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)

Nitric oxide (NO) regulates vascular tone and local blood flow, platelet aggregation and adhesion, and leukocyte-endothelial cell interactions. Abnormalities in NO production by the vascular endothelium result in endothelial dysfunction, which occurs in hypertension, diabetes, aging, and as a prelude to atherosclerosis. The common feature of endothelial dysfunction is a decrease in the amount of bioavailable NO. In this article, the physiologic roles of NO and the mechanisms of endothelial dysfunction are reviewed. Regulation of endothelial NO synthase (eNOS) activity by fatty acid modifica-tions, intracellular localization, interactions with heat shock protein 90 (hsp90) and caveolin, substrate and cofactor dependence, and phosphorylation might all affect the level of bioavailable NO. A hypothesis is proposed that the final common pathway of diverse causes of endothelial dysfunction involves abnormalities in eNOS phosphorylation at Ser 1179 and other key phosphorylation sites.
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PMID:Endothelial nitric oxide synthase and endothelial dysfunction. 1459 66

Caveolae, plasma membrane invaginations that serve as membrane organizing centers, are found in most cell types, but are enriched in adipocytes, endothelial cells, and myocytes. Three members of the caveolin family (Cav-1, -2, and -3) are essential for the formation of caveolae. Specialized motifs in the caveolin proteins function to recruit lipids and proteins to caveolae for participation in intracellular trafficking of cellular components and operation in signal transduction. Mutations in the gene encoding CAV-1 are associated with the development and progression of breast cancers, whereas mutations in the CAV-3 gene result in Rippling Muscle Disease and a form of Limb-Girdle Muscular Dystrophy. The generation of caveolin-null mice has confirmed the essential role of these proteins in caveolae biogenesis and in the pathophysiology of diverse tissues. Caveolin-null mice provide new animal models for studying the pathogenesis of a number of human diseases, including cancer, diabetes, atherosclerosis, restrictive lung disease and pulmonary fibrosis, cardiomyopathy, muscular dystrophy, and bladder dysfunction.
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PMID:The biology of caveolae: lessons from caveolin knockout mice and implications for human disease. 1499 53

Caveolae are flask-shaped invaginations in the membrane that depend on the contents of cholesterol and on the structural protein caveolin. The organisation of caveolae in parallel strands between dense bands in smooth muscle is arguably unique. It is increasingly recognised, bolstered in large part by recent studies in caveolae deficient animals, that caveolae sequester and regulate a variety of signalling intermediaries. The role of caveolae in smooth muscle signal transduction, as inferred from studies on transgenic animals and in vitro approaches, is the topic of the current review. Both G-protein coupled receptors and tyrosine kinase receptors are believed to cluster in caveolae, and the exciting possibility that caveolae provide a platform for interactions between the sarcoplasmic reticulum and plasmalemmal ion channels is emerging. Moreover, messengers involved in Ca2+ sensitization of myosin phosphorylation and contraction may depend on caveolae or caveolin. Caveolae thus appear to constitute an important signalling domain that plays a role not only in regulation of smooth muscle tone, but also in proliferation, such as seen in neointima formation and atherosclerosis.
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PMID:Caveolae-associated signalling in smooth muscle. 1521 28

Although they were discovered more than 50 years ago, caveolae have remained enigmatic plasmalemmal organelles. With their characteristic "flasklike" shape and virtually ubiquitous tissue distribution, these interesting structures have been implicated in a wide range of cellular functions. Similar to clathrin-coated pits, caveolae function as macromolecular vesicular transporters, while their unique lipid composition classifies them as plasma membrane lipid rafts, structures enriched in a variety of signaling molecules. The caveolin proteins (caveolin-1, -2, and -3) serve as the structural components of caveolae, while also functioning as scaffolding proteins, capable of recruiting numerous signaling molecules to caveolae, as well as regulating their activity. That so many signaling molecules and signaling cascades are regulated by an interaction with the caveolins provides a paradigm by which numerous disease processes may be affected by ablation or mutation of these proteins. Indeed, studies in caveolin-deficient mice have implicated these structures in a host of human diseases, including diabetes, cancer, cardiovascular disease, atherosclerosis, pulmonary fibrosis, and a variety of degenerative muscular dystrophies. In this review, we provide an in depth summary regarding the mechanisms by which caveolae and caveolins participate in human disease processes.
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PMID:Role of caveolae and caveolins in health and disease. 1538 54

Caveolae are vesicular organelles (50-100-nm in diameter) that are particularly abundant in cells of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes and fibroblasts. In these cell types, caveolae function both in protein trafficking and signal transduction, as well as in cholesterol homeostasis. Caveolins are the structural proteins that are both necessary and sufficient for the formation of caveolae membrane domains. Caveolins 1 and 2 are co-expressed in most cell types, while the expression of caveolin-3 is muscle-specific. Thus, endothelial cells and fibroblasts are rich in caveolins 1 and 2, while cardiac myocytes and skeletal muscle fibers express caveolin-3. In contrast, smooth muscle cells express all three caveolins (Cav-1, -2, and -3). Mechanistically, caveolins interact with a variety of downstream signaling molecules, including Src-family tyrosine kinases, p42/44 mitogen activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS), and hold these signal transducers in the inactive conformation until activation by an appropriate stimulus. In many ways, caveolins serve both to compartmentalize and regulate signaling. Recent studies using caveolin-deficient mouse models dramatically show that caveolae and caveolins play a prominent role in various human patho-biological conditions, especially those related to the cardiovascular system. These disease phenotypes include: atherosclerosis, cardiac hypertrophy, cardiomyopathy, pulmonary hypertension, and neointimal hyperplasia (smooth muscle cell proliferation). In addition, caveolins play a significant role in other disease phenotypes, such as cancer, diabetes, bladder dysfunction, and muscular dystrophy, as we discuss in this review. Thus, caveolin-deficient mice will serve as important new animal models to dissect the intricate role of caveolae and caveolins in the pathogenesis of human diseases.
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PMID:The Caveolin genes: from cell biology to medicine. 1576 30

Endothelial cell (EC) barrier dysfunction results in increased vascular permeability observed in inflammation, tumor angiogenesis, and atherosclerosis. The platelet-derived phospholipid sphingosine-1-phosphate (S1P) decreases EC permeability in vitro and in vivo and thus has obvious therapeutic potential. We examined S1P-mediated human pulmonary artery EC signaling and barrier regulation in caveolin-enriched microdomains (CEM). Immunoblotting from S1P-treated EC revealed S1P-mediated rapid recruitment (1 microM, 5 min) to CEMs of the S1P receptors S1P1 and S1P3, p110 PI3 kinase alpha and beta catalytic subunits, the Rac1 GEF, Tiam1, and alpha-actinin isoforms 1 and 4. Immunoprecipitated p110 PI3 kinase catalytic subunits from S1P-treated EC exhibited PIP3 production in CEMs. Immunoprecipitation of S1P receptors from CEM fractions revealed complexes containing Tiam1 and S1P1. PI3 kinase inhibition (LY294002) attenuated S1P-induced Tiam1 association with S1P1, Tiam1/Rac1 activation, alpha-actinin-1/4 recruitment, and EC barrier enhancement. Silencing of either S1P1 or Tiam1 expression resulted in the loss of S1P-mediated Rac1 activation and alpha-actinin-1/4 recruitment to CEM. Finally, silencing S1P1, Tiam1, or both alpha-actinin isoforms 1/4 inhibits S1P-induced cortical F-actin rearrangement and S1P-mediated barrier enhancement. Taken together, these results suggest that S1P-induced recruitment of S1P1 to CEM fractions promotes PI3 kinase-mediated Tiam1/Rac1 activation required for alpha-actinin-1/4-regulated cortical actin rearrangement and EC barrier enhancement.
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PMID:Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin. 1619 73

Atherosclerosis is associated with a number of functional abnormalities that affect endothelium-dependent vasomotor function, inflammation, and thrombosis. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects on many of these functions, likely explaining their benefit in reducing the incidence of clinical events in patients at high risk of cardiovascular disease. Statins may improve this vascular biology by lowering levels of low-density lipoprotein (LDL) or potentially by a number of non-LDL-related mechanisms. Cell culture and some animal studies have demonstrated LDL-independent effects of statins. The non-LDL mechanisms include effects on isoprenoid production and function, interactions between caveolin and nitric oxide synthase, and direct immunomodulatory effects. Although these mechanisms are clearly demonstrated in the experimental setting, their relevance to the clinical use of statins is unknown. From a purely pragmatic viewpoint, the debate of lipid versus nonlipid effects of statins matters little to clinical practice. Their proven effect on vascular biology and risk reduction justifies their important therapeutic role.
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PMID:Potential vascular benefits of statins. 1635 10

Although caveolae function in vesicular and cholesterol trafficking, the recent identification of various signaling molecules in caveolae and their functional interaction with caveolin suggest that they may participate in transmembrane signaling. Interestingly, many of the signaling molecules that interact with caveolin-1 (cav-1) mediate mitogenic signals to the nucleus, implying that cav-1 may play a modulating role in the pathophysiology of vascular proliferative diseases such as atherosclerosis and restenosis after angioplasty. Although much attention has been given to the predominantly antiproliferative role of cav-1 in growth-factor-induced signal transduction, we were recently able to demonstrate that cav-1 acts in mechanotransduction too. During cyclic strain, however, cav-1 is critically involved in proproliferative signaling. We propose that, at least in the vasculature which is constantly exposed to alternating mechanical force and different growth factors, cav-1 holds a dual role toward modulation of proliferation, depending on the stimulus the cells are exposed to. In vivo, the net effect of growth factors and mechanically triggered stimuli determines the amount of local cell proliferation and, therefore, the onset and progression of vascular proliferative disease.
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PMID:Caveolin-1: dual role for proliferation of vascular smooth muscle cells. 1647 62

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


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