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)

Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by lipid accumulation, lipoprotein oxidation, and inflammation. Products of the cyclooxygenase (COX) pathway participate in acute and chronic inflammation. The inducible form of COX, COX-2, generates lipid mediators of inflammation that are pro-inflammatory and COX-2-selective inhibitors are potent anti-inflammatory agents. However, clinical data suggest an increased risk of cardiovascular side effects in patients using COX-2-selective inhibitors. In this paper, we sought to determine the effect of COX-2 deficiency on atherosclerosis-related lipoprotein metabolism in mice. We demonstrate that COX-2 deficiency resulted in (i) accumulation of lipids in circulation and liver, (ii) pro-inflammatory properties of HDL as measured by HDL's increased reactive oxygen species (ROS) content, decreased paraoxonase 1 (PON1) activity, decreased serum apoA-1, reduced ability to efflux cholesterol and to prevent LDL oxidizability, and (iii) increased TXB(2) in circulation. Moreover, when placed on an atherogenic diet, COX-2 deficiency resulted in (i) increased lipid deposition in the aorta, (ii) a further dramatic imbalance in circulating eicosanoids, i.e. decreased serum PGI(2) coupled with increased PGE(2) and TXB(2), and (iii) a marked elevation of pro-inflammatory cytokines, TNF and IL-6. Our results suggest, for the first time, that COX-2 deficiency contributes to the pro-atherogenic properties of HDL in mice.
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PMID:A novel anti-atherogenic role for COX-2--potential mechanism for the cardiovascular side effects of COX-2 inhibitors. 1764 85

Long-term exposure to particulate air pollution has been implicated as a risk factor for cardiovascular disease and mortality. Short-term exposure has also been suggested to contribute to complications of atherosclerosis. Aberrant regulation of smooth muscle cell proliferation is thought to associate with the pathophysiology of vascular disorders such as atherosclerosis. In this study, we investigate the influence of organic extracts of motorcycle exhaust particulates (MEPE) on rat vascular smooth muscle cell (VSMC) proliferation and related regulation signaling. Exposure of VSMCs to MEPE (10-100 microg/mL) enhanced serum-induced VSMC proliferation. The expression of proliferating cell nuclear antigen (PCNA) was also enhanced in the presence of MEPE. VSMCs treated with MEPE induced the increase in the extent of cyclooxygenase (COX)-2 mRNA and protein expression and prostaglandin E 2 production, whereas the level of COX-1 protein was unchanged. Moreover, MEPE increased the production of reactive oxygen species (ROS) in VSMCs in a dose-dependent manner. MEPE could also trigger time-dependently extracellular signal-regulated kinase (ERK)1/2 phosphorylation in VSMCs, which was attenuated by antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC). The level of translocation of nuclear factor (NF)-kappaB-p65 in the nuclei of VSMCs was also increased under MEPE exposure. The potentiating effect of MEPE on serum-induced VSMC proliferation could be abolished by COX-2 selective inhibitor NS-398, specific ERK inhibitor PD98059, and antioxidants NAC and PDTC. Taken together, these findings suggest that MEPE may contribute to the enhancement of the pathogenesis of cardiovascular diseases by augmenting proliferation of VSMCs through a ROS-regulated ERK1/2-activated COX-2 signaling pathway.
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PMID:Upregulation of cyclooxygenase-2 by motorcycle exhaust particulate-induced reactive oxygen species enhances rat vascular smooth muscle cell proliferation. 1764 4

Prostacyclin (PGI(2)) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium. Recent studies have demonstrated that PGI(2) protects against atherothrombosis. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios [1-3]. Moreover, the recent withdrawal of rofecoxib (Vioxx) due to increased cardiovascular events further supports the critical role of prostacyclin in inhibiting atherothrombosis in humans. Such studies have paralleled intense chemical biology studies to develop more stable prostacyclin analogues. Indeed a number of these analogues are currently being successfully used for the treatment of pulmonary hypertension. In this review we will summarize the current literature on some principles of prostacyclin analogue development, our current understanding of the receptor, and recent developments which implicate prostacyclin in atherothrombotic protection. More than 68 million Americans suffer from cardiovascular disease, which causes more deaths, disability and economic loss than any other group of diseases. Further clinical investigations of orally stable prostacyclin analogues for treatment of cardiovascular diseases other than pulmonary hypertension may now be warranted.
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PMID:Prostacyclin, atherothrombosis, and cardiovascular disease. 1769 54

Prostaglandin E(2) (PGE(2)) is the most abundant prostaglandin in the human body. It has a large number of biological actions that it exerts via four types of receptors, EP1-4. PGE(2) is formed from arachidonic acid by cyclooxygenase (COX-1 and COX-2)-catalyzed formation of prostaglandin H(2) (PGH(2)) and further transformation by PGE synthases. The isomerization of the endoperoxide PGH(2) to PGE(2) is catalyzed by three different PGE synthases, viz. cytosolic PGE synthase (cPGES) and two membrane-bound PGE synthases, mPGES-1 and mPGES-2. Of these isomerases, cPGES and mPGES-2 are constitutive enzymes, whereas mPGES-1 is mainly an induced isomerase. cPGES uses PGH(2) produced by COX-1 whereas mPGES-1 uses COX-2-derived endoperoxide. mPGES-2 can use both sources of PGH(2). mPGES-1 is a member of the membrane associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) superfamily. It requires glutathione as an essential cofactor for its activity. mPGES-1 is up-regulated in response to various proinflammatory stimuli with a concomitant increased expression of COX-2. The coordinate increased expression of COX-2 and mPGES-1 is reversed by glucocorticoids. Differences in the kinetics of the expression of the two enzymes suggest distinct regulatory mechanisms for their expression. Studies, mainly from disruption of the mPGES-1 gene in mice, indicate key roles of mPGES-1-generated PGE(2) in female reproduction and in pathological conditions such as inflammation, pain, fever, anorexia, atherosclerosis, stroke, and tumorigenesis. These findings indicate that mPGES-1 is a potential target for the development of therapeutic agents for treatment of several diseases.
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PMID:Membrane prostaglandin E synthase-1: a novel therapeutic target. 1787 11

Many investigators have suggested that immune activation may trigger the atherosclerotic process. The benefits of aspirin in preventing myocardial infarction have been attributed, in part, to its anti-inflammatory effects. Several reports have documented that cyclooxygenase (COX)-2 is up-regulated in human and mouse atherosclerotic lesions. To clarify the role of COX-2 in atherosclerosis, we conducted a study to test whether the COX-2 inhibitor, celecoxib, prevents the development and progression of the atherosclerotic process. We have used the apo E-/- mouse, a relevant animal model of atherosclerosis that develops fibrofatty lesions similar to human atherosclerosis. Treatment of 4-wk old apo E-/- mice with a standard rodent no. 5020 diet supplemented with 900 ppm of celecoxib for 16 wk led to an 81% reduction in lesion size. The mean lesion area per section (mean +/- SD) of proximal aorta from the apo E-/- mice fed the diet with celecoxib (33,991 +/- 7863 microm2, P < 0.001) was significantly less than that of the untreated apo E-/- mice (183,401 +/- 36,212 microm2). There were no lesions detected in the C57B1/6 mice. Immunohistochemistry of the ileum revealed that there was 80% reduction in staining for intercellular adhesion molecule and 60% reduction in staining for vascular cell adhesion molecule in the celecoxib treated mice. The protective effect of celecoxib was not maintained when the mice were switched after feeding the celecoxib-supplemented diet to the control 5020 diet for an additional 10 wk. These findings demonstrate that selective inhibition of the COX-2 enzyme with celecoxib prevented the development of atherosclerotic lesions in the proximal aortas from apo E-/- mice. One of the possible mechanisms is reduction in expression of the endothelial cell adhesion cell molecules intercellular adhesion molecule and vascular cell adhesion molecule, which plays a key role in the recruitment of inflammatory cells during the early stages of atherogenesis.
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PMID:The select cyclooxygenase-2 inhibitor celecoxib reduced the extent of atherosclerosis in apo E-/- mice. 1795 Mar 26

Placebo-controlled trials of nonsteroidal antiinflammatory drugs (NSAIDs) selective for COX-2 have revealed an enhanced risk for cardiovascular events. COX-2 inhibitors (coxibs) selectively reduce vascular prostacyclin synthesis without disrupting COX-1-derived thromboxane synthesis in platelets. Removal of prostacyclin's capacity to restrain all known endogenous compounds contributing to platelet activation and vasoconstriction is a well-recognized mechanism for coxib action in the cardiovascular system which can pre-dispose to thrombosis, hypertension and atherosclerosis. Novel mouse models of selective COX-2 inhibition and disruption of microsomal prostaglandin E synthase-1 have been exploited to reveal the relative importance of prostacyclin and prostaglandin E2 in cardiovascular homeostasis. This review discusses the background to our current understanding of coxibs and provides further information relating to recent mechanistic insights into how COX-2 inhibition promotes cardiovascular risk.
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PMID:COX-2 inhibitors and cardiovascular risk. 1803 55

Cyclooxygenase (COX) catalyzes formation of prostaglandins that contribute to the inflammation in atherosclerosis. Our objective was to study whether the functional C variant of the -765G-->C polymorphism in the human COX-2 gene associates with the severity of coronary atherosclerosis measured at the coronary artery level. The Helsinki sudden death study autopsy material (n = 300) comprised of Finnish men who died suddenly. The area of atherosclerotic lesions in the coronary arteries was quantitated, and coronary narrowing was measured. The occurrence of myocardial infarction (MI) was assessed. Genotyping was by restriction endonuclease analysis. Men carrying the minor C allele had larger areas of complicated lesions (P = .024) and a higher number of coronary arteries that had over 50% stenosis (P = .036) compared to men representing the common GG genotype. The COX-2 polymorphism was not associated with MI. Our data suggest that COX-2 may be involved in plaque growth.
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PMID:COX-2 gene promoter polymorphism and coronary artery disease in middle-aged men: the Helsinki sudden death study. 1838 11

Cyclooxygenase (COX) is the key enzyme in the conversion of arachidonic acid to prostanoids, lipid mediators involved in several physiological and pathological processes. Two COX isoenzymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, and preferential coupling to upstream and downstream enzymes. Both isoforms play fundamental roles in atherothrombosis; however, whereas the function of COX-1 in this setting is well established, the role of COX-2 remains unclear. Indeed, the intracellular pathways regulating COX-2 induction appear numerous and complicated, varying between cell types and cellular stimulus. In recent years a long series of studies has been performed with the aim of clarifying the role of COX-2 in atherothrombosis, with the major finding that the COX-2 expression pattern in arterial vessels may be associated with either protective or plaque-destabilizing phenotypes according to the downstream synthase that couples with COX-2. In this review we summarize the role of COX-2 as well as the different downstream synthases in atherosclerosis and atherothrombosis. Finally, we briefly review the controversial vascular effects on prostanoid inhibition by COX-2 inhibitors.
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PMID:Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. 1842 Feb 77

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

Flavonoids can protect against inflammatory diseases such as atherosclerosis by decreasing vascular endothelial cell activation. Plasma microdomains called caveolae may be critical in regulating endothelial activation. Caveolae are particularly abundant in endothelial cells and play a major role in endothelial trafficking and the regulation of signaling pathways associated with the pathology of vascular diseases. We hypothesize that flavonoids can down-regulate endothelial inflammatory parameters by modulating caveolae-regulated cell signaling. We focused on the role of caveolae and its major protein, caveolin-1, in mechanisms of linoleic-acid-induced endothelial cell activation and protection by the catechin epigallocatechin-3-gallate (EGCG). Exposure to linoleic acid for 6 h induced expression of both caveolin-1 and cyclooxygenase (COX)-2. Pretreatment with EGCG blocked fatty-acid-induced caveolin-1 and COX-2 expression in a time- and concentration-dependent manner. Similar results were observed with nuclear factor-kappa B DNA binding activity, which was also reduced by caveolin-1 silencing. Exposure to linoleic acid rapidly increased phosphorylation of several kinases, including p38 MAPK, extracellular signal regulated kinase 1/2 (ERK1/2) and amino kinase terminal (Akt), with maximal induction at about 10 min. Inhibitors of ERK1/2 and Akt down-regulated the linoleic-acid-induced increase in COX-2 protein, which also occurred after pretreatment with EGCG. Caveolin-1 silencing blocked linoleic-acid-induced phosphorylation of ERK1/2 and protein expression of COX-2, suggesting that specific MAPK signaling is caveolae dependent. Our data provide evidence that caveolae may play a critical role in regulating vascular endothelial cell activation and protection by flavonoids such as EGCG.
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PMID:Role of caveolin-1 in EGCG-mediated protection against linoleic-acid-induced endothelial cell activation. 1865 37


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