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)

Beneficial cardiovascular effects of statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are particularly assigned to the modulation of inflammation. Endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) are listed among the crucial protective, anti-inflammatory genes in the vasculature. Here we show that atorvastatin at pharmacologically relevant concentration (0.1 microM) enhanced the expression of eNOS in human microvascular endothelial cells (HMEC-1). Moreover, atorvastatin prevented hypoxia-induced decrease in eNOS expression. However, in the same cells atorvastatin was ineffective in modulation of HO-1 protein level. Therefore, we suggest that the protective effect of statins at their pharmacological concentrations is not mediated by enhancement of HO-1 activity, but may involve eNOS.
Atherosclerosis 2006 Jul
PMID:Atorvastatin prevents hypoxia-induced inhibition of endothelial nitric oxide synthase expression but does not affect heme oxygenase-1 in human microvascular endothelial cells. 1662 Aug 29

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 is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P<0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61+/-2% of aorta in the LDLR KO mice, but only 36+/-3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-kappaB and the inflammatory marker CD68 in LDLR KO mice was increased (P<0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P<0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.
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PMID:Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. 1755 64

Endothelial nitric oxide synthase (eNOS), the main source of endothelium-derived nitric oxide (NO), appears to be a rational therapeutic target in atherosclerosis. The exact mechanisms regulating eNOS protein expression in human vasculature are still under intensive investigation. Recent evidence suggests that statin treatment induces the expression of eNOS in vascular endothelium, leading to a respective improvement of endothelial function. Among other mechanisms, it seems that statins increase eNOS protein levels in the vasculature, partly by up-regulating klotho protein expression. This novel observation is consistent with several lines of clinical evidence suggesting that statins have antiatherogenic effects in human vasculature, by mechanisms other than lipid-lowering.
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PMID:Statins ameliorate atherosclerosis induced by inhibition of nitric oxide synthase: another novel vascular protective mechanism? 1743 18

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

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1alpha levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS-/- and iNOS-/- mice. Male C57BL/6 wild-type (WT), eNOS-/-, and iNOS-/- mice received 10 mg.kg(-1).day(-1) Pio (Pio+) or water alone (Pio-) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4+/-1.4% vs. 39.0+/-1.1%; P<0.001), as well as in the eNOS-/- (32.0+/-1.6% vs. 44.2+/-1.9%; P<0.001) and iNOS-/- (18.0+/-1.2% vs. 45.5+/-2.3%; P<0.001) mice. The protective effect of Pio in eNOS-/- mice was smaller than in the WT (P<0.001) and iNOS-/- (P<0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS-/- mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS-/- and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF1alpha levels and cPLA2 and COX2 activity in the WT, eNOS-/-, and iNOS-/- mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.
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PMID:Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. 1893 Oct 27

This study investigated risk factors for atherosclerosis and their relationship with lesion sites. Patients (n = 160) with peripheral artery disease (PAD) completed a questionnaire regarding risk factors for PAD. Endothelial nitric oxide synthase (eNOS) and interleukin (IL)-6 gene polymorphisms and asymmetric dimethylarginine (ADMA) levels were measured. Patients with coronary artery disease had significantly higher ratios of eNOS T/C and C/C genotypes, which include the C allele, than the T/T genotype. The IL-6 gene polymorphism distribution ratios for patients with over four risk factors were significantly different compared with other patients, with a higher rate of the C/C genotype. ADMA levels did not show any significant relationship to risk factors or polymorphism. Levels were, however, slightly higher in femoral lesion sites. The results support a model in which the C/C genotype of eNOS and IL-6 gene polymorphisms promote PAD development. The eNOS C/C genotype may have an independent effect, whereas the effects of the IL-6 C/C genotype are seen in conjunction with other risk factors.
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PMID:Effects of endothelial nitric oxide synthase, interleukin-6 gene polymorphisms and asymmetric dimethylarginine levels on risk factors and lesion sites in peripheral artery disease. 1976 82

Endothelial nitric oxide synthase breaks down nitric oxide and has a key role in blood pressure regulation. Earlier studies have shown associations between single nucleotide polymorphisms (SNPs) in the NOS3 gene and hypertension. Studies also suggest that such associations may vary by dietary fat intake. We investigated associations between the NOS3 Glu298Asp SNP (rs1799983) and hypertension, as well as the interaction between NOS3 genotypes and dietary fat intake using data from baseline examination in white and African American participants in the Atherosclerosis Risk in Community (ARIC) study. Dietary fat intake was measured by a Food Frequency Questionnaire during the baseline examination in 15 792 individuals aged 45-64 years in ARIC study participants. Race-stratified unconditional logistic regression was performed to investigate the association between prevalent hypertension and NOS3 Glu298Asp genotypes. There was no significant interaction between dietary fat intake and NOS3 Glu298Asp genotype with regards to hypertension status in either African Americans or whites (P for interaction=0.3 and 0.4, respectively). We found a significant relationship between NOS3 Glu298Asp and triglycerides in African Americans. We did not find an association between the NOS3 Glu298Asp polymorphism and hypertension, and dietary fat intake did not interact with NOS3 genotypes to influence hypertension. We recommend further exploration of the relationship between NOS3 Glu298Asp and triglycerides in African Americans.
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PMID:Association of NOS3 Glu298Asp SNP with hypertension and possible effect modification of dietary fat intake in the ARIC study. 1996 19

Endothelial dysfunction is a proceeding abnormality in the development of atherosclerosis. Endothelial nitric oxide synthase (eNOS) activity has the central role in the endothelial function. Since insulin regulates the eNOS activity through the phosphorylation by AKT, insulin resistance is one of major factors associating with the endothelial dysfunction in obesity and diabetes. In addition, several lines of evidence suggests that hyperglycemia induces PKC activation, oxidative stress and increased hexosamine metabolism, and these abnormalities are reported to impair the eNOS activity. Thus, several abnormalities are suggested to be involved in the endothelial dysfunction found in diabetes. This article focuses the mechanisms how the hyperglycemia or insulin resistance causes abnormalities in endothelial function.
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PMID:[Endothelial dysfunction in diabetes]. 2044 76

Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.
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PMID:Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities. 2216 22


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