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 is a complex vascular inflammatory disease. Oxidized low-density lipoprotein (ox-LDL) is directly associated with chronic vascular inflammation. In this study, we hypothesized that nonselective cyclooxygenase inhibitor aspirin might affect the ox-LDL-induced inflammatory responses on human endothelial cells. To test this assumption, cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) expression, IkappaB and p38 mitogen-activated protein kinase (MAPK) phosphorylation were determined in endothelial cells exposed to ox-LDL in the presence of aspirin. The results showed that aspirin significantly suppressed COX-2 and ICAM-1 expression induced by ox-LDL and also inhibited IkappaB phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, aspirin reduced the level of p38 MAPK phosphorylation. Our findings suggest that aspirin can decrease inflammatory responses induced by ox-LDL, and the mechanism might be associated with NF-kappaB activation pathway and inhibition of p38 MAPK phosphorylation.
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PMID:Protective effects of aspirin against oxidized LDL-induced inflammatory protein expression in human endothelial cells. 1820 66

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction. Ang II with AT(1) receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT(1) receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT(1) receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT(1) receptor enhances the activation of nuclear factor NF-kappaB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT(1) receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT(1) receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.
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PMID:The role of angiotensin type 1 receptor in inflammation and endothelial dysfunction. 1822 Oct 99

Lysophosphatidylcholine (LysoPtdCho) levels are elevated in sera in patients with atherosclerosis and in atherosclerotic tissue. Previous studies have shown that reactive chlorinating species attack plasmalogens in human coronary artery endothelial cells (HCAEC), forming lysoPtdCho and lysoPtdCho-chlorohydrin (lysoPtdCho-ClOH). The results herein demonstrate for the first time that lysoPtdCho-ClOH is elevated over 60-fold in human atherosclerotic lesions. In cultured HCAEC, 18:0 lysoPtdCho-ClOH led to a statistically significant increase in P-selectin cell-surface expression, but unlike 18:1 lysoPtdCho did not lead to cyclooxygenase-2 protein expression. These data show that 18:0 lysoPtdCho-ClOH is elevated in atherosclerotic tissue and may have unique pro-atherogenic properties compared to lysoPtdCho.
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PMID:Identification of lysophosphatidylcholine-chlorohydrin in human atherosclerotic lesions. 1825 67

Recent increased adverse cardiovascular events observed with selective cyclooxygenase-2 inhibition led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra), but the mechanisms underlying these atherothrombotic events remain unclear. Prostacyclin is the major end product of cyclooxygenase-2 in vascular endothelium. Using a naturally occurring mutation in the prostacyclin receptor, we report for the first time that a deficiency in prostacyclin signaling through its G protein-coupled receptor contributes to atherothrombosis in human patients. We report that a prostacyclin receptor variant (R212C) is defective in adenylyl cyclase activation in both patient blood and in an in vitro COS-1 overexpression system. This promotes increased platelet aggregation, a hallmark of atherothrombosis. Our analysis of patients in 3 separate white cohorts reveals that this dysfunctional receptor is not likely an initiating factor in cardiovascular disease but that it accelerates the course of disease in those patients with the greatest risk factors. R212C was associated with cardiovascular disease only in the high cardiovascular risk cohort (n=980), with no association in the low-risk cohort (n=2293). In those at highest cardiovascular risk, both disease severity and adverse cardiovascular events were significantly increased with R212C when compared with age- and risk factor-matched normal allele patients. We conclude that for haploinsufficient mutants, such as the R212C, the enhanced atherothrombotic phenotype is likely dependent on the presence of existing atherosclerosis or injury (high risk factors), analogous to what has been observed in the cyclooxygenase-2 inhibition studies or prostacyclin receptor knockout mice studies. Combining both biochemical and clinical approaches, we conclude that diminished prostacyclin receptor signaling may contribute, in part, to the underlying adverse cardiovascular outcomes observed with cyclooxygenase-2 inhibition.
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PMID:Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. 1832 28

Prostaglandins (PGs), particularly PGE2 and prostacyclin (PGI2), are potent mediators of pain and inflammation. Both atherosclerosis and aortic aneurysm exhibit the hallmarks of inflammation. However, randomized trials of inhibitors of PG synthesis--nonsteroidal anti-inflammatory drugs--reveal that they predispose to cardiovascular risk. This appears to be consequent to inhibition of PGI2 and PGE2 formed by cyclooxygenase-2 (COX-2). Inhibitors of microsomal PGE synthase-1 (mPGES-1) are being developed for relief of pain and interest has focused on their potential impact on the cardiovascular system. Deletion of mPGES-1 retards atherogenesis and limits aortic aneurysm formation in hyperlipidaemic mice. However, it does not predispose to thrombogenesis and has a limited impact on blood pressure compared to inhibition of COX-2. This occurs despite the potential of the suppressed PGE2 in affording cardioprotection via its EP2 and EP4 receptors. However, deletion of mPGES-1 permits rediversion of the PGH2 substrate to other PG synthases and augmented formation of PGI2 and PGD2 mitigates this effect. However, increased PGI2 may also attenuate relief of pain. Pain relief seems likely to be a nuanced indication for mPGES-1 inhibitors, but they have therapeutic potential in syndromes of cardiovascular inflammation, cancer and perhaps in neurodegenerative disease. However, as the products of substrate rediversion vary according to cell type, these drugs may have contrasting impact amongst individuals at varied stages of disease evolution.
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PMID:Microsomal prostaglandin E synthase-1 inhibition in cardiovascular inflammatory disease. 1841 May 93

Endothelial dysfunction by proinflammatory stimuli represents an important link between risk factors and the pathologic mechanisms underlying atherosclerosis. Thus, control of the inflammatory status of endothelial cells is crucial to limiting the disease. Tobacco smoking induces inflammatory reactions and promotes atherosclerosis; however, the mechanism that links cigarette smoking to an increased incidence of atherosclerosis is poorly understood. Our study demonstrates that acrolein, a known toxin in tobacco smoke, elevates oxidative stress via inactivation of thioredoxin reductase and stimulates expression of cyclooxygenase-2 through activation of the protein kinase C, p38 mitogen-activated protein kinase, and cAMP response element-binding protein pathway in endothelial cells. Our finding suggests that acrolein may play a role in the progression of atherosclerosis.
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PMID:Acrolein induces inflammatory response underlying endothelial dysfunction: a risk factor for atherosclerosis. 1844 14

Several lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the modified proteins have been found in cells during aging, oxidative stress, and in various pathological states including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. The important agents that give rise to the modification of a protein may be represented by reactive aldehydic intermediates, such as ketoaldehydes, 2-alkenals and 4-hydroxy-2-alkenals. These reactive aldehydes are considered important mediators of cell damage due to their ability to covalently modify biomolecules, which can disrupt important cellular functions and can cause mutations. Furthermore, the adduction of aldehydes to apolipoprotein B in low-density lipoproteins (LDL) has been strongly implicated in the mechanism by which LDL is converted to an atherogenic form that is taken up by macrophages, leading to the formation of foam cells. During the search for an endogenous inducer of cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses, 4-hydroxy-2-noennal (HNE), one of the most representative lipid peroxidation product, has been identified as the potential inducer of COX-2. In addition, the following study on the molecular mechanism of the COX-2 induction by HNE has unequivocally established that a serum component, which is eventually identified to be denatured LDL, is essential for COX-2 induction. Here I review current understanding of the mechanisms by which HNE in cooperation with the serum component activates gene expression of COX-2.
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PMID:A lipid-derived endogenous inducer of COX-2: a bridge between inflammation and oxidative stress. 1848 67

In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.
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PMID:Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid arthritis. 1867 61

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.
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PMID:Altered lipid metabolism in brain injury and disorders. 1875 14

Although the presence of an elevated level of serum amyloid A (SAA) has been regarded as a cardiovascular risk factor, the role of SAA on the progress of atherosclerosis has not been fully elucidated. In the present study, we investigated the effect of SAA on the production of CCL2, an important mediator of monocyte recruitment, and the mechanism underlying the action of SAA in human monocytes. The stimulation of human monocytes with SAA elicited CCL2 production in a concentration-dependent manner. The production of CCL2 by SAA was found to be mediated by the activation of NF-kappaB. Moreover, the signaling events induced by SAA included the activation of ERK and the induction of cyclooxygenase-2, which were required for the production of CCL2. Moreover, SAA-induced CCL2 induction was inhibited by a formyl peptide receptor-like 1 (FPRL1) antagonist. We also found that the stimulation of FPRL1-expressing RBL-2H3 cells induced CCL2 mRNA accumulation, but the vector-expressing RBL-2H3 cells combined with SAA did not. Taken together, our findings suggest that SAA stimulates CCL2 production and, thus, contributes to atherosclerosis. Moreover, FPRL1 was found to be engaged in SAA-induced CCL2 induction, and cyclooxygenase-2 induction was found to be essential for SAA-induced CCL2 expression. These results suggest that SAA and FPRL1 offer a developmental starting point for the treatment of atherosclerosis.
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PMID:Serum amyloid A induces CCL2 production via formyl peptide receptor-like 1-mediated signaling in human monocytes. 1876 91


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