). The highest concentrations of gallic, syringic and ferulic acids were found in organic Cabernet Sauvignon; 2,3-dihydroxybenzoic acid in organic Carignan and p-coumaric and vanillic acids in non-organic Merlot wine. High levels of antioxidant activity (AOA), inhibition of LDL oxidation and total phenol levels were found in non-organic Merlot (101.950% AOA; 88.570% LDL-diene; 41.000% LDL-MDA; 4700.000 mg/l GAE total phenol) and non-organic Cabernet Sauvignon (92.420% AOA; 91.430% LDL-diene; 67.000% LDL-MDA; 3500.000 mg/l GAE total phenol) grape varieties. Concentrations of some individual phenolic constituents (ferulic, p-coumaric, vanillic) are correlated with high antioxidant activity and inhibition of LDL oxidation. The best r value for all examined characteristics was determined for gallic acid, followed by 2,3-dihydroxybenzoic, syringic, ferulic and p-coumaric acids. Negative correlation of vanillic with MDA and p-hydroxybenzoic acid with LDL were

Agreement between fasting and postprandial LDL cholesterol measured with 3 methods in patients with type 2 diabetes mellitus

DEFF Research Database (Denmark)

Lund, Søren S.; Petersen, Martin; Frandsen, Merete

2011-01-01

LDL cholesterol (LDL-C) is a modifiable cardiovascular disease risk factor. We used 3 LDL-C methods to study the agreement between fasting and postprandial LDL-C in type 2 diabetes (T2DM) patients.......LDL cholesterol (LDL-C) is a modifiable cardiovascular disease risk factor. We used 3 LDL-C methods to study the agreement between fasting and postprandial LDL-C in type 2 diabetes (T2DM) patients....

Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation

DEFF Research Database (Denmark)

Storey, Benjamin C; Staplin, Natalie; Haynes, Richard

2018-01-01

in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial...... LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients...

Integrative pathway dissection of molecular mechanisms of moxLDL-induced vascular smooth muscle phenotype transformation

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Karagiannis George S

2013-01-01

Full Text Available Abstract Background Atherosclerosis (AT is a chronic inflammatory disease characterized by the accumulation of inflammatory cells, lipoproteins and fibrous tissue in the walls of arteries. AT is the primary cause of heart attacks and stroke and is the leading cause of death in Western countries. To date, the pathogenesis of AT is not well-defined. Studies have shown that the dedifferentiation of contractile and quiescent vascular smooth muscle cells (SMC to the proliferative, migratory and synthetic phenotype in the intima is pivotal for the onset and progression of AT. To further delineate the mechanisms underlying the pathogenesis of AT, we analyzed the early molecular pathways and networks involved in the SMC phenotype transformation. Methods Quiescent human coronary artery SMCs were treated with minimally-oxidized LDL (moxLDL, for 3 hours and 21 hours, respectively. Transcriptomic data was generated for both time-points using microarrays and was subjected to pathway analysis using Gene Set Enrichment Analysis, GeneMANIA and Ingenuity software tools. Gene expression heat maps and pathways enriched in differentially expressed genes were compared to identify functional biological themes to elucidate early and late molecular mechanisms of moxLDL-induced SMC dedifferentiation. Results Differentially expressed genes were found to be enriched in cholesterol biosynthesis, inflammatory cytokines, chemokines, growth factors, cell cycle control and myogenic contraction themes. These pathways are consistent with inflammatory responses, cell proliferation, migration and ECM production, which are characteristic of SMC dedifferentiation. Furthermore, up-regulation of cholesterol synthesis and dysregulation of cholesterol metabolism was observed in moxLDL-induced SMC. These observations are consistent with the accumulation of cholesterol and oxidized cholesterol esters, which induce proinflammatory reactions during atherogenesis. Our data implicate for the

Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake.

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Demonty, Isabelle; Ras, Rouyanne T; van der Knaap, Henk C M; Duchateau, Guus S M J E; Meijer, Linsie; Zock, Peter L; Geleijnse, Johanna M; Trautwein, Elke A

2009-02-01

Phytosterols (plant sterols and stanols) are well known for their LDL-cholesterol (LDL-C)-lowering effect. A meta-analysis of randomized controlled trials in adults was performed to establish a continuous dose-response relationship that would allow predicting the LDL-C-lowering efficacy of different phytosterol doses. Eighty-four trials including 141 trial arms were included. A nonlinear equation comprising 2 parameters (the maximal LDL-C lowering and an incremental dose step) was used to describe the dose-response curve. The overall pooled absolute (mmol/L) and relative (%) LDL-C-lowering effects of phytosterols were also assessed with a random effects model. The pooled LDL-C reduction was 0.34 mmol/L (95% CI: -0.36, -0.31) or 8.8% (95% CI: -9.4, -8.3) for a mean daily dose of 2.15 g phytosterols. The impacts of subject baseline characteristics, food formats, type of phytosterols, and study quality on the continuous dose-response curve were determined by regression or subgroup analyses. Higher baseline LDL-C concentrations resulted in greater absolute LDL-C reductions. No significant differences were found between dose-response curves established for plant sterols vs. stanols, fat-based vs. non fat-based food formats and dairy vs. nondairy foods. A larger effect was observed with solid foods than with liquid foods only at high phytosterol doses (>2 g/d). There was a strong tendency (P = 0.054) towards a slightly lower efficacy of single vs. multiple daily intakes of phytosterols. In conclusion, the dose-dependent LDL-C-lowering efficacy of phytosterols incorporated in various food formats was confirmed and equations of the continuous relationship were established to predict the effect of a given phytosterol dose. Further investigations are warranted to investigate the impact of solid vs. liquid food formats and frequency of intake on phytosterol efficacy.

CD36 Mediated Fatty Acid-Induced Podocyte Apoptosis via Oxidative Stress.

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Wei Hua

Full Text Available Hyperlipidemia-induced apoptosis mediated by fatty acid translocase CD36 is associated with increased uptake of ox-LDL or fatty acid in macrophages, hepatocytes and proximal tubular epithelial cells, leading to atherosclerosis, liver damage and fibrosis in obese patients, and diabetic nephropathy (DN, respectively. However, the specific role of CD36 in podocyte apoptosis in DN with hyperlipidemia remains poorly investigated.The expression of CD36 was measured in paraffin-embedded kidney tissue samples (Ctr = 18, DN = 20 by immunohistochemistry and immunofluorescence staining. We cultured conditionally immortalized mouse podocytes (MPC5 and treated cells with palmitic acid, and measured CD36 expression by real-time PCR, Western blot analysis and immunofluorescence; lipid uptake by Oil red O staining and BODIPY staining; apoptosis by flow cytometry assay, TUNEL assay and Western blot analysis; and ROS production by DCFH-DA fluorescence staining. All statistical analyses were performed using SPSS 21.0 statistical software.CD36 expression was increased in kidney tissue from DN patients with hyperlipidemia. Palmitic acid upregulated CD36 expression and promoted its translocation from cytoplasm to plasma membrane in podocytes. Furthermore, palmitic acid increased lipid uptake, ROS production and apoptosis in podocytes, Sulfo-N-succinimidyloleate (SSO, the specific inhibitor of the fatty acid binding site on CD36, decreased palmitic acid-induced fatty acid accumulation, ROS production, and apoptosis in podocytes. Antioxidant 4-hydroxy-2,2,6,6- tetramethylpiperidine -1-oxyl (tempol inhibited the overproduction of ROS and apoptosis in podocytes induced by palmitic acid.CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress might participate in the process of DN.

LDL Receptors as Gateways for Intracellular Porphyrin Uptake

International Nuclear Information System (INIS)

Novick, S.; Laster, B.; Quastel, M.

2004-01-01

Boronated compounds are currently being studied for possible use in Boron Neutron Capture Therapy (BNCT). We found that one of these agents, BOPP (tetrakis-carborane-carboxylate, esters of 2,4-bis (a,b- dihydroxyethyl) deuteroporphyrin IX), could also be labeled with indium (In-BOPP) and, therefore, could also be used potentially to transport high Z atoms into tumor cell DNA for AET (Auger Electron Therapy). In order to assess the uptake of these agents into cells, the role of the LDL receptor in the intracellular accumulation of BOPP and In-BOPP was investigated. Pre-incubation of V-79 Chinese hamster cells in medium containing delipidized fetal bovine serum (FBS) markedly increased the subsequent uptake of intracellular boron transported by both BOPP and In-BOPP when compared with cells that had been pre-incubated with medium containing 10% normal FBS (lipidized). The increased uptake was characterized by elevated levels of receptor, and greater affinity was shown for both BOPP and In-BOPP, although less marked with the latter. Positive cooperativity was demonstrated by sigmoid saturation curves, Scatchard analysis and Hill plots. Increasing the amount of LDL in the incubation medium had a relatively small effect on the total accumulation of either indium or boron atoms inside the cell. Furthermore, chemical acetylation of LDL did not decrease the intracellular uptake of either boron or indium transported by BOPP or In-BOPP. It is thus concluded that BOPP and In-BOPP preferentially enter the cells directly by way of the LDL receptor and that only a small fraction of these molecules are transported into the cells indirectly using serum LDLs as their carriers. These data suggest a novel way of bringing greater amounts of boron and indium (and perhaps other agents) into tissues. Porphyrins can be used to transport different agents into tumor cells because they are tumor affinic molecules. Tumors express a higher number of LDL receptors than do most normal tissues

Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins

DEFF Research Database (Denmark)

Pattison, David I; Hawkins, Clare Louise; Davies, Michael Jonathan

2003-01-01

Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates...... of reaction of HOCl with the reactive sites in proteins were investigated (Pattison, D. I., and Davies, M. J. (2001) Chem. Res. Toxicol. 14, 1453-1464). The work presented here expands on those studies to determine absolute second-order rate constants for the reactions of HOCl with various lipid components...... nitrogen- and carbon-centered radicals. Subsequent reactions of these species may induce oxidation of the LDL lipid component. In contrast, phosphoryl-choline reacted much more slowly (k Reaction of HOCl with 3-pentenoic acid was used as a model of lipid double bonds...

Characterization of LDL-receptors of freshly isolated mononuclear cells of healthy subjects and of FH-patients

International Nuclear Information System (INIS)

Banyai, M.

1991-05-01

The central role of the LDL (=low density lipoproteins) receptor in artherosclerosis was first appreciated when it was shown that its absence was responsible for FH (familial hypercholesterolemia). To determine the high affinity cell surface binding activity in circulating human mononuclear cells (MNCs), these cells were incubated with low concentrations (1-50 μg protein/ml) of 123 I-LDL or 111 In-LDL either in the presence or absence of an excess of unlabeled LDL at 4 deg C for 45 minutes. MNCs of healthy subjects and of heterozygous FH-patients were found to possess high affinity LDL receptors immediately after they were isolated from the blood stream. The results indicate that the FH-patients enclosed in this study possess a reduced number of the same high affinity binding sites as healthy subjects confirming the diagnosis of heterozygous FH. In this study 123 I-LDL binding and 111 In-LDL binding to MNCs has been shown to saturable, reversible and displaceable and time-dependent. 123 I-LDL and 111 In-LDL as well can be recommended for the in-vitro determination of LDL-receptor binding activity as both binding processes show approximately the same characteristics. (author)

Air pollution is associated with the development of atherosclerosis via the cooperation of CD36 and NLRP3 inflammasome in ApoE-/- mice.

Science.gov (United States)

Du, Xihao; Jiang, Shuo; Zeng, Xuejiao; Zhang, Jia; Pan, Kun; Zhou, Ji; Xie, Yuquan; Kan, Haidong; Song, Weimin; Sun, Qinghua; Zhao, Jinzhuo

2018-06-15

Previous studies have indicated that the main air pollutant fine particulate matter (≤2.5 μm; PM 2.5 ) exposure is associated with the development of atherosclerosis. Although the mechanism is not fully illustrated, the inflammatory responses play an important role. The present study aimed to explore whether PM 2.5 -exacerbated atherosclerosis was mediated by the cooperation of cluster of differentiation 36 (CD36) and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammasome in apolipoprotein E -/- (ApoE -/- ) mice. Thirty-two ApoE -/- mice were randomly divided into two groups. One group was fed with high fat chow (HFC) for 10 weeks to establish atherosclerotic model, and the other was fed with normal chow (NC). From week 11, the mice were exposed to concentrated PM 2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM 2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic root than that in the FA mice. Compared with the FA mice, PM mice appeared a decrease in high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 along with an increase in apolipoprotein B, low density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL). Moreover, PM 2.5 exposure induced increase of CD36 in serum and aorta. In both NC and HFC groups, NLRP3 inflammasome activation-related indicators were activated or increased in the aorta of the PM mice when compared with the FA mice. The cooperation of CD36 and NLRP3 inflammasome activation may be the potential mechanisms linkixposed to concentrated PM 2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM 2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic

Gambaran Kadar Kolesterol-LDL (Low Density Lipoprotein Sebelum dan 48 Jam Sesudah Melakukan Satu Kali Terapi Bekam Basah Pada Penderita Hipertensi Dengan Pola lima titik

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Suryanta Suryanta

2016-09-01

Full Text Available Hypertension, or more commonly known as high blood pressure is a condition in which a person got an increasing blood pressure upper normal, resulting in increasing morbidity and mortality. The long hypertension is one risk factor for cardiovascular disease, which is one cause of atherosclerosis. Atherosclerosis is a very progressive diseases that causes hardening of the arteries due to the blockage by oxidized cholesterol. Atherosclerosis begins with the build up of LDL-cholesterol. There are two handling of LDL-cholesterol; pharmacological and non-pharmacological. Nonpharmacologic is done with wet cupping therapy. The aim of this study is to determine the average LDL-cholesterol levels before and after the wet cupping therapy with five-point pattern. This research is descriptive research, then presented in the form of tables to showing the results of the study. This study was done Talunombo, Sidomulya, Pengasih, Kulon Progo. This research object is venous blood samples taken from hypertensive patients as research subjects. Descriptive test results obtained an average LDL-cholesterol levels before the wet cupping therapy is 114,182 mg/dl and after wet cupping is 115,618 mg/dl. The conclusion of this study is the average LDL-cholesterol levels prior to the wet cupping therapy with a five-point pattern is 114,182 mg/dl and after wet cupping with five-point pattern is 115,618 mg/dl.

Mangifera indica L. extract (Vimang®) reduces plasma and liver cholesterol and leucocyte oxidative stress in hypercholesterolemic LDL receptor deficient mice.

Science.gov (United States)

Dorighello, Gabriel G; Inada, Natália M; Paim, Bruno A; Pardo-Andreu, Gilberto L; Vercesi, Anibal E; Oliveira, Helena C F

2018-06-01

Cardiovascular diseases are major causes of death worldwide. Beyond the classical cholesterol risk factor, other conditions such as oxidative stress are well documented to promote atherosclerosis. The Mangifera indica L. extract (Vimang®) was reported to present antioxidant and hypocholesterolemic properties. Thus, here we evaluate the effects of Vimang treatment on risk factors of the atherosclerosis prone model of familial hypercholesterolemia, the LDL receptor knockout mice. Mice were treated with Vimang during 2 weeks and were fed a cholesterol-enriched diet during the second week. The Vimang treated mice presented significantly reduced levels of plasma (15%) and liver (20%) cholesterol, increased plasma total antioxidant capacity (10%) and decreased reactive oxygen species (ROS) production by spleen mononuclear cells (50%), P Vimang treated mice. Therefore, in this study we demonstrated that Vimang has protective effects on systemic and tissue-specific risk factors, but it is not sufficient to promote a reduction in the initial steps of atherosclerosis development. In addition, we disclosed a new antioxidant target of Vimang, the spleen mononuclear cells that might be relevant for more advanced stages of atherosclerosis. © 2018 International Federation for Cell Biology.

Novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit

International Nuclear Information System (INIS)

Naruszewicz, M.; Carew, T.E.; Pittman, R.C.; Witztum, J.L.; Steinberg, D.

1984-01-01

Treatment of low density lipoprotein (LDL) receptor-deficient rabbits (WHHL rabbits) with probucol (1% w/w in a chow diet) lowered their LDL-cholesterol levels by 36%, consonant with the reported effectiveness of the drug in patients deficient in the LDL receptor. Initial studies of LDL fractional catabolic rate (FCR) using 125 I-labeled LDL prepared from the serum of untreated WHHL rabbits showed no difference between probucol-treated WHHL rabbits and untreated WHHL rabbits. When, however, 125 I-labeled LDL was prepared from donor WHHL rabbits under treatment with probucol and injected back into them, the FCR was found to be increased by about 50% above that measured simultaneously using 131 I-labeled LDL prepared from untreated WHHL donors. The labeled LDL from probucol-treated donors was also metabolized more rapidly than that from untreated donors when injected into untreated WHHL rabbits or into untreated wild-type New Zealand White rabbits. Finally, it was shown that rabbit skin fibroblasts in culture degraded labeled LDL prepared from probucol-treated WHHL rabbits more rapidly than that prepared from untreated WHHL donors. This was true both for normal rabbit fibroblasts and also for WHHL skin fibroblasts, although the absolute degradation rates in the latter were, of course, much lower for both forms of LDL. The data indicate that a major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL of the probucol-treated animal

Association of Serum LDL Cholesterol Level with Periodontitis among Patients Visiting a Tertiary-care Hospital

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S Sharma

2011-09-01

Full Text Available Introduction: High low-density lipoproteins (LDL cholesterol is one of the major risk factors for cardiovascular disease. In recent years, some evidence has been presented that periodontitis,an infectious inflammatory condition of the periodontium, is associated with an increased risk of cardiovascular disease. To further elucidate this association, we have studied the levels of LDL cholesterol, a known risk marker for cardiovascular disease, in a periodontally-diseased group. Methods: The levels of serum LDL cholesterol in 47 subjects with mild to severe (clinical attachment loss equal to or greater than 1 mm chronic generalized (at least 30% of teeth affected periodontitis with the mean age of 42.21 ± 1.46 years were measured and compared with those obtained from 42 age (39.83 ± 0.94 and sex matched controls. Both groups were free from systemic illnesses. Results: The mean serum LDL cholesterol in periodontitis patients was found to be signifi cantly higher (P < 0.001 as compared to that of the controls. The mean clinical attachment loss was positively correlated with serum LDL cholesterol (P < 0.01 and gingival index (P<0.05. The frequency of persons with pathologic values of LDL cholesterol was signifi cantly higher in periodontitis patients compared with that of the controls. Conclusions: These results showed that high serum LDL cholesterol may be associated with periodontitis in healthy people. However, it is unclear whether periodontitis causes an increase in the levels of serum LDL or an increased LDL is a risk factor for both periodontitis and cardiovascular disease. Keywords: Cardiovascular disease, LDL cholesterol, periodontitis.

Inhibitory effect of three C-glycosylflavonoids from Cymbopogon citratus (Lemongrass) on human low density lipoprotein oxidation.

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Orrego, Roxana; Leiva, Elba; Cheel, José

2009-09-30

This study assessed the inhibitory effect of three C-glycosylflavonoids from Cymbopogon citratus leaves--isoorientin (1), swertiajaponin (2) and isoorientin 2"-Orhamnoside (3)--on human LDL oxidation. Isolated LDL was incubated with compounds 1-3 and the kinetics of lipid peroxidation were assessed by conjugated diene and malondialdehyde-thiobarbituric acid reactive substances (MDA-TBARS) formation after addition of copper ions. Significant differences (p < 0.05) between the lag time phase of the control and the lag time phase in the presence of the compounds 1 (0.25 microM) and 2 (0.50 microM) were observed. After five hours of incubation all three compounds showed a significant inhibitory effect on MDA-TBARS formation with respect to the control. After six hours of incubation only compound 1 kept a remarkable antioxidant effect. This study demonstrates that isoorientin (1) is an effective inhibitor of in vitro LDL oxidation. As oxidative damage to LDL is a key event in the formation of atherosclerotic lesions, the use of this natural antioxidant may be beneficial to prevent or attenuate atherosclerosis.

Intradomain Confinement of Disulfides in the Folding of Two Consecutive Modules of the LDL Receptor.

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Juan Martínez-Oliván

Full Text Available The LDL receptor internalizes circulating LDL and VLDL particles for degradation. Its extracellular binding domain contains ten (seven LA and three EGF cysteine-rich modules, each bearing three disulfide bonds. Despite the enormous number of disulfide combinations possible, LDLR oxidative folding leads to a single native species with 30 unique intradomain disulfides. Previous folding studies of the LDLR have shown that non native disulfides are initially formed that lead to compact species. Accordingly, the folding of the LDLR has been described as a "coordinated nonvectorial" reaction, and it has been proposed that early compaction funnels the reaction toward the native structure. Here we analyze the oxidative folding of LA4 and LA5, the modules critical for ApoE binding, isolated and in the LA45 tandem. Compared to LA5, LA4 folding is slow and inefficient, resembling that of LA5 disease-linked mutants. Without Ca++, it leads to a mixture of many two-disulfide scrambled species and, with Ca++, to the native form plus two three-disulfide intermediates. The folding of the LA45 tandem seems to recapitulate that of the individual repeats. Importantly, although the folding of the LA45 tandem takes place through formation of scrambled isomers, no interdomain disulfides are detected, i.e. the two adjacent modules fold independently without the assistance of interdomain covalent interactions. Reduction of incredibly large disulfide combinatorial spaces, such as that in the LDLR, by intradomain confinement of disulfide bond formation might be also essential for the efficient folding of other homologous disulfide-rich receptors.

Targeting LDL Cholesterol: Beyond Absolute Goals Toward Personalized Risk.

Science.gov (United States)

Leibowitz, Morton; Cohen-Stavi, Chandra; Basu, Sanjay; Balicer, Ran D

2017-06-01

The aim of this study was to review and assess the evidence for low-density lipoprotein cholesterol (LDL-C) treatment goals as presented in current guidelines for primary and secondary prevention of cardiovascular disease. Different sets of guidelines and clinical studies for secondary prevention have centered on lower absolute LDL-C targets [achieve greater reductions in cardiovascular risk. Population-based risk models serve as the basis for statin initiation in primary prevention. Reviews of current population risk models for primary prevention show moderate ability to discriminate [with c-statistics ranging from 0.67 to 0.77 (95% CIs from 0.62 to 0.83) for men and women] with poor calibration and overestimation of risk. Individual clinical trial data are not compelling to support specific LDL-C targets and percent reductions in secondary prevention. Increasing utilization of electronic health records and data analytics will enable the development of individualized treatment goals in both primary and secondary prevention.

Cryoprotection effectiveness of low concentrations of natural and lyophilized LDL (low density lipoproteins on canine spermatozoa

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M.M. Neves

2014-06-01

Full Text Available The aim of this study was to evaluate the use of low concentrations of natural and lyophilized low density lipoprotein (LDL from hen's egg yolk for cryopreservation of canine semen. Different ammonium sulphate concentrations were tested to extract LDL from egg yolk. The yolk was centrifuged, and LDL was isolated using 10, 20, 40, 45, or 50% ammonium sulphate solution (ASS. The LDL-rich floating fraction was collected for chemical characterization. Dry matter content was lowest (P<0.05 in the LDL extracted with the 50% ASS. The purification of LDL increased in association with increasing ammonium sulphate concentrations. SDS-PAGE showed that the 50% ASS solution yielded a purer fraction of LDL from egg yolk. For semen cryopreservation, TRIS extender was used replacing 20% egg yolk (control by natural or lyophilized LDL using 1, 2, and 3% (w/v. Semen was centrifuged (755Xg for 7 min, diluted with one of the extenders, packed into 0.5mL straws (100x106 sperm/mL, and placed in a programmable cryopreservation machine. Thawed semen (37°C/ 30s was analyzed for sperm motility, morphology, and by the hypoosmotic and epifluorescence tests (CFDA/ PI. Natural LDL extracted with 50% ASS was as effective as whole egg yolk to preserve canine frozen sperm when using low concentrations. The lyophilized LDL, mainly in the two higher concentrations tested (2 and 3%, was unsuitable to maintain the effectiveness of the LDL cryoprotective effect on dog sperm.

Influence of fish oil supplementation on in vivo and in vitro oxidation resistance of low-density lipoprotein in type 2 diabetes

DEFF Research Database (Denmark)

Pedersen, H.; Petersen, M.; Major-Pedersen, A.

2003-01-01

in vitro with Cue(2+). As a marker of in vivo oxidation malondialdehyde concentration in LDL (LDL-MDA) was measured.Results: Fish oil reduced both mean lag time (before, 57.8; after, 48.8 min, P propagation rate (before, 0.018 &udelta;OD/min; after, 0.015 &udelta;OD/min, P ... corn oil had no influence on lag time and propagation rate. The changes in lag time and propagation rate differed significantly between fish oil and corn oil treatment. LDL-MDA changes differed borderline significantly between groups (FO, 110.4 pmol/mg protein; CO, 6.7 pmol/mg protein; P = 0.057). Fish...... oil supplementation had no influence on glycemic control as assessed from HbA(1c) and fasting blood glucose.Conclusion: According to our findings, fish oil supplementation leads to increased in vivo oxidation and increased in vitro oxidation susceptibility of LDL particles. More studies are needed...

Selenium modulates MMP2 expression through the TGFβ1/Smad signalling pathway in human umbilical vein endothelial cells and rabbits following lipid disturbance.

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Xu, Chenggui; Lu, Guihua; Li, Qinglang; Zhang, Juhong; Huang, Zhibin; Gao, Xiuren

2017-07-01

A high-fat diet is a major risk factor for coronary heart diseases. Matrix metalloprotease (MMP) expression is changed in many cardiovascular diseases. Selenium, which is an important trace element in animals, has a close relationship with cardiovascular diseases. The TGFβ1/Smad signalling pathway is ubiquitous in diverse tissues and cells, and it is also associated with the occurrence and development of cardiovascular diseases. Therefore, in this study, we aimed to determine selenium's effect on lipid metabolism, atherosclerotic plaque formation, and MMP2 expression, as well as the underlying functional mechanism. In vivo tests: 24 male New Zealand white rabbits were randomly divided into 4 groups: regular diet, high-fat diet, high-fat diet+selenium and regular diet+selenium groups. The high-fat diet induced the lipid disturbances of rabbits at week 12. Selenium supplementation lowered total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels (pSelenium supplementation also suppressed MMP2 over-expression in thoracic aortas. In vitro tests: Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of selenium or ox-LDL. Ox-LDL promoted MMP2 expression by increasing TGFβ1, pSmad2, pSmad3 and Smad3 expression (pSelenium attenuated MMP2 over-expression by regulating the TGFβ1/Smad signalling pathway. Selenium suppressed high-fat diet-induced MMP2 over-expression in vivo by improving lipid metabolism. In vitro, selenium attenuated MMP2 over-expression through the TGFβ1/Smad signalling pathway. Copyright © 2017 Elsevier GmbH. All rights reserved.

A phase 1 study to evaluate the safety and LDL cholesterol-lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9.

Science.gov (United States)

Baruch, Amos; Luca, Diana; Kahn, Robert S; Cowan, Kyra J; Leabman, Maya; Budha, Nageshwar R; Chiu, Cecilia P C; Wu, Yan; Kirchhofer, Daniel; Peterson, Andrew; Davis, John C; Tingley, Whittemore G

2017-07-01

Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low-density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL-C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo-controlled, phase 1 ascending-dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL-C-lowering drug. Anti-PCSK9 antibody therapy safely and effectively reduces LDL-C. Subjects (N = 80) were randomized into 10 cohorts. Six sequential single-dose cohorts received 10, 40, 150, 300, 600, or 800 mg of RG7652 via subcutaneous injection. Four multiple-dose cohorts received 40 or 150 mg of RG7652 once weekly for 4 weeks, either with or without statin therapy (atorvastatin). Adverse events (AEs) were generally mild; the most common AEs were temporary injection-site reactions. No serious AEs, severe AEs, AEs leading to study-drug discontinuation, or dose-limiting toxicities were reported. RG7652 monotherapy reduced mean LDL-C levels by up to 64% and as much as 100 mg/dL at week 2; the effect magnitude and duration increased with dose (≥57 days following a single RG7652 dose ≥300 mg). Exploratory analyses showed reduced oxidized LDL, lipoprotein(a), and lipoprotein-associated phospholipase A2 with RG7652. Antidrug antibody against RG7652 tested positive in 2 of 60 (3.3%) RG7652-treated and in 4 of 20 (20.0%) placebo-treated subjects. Simultaneous atorvastatin administration did not appear to impact the pharmacokinetic profile or lipid-lowering effects of RG7652. Overall, RG7652 elicited substantial and sustained dose-related LDL-C reductions with an acceptable safety profile and minimal immunogenicity. © 2017 Wiley Periodicals, Inc.