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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One aspect of homocysteine (Hcy) action is the impairment of endothelial cell function due to an impairment of endothelial nitric oxide (NO) production. The activity of the endothelial isoform of NO synthase (eNOS) is regulated by its interaction with caveolin-1 (Cav-1). The aim of this study was to determine whether Hcy may alter the levels of Cav-1 and eNOS in endothelial caveolae. We isolated caveolae-enriched membrane fractions from Hcy-treated human coronary artery endothelial cells. We found that treatment with 500 microM Hcy for 6h significantly reduced the levels of Cav-1 and eNOS in caveolae compared to untreated control by 47+/-7% and by 38+/-14%, respectively. Similarly, long-term incubation (96h) of HCAEC with 100 microM Hcy led to a comparable effect. The decreased Cav-1 abundance in endothelial caveolae in response to Hcy resulted from a decrease in Cav-1 expression at the transcriptional level. The reduced levels of eNOS in caveolae were caused by a translocation of eNOS from the caveolar fractions to noncaveolar fractions. The effects of Hcy were associated with an impairment of stimulated release of NO. These results suggest that Hcy induced impairment of NO production through a modulation of Cav-1 expression associated with a loss of eNOS in caveolae.
Atherosclerosis 2007 Feb
PMID:Effects of homocysteine on the levels of caveolin-1 and eNOS in caveolae of human coronary artery endothelial cells. 1661 46

Endothelial nitric oxide synthase (eNOS) plays a crucial role in the regulation of a variety of cardiovascular functions. Many studies have shown that dietary n-3 polyunsaturated fatty acids (PUFAs) have beneficial effects on coronary atherosclerosis. However, the mechanisms of n-3 PUFAs regulation in eNOS activation remain unknown. In the present study we investigated the effects of eicosapentaenoic acid (EPA, 20:5 n-3) on subcellular distribution of eNOS and lipid composition of caveolae. We demonstrated for the first time that EPA treatment profoundly altered lipid composition and fatty acyl substitutions of phospholipids in caveolae. We found that caveolin-1 was solely located in caveolae fractions in control cells, and EPA treatment displaced caveolin-1 from caveolae. eNOS was detected in the caveolin-enriched fractions and noncaveolae fractions in control cells. EPA treatment induced the translocation of eNOS from caveolae fractions to soluble fractions. P-eNOS was also distributed in both fractions. After EPA treatment, the level of p-eNOS in each fraction was increased but the distribution of which was unaffected. Moreover, the results of immunofluorescence confirmed that EPA could redistribute caveolin-1 and eNOS in plasma membrane. eNOS activity in HUVEC cells was increased after EPA treatment, which was in a dose dependent manner. And incubation with 50 microM EPA had the maximum effect on eNOS activity. Our results suggested that eNOS translocation was paralleled by a stimulated capacity for NO production in the cells. We found that total Akt and p-Akt were primarily presented in heavy membranes in control cells, and the relative level of p-Akt increased but the distribution did not change after EPA treatment. The distribution of CaM was slightly changed after EPA treatment. Our results indicated that n-3 PUFAs profoundly altered caveolae microenvironment, thereby modifying location and function of proteins in caveolae. EPA-induced alterations of lipid and proteins in caveolae may be an important mechanism in the pathophysiologic process of atherosclerosis.
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PMID:Eicosapentaenoic acid modifies lipid composition in caveolae and induces translocation of endothelial nitric oxide synthase. 1712

Atherosclerosis, an inflammatory disease, is closely associated with hyperglycemia, major sign of diabetes mellitus. Caveolae are vesicular invaginations of the plasma membrane that mediate the intracellular transport of lipids such as cholesterol. We evaluated the relationship between the expression of caveolin-1 and the number of caveolae in macrophages under conditions of high glucose concentration. Increased superoxide production, induction of inducible nitric oxide synthase (iNOS), and decreased caveolin-1 were observed in a concentration-dependent manner in THP-1 derived macrophages with high glucose concentrations. Mannitol, used as an osmotic control, showed no effects. Furthermore, co-localization of the NADPH oxidase component, p47(phox), and caveolin was confirmed by confocal microscopy. An atomic force microscopy (AFM) study showed that high glucose concentrations reduced the number and size of the caveolae. The percentage of cells with fragmented DNA was increased in cells grown in hyperglycemic media. Taken together, high glucose concentrations suppress the levels of caveolin-1 expression and reduce the number of caveolae. This might be due to the actions of superoxide via the activation of NADPH oxidase by translocation of its component and uncoupling of induced iNOS in macrophages. Furthermore, the apoptosis of macrophages might occur with high glucose concentrations, leading to the spreading of lipids from macrophages into intracellular spaces in the vessel wall.
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PMID:High glucose downregulates the number of caveolae in monocytes through oxidative stress from NADPH oxidase: implications for atherosclerosis. 1724 Jan 21

Vascular endothelial dysfunction is considered an initial step of atherogenesis, and the complicated cellular events of atherosclerosis begin with focal inflammation leading to foam cell formation and accumulation of cholesterol in the subendothelial space. Of the cells that make up atherosclerotic plaque, vascular endothelial cells (ECs) are the most resistant to cholesterol accumulation. However, ECs express receptors for modified lipoproteins and have the biochemical pathways for sterol synthesis and receptor-mediated endocytosis of lipoproteins. Cholesterol efflux continues even when cellular cholesterol mass is unchanged. Therefore, cholesterol efflux pathways may play an important role in endothelial cholesterol homeostasis. Recent study results suggest that apolipoprotein A-I and high density lipoproteins promote cellular cholesterol efflux through mechanisms depending on ATP-binding cassette transporter A1 in ECs. Caveolae and its structural protein caveolin-1 are abundant in ECs and could be contributors to cholesterol trafficking as well. However, the roles of each pathway in efflux and homeostasis of cellular cholesterol in ECs are still controversial. This article reviews recent progress in the understanding of cholesterol efflux and underlying mechanisms in ECs and proposes a model of efflux of cellular cholesterol. Such a cholesterol efflux pathway could provide insight into the efficient removal of excess cellular cholesterol in preventing atherogenesis.
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PMID:Insights into cholesterol efflux in vascular endothelial cells. 1758 47

Caveolae are 50-100 nm cell surface plasma membrane invaginations that are highly enriched in cholesterol and sphingolipids and are characterized by the protein marker caveolin-1. Caveolin-1 is highly expressed in terminally differentiated cells. Among these cells, endothelial cells, smooth muscle cells, and macrophages have all been shown to play key roles in the development of vascular disease. Atherosclerosis and neointimal formation are two major processes that have been associated with arterial occlusion. In both cases, caveolin-1 has been shown to play an important role. However, depending on the cell type and the metabolic pathways regulated by this protein, caveolin-1 may positively or negatively influence the development of vascular disease. Both of these aspects will be discussed in this review.
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PMID:Caveolae and caveolin-1: novel potential targets for the treatment of cardiovascular disease. 1758 6

n-3 Polyunsaturated fatty acids are assumed to play an important role in the prevention and treatment of atherosclerosis. Endothelial nitric-oxide synthase (eNOS) is responsible for cardiovascular homeostasis involving in regulation of vascular function, and the subcellular localization is critical for its activation. Here we determined the effect of docosahexaenoic acid (DHA, 22:6 n-3) on distribution of eNOS and its activity. DHA treatment markedly altered lipid environment of caveolae microdomains, which was coincided with selective displacement of caveolin-1 and eNOS from caveolae. Akt was not detected in caveolae fractions and CaM was distributed in both of caveolin-1-enriched membranes and non-caveolar fractions, whose distribution was unaffected by DHA. These data demonstrated for the first time that DHA altered caveolae microenvironment not only by modifying membrane lipid composition, but also by changing distribution of major structural proteins. DHA-induced alterations in caveolae lipid/protein environment may be an important mechanism in the development of pathogenesis of atherosclerosis.
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PMID:Docosahexaenoic acid affects endothelial nitric oxide synthase in caveolae. 1766 56

Polychlorinated biphenyls (PCBs) may contribute to the pathology of atherosclerosis by activating inflammatory responses in vascular endothelial cells. Endothelial nitric oxide synthase (eNOS) is colocalized with caveolae and is a critical regulator of vascular homeostasis. PCBs may be proatherogenic by causing dysfunctional eNOS signaling. The objective of this study was to investigate the role of caveolin-1 in PCB-induced endothelial dysfunction with a focus on mechanisms associated with eNOS signaling. Cells derived from an immortalized human vascular endothelial cell line were treated with PCB77 to study nitrotyrosine formation through eNOS signaling. Phosphorylation studies of eNOS, caveolin-1, and kinases, such as Src, phosphatidylinositol 3-kinase (PI3K), and Akt, were conducted in cells containing either functional or small-interfering RNA-silenced caveolin-1 protein. We also investigated caveolin-1-regulated mechanisms associated with PCB-induced markers of peroxynitrite formation and DNA binding of NF-kappaB. Cellular exposure to PCB77 increased eNOS phosphorylation and nitric oxide production, as well as peroxynitrite levels. A subsequent PCB-induced increase in NF-kappaB DNA binding may have implications in oxidative stress-mediated inflammatory mechanisms. The activation of eNOS by PCB77 treatment was blocked by inhibitors of the Src/PI3K/Akt pathway. PCB77 also increased phosphorylation of caveolin-1, indicating caveolae-dependent endocytosis. Caveolin-1 silencing abolished both the PCB-stimulated Akt and eNOS phosphorylation, suggesting a regulatory role of caveolae in PCB-induced eNOS signaling. These findings suggest that PCB77 induces eNOS phosphorylation in endothelial cells through a Src/PI3K/Akt-dependent mechanism, events regulated by functional caveolin-1. Our data provide evidence that caveolae may play a critical role in regulating vascular endothelial cell activation and toxicity induced by persistent environmental pollutants such as coplanar PCBs.
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PMID:The role of caveolin-1 in PCB77-induced eNOS phosphorylation in human-derived endothelial cells. 1793 68

Oxidized low-density lipoprotein (oxLDL)-induced apoptosis of vascular cells may participate to plaque instability and rupture. Caveolin-1 has emerged as an important regulator of several signal transduction pathways and processes that play a role in atherosclerosis. In this study we examined the potential role of caveolin-1 in the regulation of oxLDL-induced Ca(2+) signaling and apoptosis in vascular smooth muscle cells (VSMC). Cells expressing caveolin-1 were more susceptible to oxLDL-induced apoptosis, and this was correlated with enhanced Ca(2+) entry and pro-apoptotic events. Moreover, caveolin-1 silencing by small interfering RNA decreased the level of apoptotic cells after oxLDL treatment. These findings provide new insights about the potential role of caveolin-1 in the regulation of oxLDL-induced apoptosis in vascular cells and its contribution to the instability of the plaque.
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PMID:Caveolin-1 sensitizes vascular smooth muscle cells to mildly oxidized LDL-induced apoptosis. 1832 7

Lipoprotein metabolism plays an important role in the development of several human diseases, including coronary artery disease and the metabolic syndrome. A good comprehension of the factors that regulate the metabolism of the various lipoproteins is therefore key to better understanding the variables associated with the development of these diseases. Among the players identified are regulators such as caveolins and caveolae. Caveolae are small plasma membrane invaginations that are observed in terminally differentiated cells. Their most important protein marker, caveolin-1, has been shown to play a key role in the regulation of several cellular signaling pathways and in the regulation of plasma lipoprotein metabolism. In the present paper, we have examined the role of caveolin-1 in lipoprotein metabolism using caveolin-1-deficient (Cav-1(-/-)) mice. Our data show that, while Cav-1(-/-) mice show increased plasma triglyceride levels, they also display reduced hepatic very low-density lipoprotein (VLDL) secretion. Additionally, we also found that a caveolin-1 deficiency is associated with an increase in high-density lipoprotein (HDL), and these HDL particles are enriched in cholesteryl ester in Cav-1(-/-) mice when compared with HDL obtained from wild-type mice. Finally, our data suggest that a caveolin-1 deficiency prevents the transcytosis of LDL across endothelial cells, and therefore, that caveolin-1 may be implicated in the regulation of plasma LDL levels. Taken together, our studies suggest that caveolin-1 plays an important role in the regulation of lipoprotein metabolism by controlling their plasma levels as well as their lipid composition. Thus caveolin-1 may also play an important role in the development of atherosclerosis.
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PMID:Role of caveolin-1 in the regulation of lipoprotein metabolism. 1850 10

Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice. This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.
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PMID:Caveolin-1 influences vascular protease activity and is a potential stabilizing factor in human atherosclerotic disease. 1859 70


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