Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte scavenger receptor, CD36 has been implicated in the pathogenesis of atherosclerosis as a major oxidised LDL receptor mediating lipid accumulation and foam cell formation. Previously, we found that treatment of monocyte cultures with the carboxyl terminal fragment of alpha1-antitrypsin (C-36) increases lipid binding and uptake, induces LDL receptor mRNA and CD36 receptor protein expression, and also significantly increases production of pro-inflammatory molecules. To assess the role of the CD36 receptor in proatherogenic monocyte activation by the C-36 fragment, we tested whether specific anti-CD36 receptor antibodies would block the effects of C-36 on monocyte activation. We find that pre-incubation of cells with anti-LDL and anti-CD36 receptor antibodies (10 microg/ml) blocks binding of 125I-C-36 by about 50%. Similarly, cells pre-incubated with oxidised LDL or native LDL at concentrations from 2.5 to 10 microg/ml showed a loss of 125I-C-36 binding (up to 49 and 57%) and uptake (up to 47 and 59.8%), respectively. In parallel experiments, monocytes were first incubated for 1 or 6 h with anti-CD36 antibodies (10 microg/ml) prior to adding C-36 peptide. Anti-CD36 antibodies suppressed C-36-induced production of gelatinase B, monocyte chemoattractant protein-1, interleukin-6 and cellular oxygen consumption to control levels, whereas levels of TNFalpha were unaffected. In contrast, saturation of LDL receptors with excess of anti-LDL (20 microg/ml) significantly inhibited C-36 induced TNFalpha levels. Results indicate that the C-36 peptide binds to both LDL and CD36 scavenger receptors which involves selective upregulation of pro-inflammatory molecules and activation of the respiratory burst in human monocytes. This also supports important roles for CD36 and LDL receptors in atherogenesis and suggests that blockade of CD36 receptor can be protective in pro-inflammatory activation of human monocytes.
Atherosclerosis 2001 Sep
PMID:C-terminal fragment of alpha1-antitrypsin activates human monocytes to a pro-inflammatory state through interactions with the CD36 scavenger receptor and LDL receptor. 1150 Jan 73

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide exerting its effects predominantly by paracrine and autocrine mechanisms. ET-1 acts as a mitogen and co-mitogen on vascular smooth muscle cells, and accumulating evidence suggests that ET-1 is involved in the pathogenesis of atherosclerosis. Deposition of low density lipoproteins (LDL) in the vessel wall is known to play a crucial role in the development of atherosclerotic lesions. In the present study, we have investigated the effect of native LDL (nLDL) and oxidatively modified LDL (oxLDL) on ET-1 synthesis and endothelin receptor expression in cultured human coronary artery smooth muscle cells and human monocyte-derived macrophages. Native LDL and oxLDL induced a significant stimulation of ET-1 release and ET-1 mRNA expression in human coronary artery smooth muscle cells and monocyte-derived macrophages. Antibodies against the scavenger receptor CD36 significantly reduced the oxLDL-induced stimulation of ET-1 synthesis. The antioxidants trolox and probucol did not significantly inhibit the LDL-induced rise of ET-1 release. Endothelin B receptor expression was up-regulated in both cell types after incubation with nLDL and oxLDL. In coronary smooth muscle cells, endothelin A receptor expression was slightly increased by LDL, whereas endothelin A receptor was not detectable in monocyte-derived macrophages. Coronary artery smooth muscle cells secreted a more than 150-fold higher amount of immunoreactive ET-1 into the cell culture medium than monocyte-derived macrophages. In summary, the present data, demonstrating a LDL-induced up-regulation of the endothelin system in coronary smooth muscle cells and in monocyte-derived macrophages, provide further support for a pathophysiological role of endothelin in coronary atherosclerosis and suggest that ET-1 might be involved in mediating the atherogenic effects of LDL.
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PMID:Endothelin-1 synthesis and endothelin B receptor expression in human coronary artery smooth muscle cells and monocyte-derived macrophages is up-regulated by low density lipoproteins. 1154 48

The goal of the present study was to elucidate mechanisms for angiotensin II (Ang II) induction of oxidized low density lipoprotein (Ox-LDL) uptake by macrophages, the hallmark of early atherosclerosis. Compared with placebo treatment, Ang II injections (0.1 mL, 10(-7) mol/L per day) for 2 weeks to apolipoprotein E-deficient mice significantly increased Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). These effects were abolished by treatment with losartan (5 to 50 mg/kg per day) before Ang II administration. Because no such effect was obtained in vitro, the ex vivo effect of Ang II on macrophage uptake of Ox-LDL could be mediated by a factor that is not expressed at a significant level in vitro. Because Ang II stimulates cellular production of interleukin-6 (IL-6), we analyzed the possible role of IL-6 as a mediator of Ang II-mediated cellular uptake of Ox-LDL by using several approaches. First, incubations of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Second, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression compared treatment with Ang II alone. Finally, Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Thus, we conclude that a novel mechanism for Ang II atherogenicity, related to macrophage cholesterol accumulation and foam cell formation, may involve its stimulatory effect on macrophage uptake of Ox-LDL, a process mediated byIL-6.
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PMID:Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6. 1155 73

The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.
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PMID:The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. 1155 74

Interaction between leukocyte and endothelial cells (ECs) is essential for vascular homeostasis and competent immune-inflammatory responses in vivo. Platelet-derived microparticles (PMPs) are generated by high shear stress and may appear in diseased small arteries and arterioles in various clinical settings. In this study, we used flow cytometry and confocal laser scanning microscopy to investigate the effects of high-shear-induced platelet and microparticle activation in adhesion molecules of THP-1 and ECs. We also measured the production of some cytokines and studied cytokine mRNA from THP-1 and ECs after PMP stimulation. PMP stimulation of THP-1 cells increased CD11b, CD32, and CD33 but not CD29, CD31, and CD36. PMP stimulation of ECs increased CD54 and CD63 but not CD9, CD29, and CD31. PMPs induced interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) production by THP-1. PMPs also induced IL-8, IL-1 beta, and interleukin-6 (IL-6) production by ECs. Production was time-dependent. With RT-PCR, some cytokine mRNAs were detected in THP-1 and ECs after PMP stimulation. In relation to adhesiveness after PMP stimulation, we could clearly observe a shift in distribution not only of CD11b in THP-1 cells but also of CD54 in ECs. In addition, anti-P-selectin glycoprotein ligand-1 antibody reduced the expression of CD11b, CD32, and CD33 in THP-1 after PMP stimulation. These results suggest that high-shear-induced microparticles may contribute to the development of atherosclerosis and participate in vascular damage in inflammatory disorders.
Atherosclerosis 2001 Oct
PMID:High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. 1158 5

We previously isolated THP-1 subtype cells (sTHP-1), a cell line that expresses scanty amounts of scavenger receptor A (ScR-A) and does not undergo foam cell formation when incubated with acetylated low-density lipoprotein (Ac-LDL). In this study, we investigated the accumulation of esterified cholesterol in sTHP-1 cells incubated with oxidized LDL (Ox-LDL), a physiologically modified lipoprotein in human. While sTHP-1 cells incubated with Ac-LDL accumulated only small amounts of esterified cholesterol, those incubated with Ox-LDL accumulated amounts similar to those accumulated by parent THP-1 (pTHP-1) cells. sTHP-1 cells expressed CD36 in amounts similar to the amounts expressed by pTHP-1 cells, and Ox-LDL was internalized through this CD36. The amount of accumulated esterified cholesterol was 73-81% of that accumulated in pTHP-1 cells expressing ScR-A. The levels of 125I-Ox-LDL binding, association, and degradation in sTHP-1 cells were 64-70% of the corresponding levels in pTHP-1 cells. In our experiments utilizing ScR-A-deficient sTHP-1 cells and a specific antibody against human CD36, most of the Ox-LDL interacted with the CD36 receptor. In addition, a substantial amount of Ox-LDL (28-42%) was bound and degraded by sTHP-1 macrophages when both of the two major scavenger receptors, ScR-A and CD36, were deficient or blocked. These results indicate that CD36 in macrophages plays an important role in foam cell formation by Ox-LDL, while additional scavenger receptor(s) may take part in significant pathways of Ox-LDL uptake in macrophages.
Atherosclerosis 2001 Oct
PMID:Uptake of oxidized low-density lipoprotein in a THP-1 cell line lacking scavenger receptor A. 1158 13

Recent work in the field of atherosclerosis has greatly expanded our knowledge of the pathogenesis of this disease. Scavenger receptors, including CD36, are thought to be most important early in the disease progression during macrophage uptake of modified LDL and foam cell formation. Genetically engineered murine models have been used to elucidate the contribution of the different scavenger receptors, to identify specific ligands related to LDL modifications, and to assess the possible therapeutic ramifications of targeting scavenger receptors. We have demonstrated a major role for CD36 in macrophage foam cell development and subsequent lesion development in vivo. Absence of CD36 in an atherogenic Apo E null background resulted in a 70% decrease in total lesion area in Western diet-fed mice. We have also made significant progress in our understanding of the regulation of expression of CD36 and have demonstrated that OxLDL can stimulate its own uptake by induction of CD36 gene expression. The mechanism by which OxLDL upregulates CD36 involves activation of the transcription factor, PPAR-gamma.
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PMID:Role of CD36, the macrophage class B scavenger receptor, in atherosclerosis. 1179 70

Recent research on alpha-tocopherol has revealed specific cellular functions of this compound belonging to the vitamin E family. Alpha-tocopherol can act as a radical scavenger, as a pro-oxidant, as an anti-alkylation agent and, most important, by mechanisms that are independent of the above properties. To the last group belong protein kinase C and 5-lipoxygenase inhibition at post-translational level, as well as alpha-tocopherol activation of protein phosphatase 2A and diacylglycerol kinase. Furthermore, at transcriptional level, several genes (CD36, alpha-TTP, alpha-tropomyosin, and collagenase) are modulated by alpha-tocopherol. These effects result in inhibition of smooth muscle cell proliferation, platelet aggregation, and monocyte adhesion and may be related to the alleged protection of atherosclerosis by vitamin E. On the other side, epidemiological and intervention studies have shown some inconsistent results. Rather than disregarding vitamin E as a means to protect against atherosclerosis progression, it would be wiser to better design clinical trials based on current knowledge of the biological properties of the molecule.
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PMID:Vitamin E 80th anniversary: a double life, not only fighting radicals. 1179 98

Foam cell formation, the hallmark of early atherosclerosis, results from cholesterol accumulation in arterial macrophages. Angiotensin-II stimulates foam cell formation and angiotensin converting enzyme (ACE) inhibitors reduce atherosclerosis in animal models. The goal of the present study was to determine the effect of the ACE inhibitor Ramipril on the progression of atherosclerosis in apolipoprotein-E-deficient (E0) mice with already advanced atherosclerosis. Therefore, 4-month-old atherosclerotic E0 mice were treated with Ramipril for 2 and 4 months and compared to age-matched placebo-treated mice, as well as to control young (4-month-old) non-treated E0 mice, for their atherosclerosis. Histomorphometry showed that Ramipril treatment substantially inhibited atherogenesis as shown by 48 and 72% reduction in lesion size at 6 and 8 months of age, respectively, compared to the lesion size in age-matched placebo-treated mice. Moreover, the size of the atherosclerotic lesions in 6- and 8-month-old Ramipril-treated mice was almost identical to the size of atherosclerosis of the 4-month-old control mice. Moreover, Ramipril treatment of E0 mice, significantly reduced oxidized low-density lipoprotein (Ox-LDL) uptake by their peritoneal macrophages (MPM) by 32%, compared to Ox-LDL uptake by MPM from 6-month-old placebo mice, and even reduced it by 12% in comparison to Ox-LDL uptake by MPM from 4-month-old control mice. A significant decrease in the mRNA levels of the Ox-LDL receptor CD36 by 58% was observed in macrophages from 6-month-old Ramipril-treated mice compared to macrophages from the 6-month-old placebo-treated mice. There was even a significant reduction (by 32%) in CD36 mRNA levels in macrophages from the 6-month-old Ramipril-treated mice, compared to the CD36 mRNA levels in macrophages from the 4-month-old control mice. We thus conclude that administration of the ACE inhibitor Ramipril to E0 mice, which already exhibit significant atherosclerosis, blocked the progression of the atherosclerotic lesion build-up, a phenomenon that could be related to Ramipril-induced inhibition of Ox-LDL uptake by macrophages.
Atherosclerosis 2002 Mar
PMID:Ramipril administration to atherosclerotic mice reduces oxidized low-density lipoprotein uptake by their macrophages and blocks the progression of atherosclerosis. 1188 18

CD36, a member of the scavenger receptor family, is centrally involved in the uptake of oxidized low density lipoproteins (oxLDLs) from the bloodstream. During the atherosclerotic process, the lipid cargo of oxLDL accumulates in macrophages and smooth muscle cells (SMCs), inducing their pathological conversion to foam cells. Increased expression of CD36 occurs in human atherosclerotic lesions, and CD36 knockout mice show reduced uptake of modified LDLs and reduced atherosclerosis. Here, we describe a novel exon 1b and extended CD36 promoter in human SMCs. Exon 1b is specifically transcribed in activated aortic SMCs and mainly expressed in atherosclerotic plaques. Thus, switching to exon 1b transcription may be an important step for the activation of SMCs and their conversion to foam cells. Using an antisense oligonucleotide to exon 1b, we inhibit CD36 translation and highly reduce oxLDL uptake. The antisense to exon 1b does not affect CD36 in cell lines not expressing the new exon. The possibility of a novel antiatherosclerotic therapy and the use of exon 1b as a marker of atherosclerosis are discussed.
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PMID:Novel 5' exon of scavenger receptor CD36 is expressed in cultured human vascular smooth muscle cells and atherosclerotic plaques. 1188 83


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