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)

Markers of lipid peroxidative damage have been shown to be elevated in individuals with risk factors for cardiovascular disease, and human atherosclerotic plaque contains products resulting from lipid peroxidation. In particular, the presence of fatty acid oxidation products such as hydroxyeicosatetraenoic acids (HETEs) has previously been suggested as a marker of plaque instability and symptomatic cerebrovascular disease. The aim of the present study was to quantitate the levels of various oxidation products of linoleic acid (HODEs) and arachidonic acid (HETEs), respectively, in human atherosclerotic plaque tissue and assess their level in relation to plaque histopathology, symptoms of cerebrovascular disease and preexisting atherosclerotic risk factors. We also assessed the correlation between the levels of the hydroxy fatty acid compounds and F(2)-isoprostanes, an established marker of in vivo free radical mediated oxidation. Hydroxy fatty acid oxidation products were identified in all histological subtypes of advanced plaque. However, there were no significant differences in levels between the histopathologically classified sub-groups or between patients symptomatic or asymptomatic for cerebrovascular disease. Arachidonic acid oxidation products were significantly higher in those subjects who also had symptomatic peripheral vascular disease. The level of linoleic acid oxidation products was significantly higher in individuals who consumed alcohol on a regular basis. While F(2)-isoprostanes and fatty acid oxidation products were highly correlated (P<0.01), levels of the hydroxy fatty acid compounds were 20-40-fold higher than F(2)-isoprostanes. Chiral analysis of the plaque extracts indicated that all HODEs and HETEs originated primarily from non-enzymatic lipid peroxidation. While our results do not support previous reports that fatty acid oxidation products such as the HETEs are associated with plaque instability and symptomatic cerebrovascular disease, further work is warranted to determine the potential of these compounds as circulating markers for underlying atherosclerotic disease and lipid peroxidative stress.
Atherosclerosis 2003 Mar
PMID:Fatty acid oxidation products in human atherosclerotic plaque: an analysis of clinical and histopathological correlates. 1261 75

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are successfully used for the treatment of hypercholesterolemia and profoundly reduce cardiovascular morbidity and mortality in hypercholesterolemic patients. Endothelial dysfunction is the early state of atherosclerosis and predicts adverse cardiac events and mortality. Reduced nitric oxide (NO) bioactivity in the vascular wall, caused by increased free oxygen-radical generation and decreased NO production, seems to be an important underlying mechanism. It is well established that statins improve endothelial dysfunction in hypercholesterolemic patients. However, results from in vitro studies, animal experiments, and small clinical trials suggest that statins may improve vascular function after short-term treatment in hyper- and normocholesterolemic individuals. The underlying mechanisms may at least in part be related to the cholesterol-independent effects of statins on vascular cells. Cellular antioxidative properties of statins, leading to decreased oxidative stress and restoration of NO bioactivity, may be of special relevance for the improvement of vascular function. However, further studies and clinical intervention trials are required to clarify the clinical importance of the pleiotropic effects in humans and their contribution to the well-established clinical benefits of statins and to confirm a beneficial effect of statin therapy on endothelial dysfunction and cardiovascular events in normocholesterolemic patients.
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PMID:Interrelationship of free oxygen radicals and endothelial dysfunction--modulation by statins. 1269 74

The observation that almost half of all myocardial infarctions and strokes occur in persons without elevated levels of low-density lipoprotein cholesterol has prompted the study of factors other than hyperlipidemia that contribute to the development of atherosclerosis. A growing body of evidence indicates that inflammation plays a substantial role in plaque progression and rupture. Research interest has increasingly focused on biomarkers of inflammation as a means of predicting more accurately which patients are at high risk for cardiovascular disease (CVD). Clinical studies indicate that C-reactive protein (CRP), a marker of systemic inflammation, independently predicts cardiovascular risk in healthy persons as well as in persons with established CVD and those with acute ischemia. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to reduce levels of CRP through mechanisms independent of their effects on lipid levels. Initial clinical studies also suggest that CRP levels may have utility in the targeting of statin therapy, particularly in primary prevention. These results need direct testing in large, prospective clinical trials to determine whether statin therapy will benefit persons without overt hyperlipidemia but with evidence of systemic inflammation. Confirmation of these preliminary findings, if incorporated into evidence-based guidelines, may profoundly change the approach to diagnosis and treatment of CVD.
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PMID:Connecting the role of C-reactive protein and statins in cardiovascular disease. 1270 38

4-Hydroxy-2-nonenal (HNE) has been suggested to contribute to the pathogenesis of atherosclerosis. One of the major metabolic transformation pathways of HNE involves conjugation with glutathione (GSH) catalyzed by GSH S-transferase (GST). In this study, we have characterized the induction of GSH and GST by 3H-1,2-dithiole-3-thione (D3T) and the protective effects of the D3T-elevated cellular defenses on HNE-mediated toxicity in rat aortic smooth muscle A10 cells. Incubation of A10 cells with D3T resulted in a marked concentration- dependent induction of both GSH and GST. The induction of cellular GST by D3T also exhibited a time-dependent response. Pretreatment of A10 cells with D3T led to a dramatic decrease of HNE-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay and scanning electron microscopy. Incubation of A10 cells with HNE for 0.5 h and 1 h resulted in a significant depletion of cellular GSH, which preceded the decrease of cell viability. To further demonstrate the involvement of GSH and GST in protecting against HNE-induced cytotoxicity, buthionine sulfoximine (BSO) and sulfasalazine were used to inhibit cellular GSH biosynthesis and GST activity, respectively. Either depletion of GSH by BSO or inhibition of GST by sulfasalazine caused great potentiation of HNE-mediated cytotoxicity. Moreover, cotreatment of A10 cells with BSO was found to completely block the D3T-mediated GSH induction and to largely reverse the cytoprotective effects of D3T on HNE-induced toxicity. Taken together, this study demonstrates that D3T can induce both GSH and GST in aortic smooth muscle cells, and that the D3T-augmented cellular defenses afford a marked protection against HNE-induced vascular cell injury.
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PMID:The role of chemically induced glutathione and glutathione S-transferase in protecting against 4-hydroxy-2-nonenal-mediated cytotoxicity in vascular smooth muscle cells. 1450 Oct 34

The terminal complement complex C5b-9 is known to participate in inflammatory processes including atherosclerosis. Inflammation appears to be a direct consequence of C5b-9-mediated cell stimulation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may exert anti-inflammatory effects on vascular cells independent of lowering plasma cholesterol. Thus, we studied activation of vascular smooth muscle cells (VSMCs) by C5b-9 focusing on whether inhibition of the HMG-CoA reductase can reduce the proinflammatory effects of C5b-9.C5b-9 in sublytic concentrations increased the proliferation of human VSMCs and induced a time-dependent activation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Proliferation and ERK1/2 activation could be inhibited by the specific ERK inhibitor PD98059. HMG-CoA inhibition with cerivastatin-reduced VSMC proliferation and C5b-9-induced ERK1/2 activation. Cerivastatin also reduced the C5b-9-induced synthesis of the proinflammatory interleukin-6 (IL-6). Furthermore, C5b-9 induced activation of the transcription factors activator protein- 1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which could be inhibited by pretreatment of VSMCs with cerivastatin. L-mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effects of cerivastatin. The present study in VSMCs shows that cerivastatin inhibits IL-6 synthesis and cell proliferation induced by the terminal complement complex C5b-9. This may be an important mechanism contributing to the beneficial effects of HMG-CoA reductase inhibitors beyond lowering of plasma cholesterol.
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PMID:HMG-CoA reductase inhibition reduces the proinflammatory activation of human vascular smooth muscle cells by the terminal complement factor C5b-9. 1455 80

3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are effective in patients with hypercholesterolemia to reduce risk of cardiovascular diseases, because of not only their lowering cholesterol effects but also their pleiotropic effects, such as improvement of endothelial cell dysfunction. On the other hand, statins prevent cell proliferation of various cells, including endothelial cells. We examined effects of all statins available at present on the viability of cultured rat pulmonary vein endothelial cells. Lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin, which are hydrophobic statins, markedly reduced cell viability associated with DNA fragmentation, DNA laddering and activation of caspase-3, suggesting apoptotic cell death. Pravastatin, which is a hydrophilic statin, however, did not induce cell apoptosis. Apoptosis induced by hydrophobic statins was associated with activation of apoptosis-related intracellular signal transduction systems; attenuation of localization of RhoA to the membrane, induction of Rac1, and increase in phosphorylation of c-Jun N-terminal kinase and c-Jun. Endothelial cell apoptosis is underlying the improvement of the endothelial dysfunction with hydrophobic statins.
Atherosclerosis 2003 Oct
PMID:All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. 1461 3

CD36 is an important scavenger receptor mediating uptake of oxidized low-density lipoproteins (oxLDLs) and plays a key role in foam cell formation and the pathogenesis of atherosclerosis. We report the first evidence that the transcription factor Nrf2 is expressed in vascular smooth muscle cells, and demonstrate that oxLDLs cause nuclear accumulation of Nrf2 in murine macrophages, resulting in the activation of genes encoding CD36 and the stress proteins A170, heme oxygenase-1 (HO-1), and peroxiredoxin I (Prx I). 4-Hydroxy-2-nonenal (HNE), derived from lipid peroxidation, was one of the most effective activators of Nrf2. Using Nrf2-deficient macrophages, we established that Nrf2 partially regulates CD36 expression in response to oxLDLs, HNE, or the electrophilic agent diethylmaleate. In murine aortic smooth muscle cells, expressing negligible levels of CD36, both moderately and highly oxidized LDL caused only limited Nrf2 translocation and negligible increases in A170, HO-1, and Prx I expression. However, treatment of smooth muscle cells with HNE significantly enhanced nuclear accumulation of Nrf2 and increased A170, HO-1, and Prx I protein levels. Because PPAR-gamma can be activated by oxLDLs and controls expression of CD36 in macrophages, our results implicate Nrf2 as a second important transcription factor involved in the induction of the scavenger receptor CD36 and antioxidant stress genes in atherosclerosis.
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PMID:Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal. 1475 28

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC(50) of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 microM. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5' region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10(-6)M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques.
Atherosclerosis 2004 May
PMID:Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability. 1513 56

In the majority of patients with chronic renal failure, it is essential to substitute erythropoietic agents and iron to maintain a haemoglobin level above 11 g dL-1. Intravenous iron is more effective than oral iron. Substitution of intravenous iron is mainly performed using iron(III)-hydroxide-sucrose complex (iron sucrose) and iron(III)-sodium-gluconate in sucrose (iron gluconate), and is, in general, well-tolerated. Nonetheless, intravenous iron therapy has effects on endothelial cells, polymorphonuclear leucocytes and cytokines which are most likely related to non-transferrin bound labile iron. These effects suggest a role of iron in infection or atherosclerosis. Yet, not all available data support the association of iron with infection and atherosclerosis. A recent trial showed that iron sucrose is safe when given as treatment for iron deficiency or for maintenance of iron stores. Nevertheless, iron therapy should be handled with caution but its use should not be feared whenever indicated.
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PMID:Intravenous iron therapy: well-tolerated, yet not harmless. 1628 58

The 3-Hydroxy-3-methyl-glutaryl coenzyme A (HGM-CoA) reductase inhibitors, or statins, are competitive inhibitors of the rate-limiting enzyme in cholesterol synthesis. Generally, statins have an excellent safety profile. Elevations of liver transaminases and creatine phosphokinase with myalgia have been associated with the use of HGM-Co A reductase inhibitors, case reports of rhabdomyolysis are rare, most occurring with concomitant use with other drugs such as cyclosporin, fusidic acid and gemfibrozil. We describe here the clinical case of a patient who developed interstitial lung disease as probably a result of the use of statins which particularly increased with long-term atorvastatin treatment. The present review details some case-reports of interstitial lung disease reported under statins in the literature. Few systemic adverse effects such as lupus-like-syndromes and polymyositis have been reported. Recent experimentations have demonstrated that cholesterol is not the only intracellular target of statins but that they also have a potential role in atherosclerosis and in organ transplantation as immunosuppressor agents.
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PMID:[A case of interstitial lung disease with atorvastatin (Tahor) and a review of the literature about these effects observed under statins]. 1679 55


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