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)

Oxidative stress plays a crucial role in the pathogenesis of atherosclerosis by promoting endothelial dysfunction and impairing vascular relaxation. Flavonoids are largely investigated for their biological properties and particularly for their scavenging and antioxidant properties. In the current study, we evaluated the clastogenicity of the chalcone plicatin B in peripheral human lymphocytes (whole blood and pure lymphocytes) as well as its antioxidant activity and its ability to contrast dysfunction on human microvascular endothelial cells (HMEC-1) exposed to hydrogen peroxide. We measured in the cell culture medium the levels of 8-isoprostane, NOx, ET-1, and ICAM-1, as well as the expression of e-NOS, prepro-ET-1, and ICAM-1. In conclusion, our results demonstrate that the chalcone plicatin B (1-10 microM) may represent a good candidate for the prevention of atherosclerosis, as it consistently reduces the oxidative/inflammatory process and is not genotoxic to human lymphocytes.
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PMID:Antioxidant activity of plicatin B on cultured human microvascular endothelial cells exposed to H2O2. 1793 21

Pathophysiology of asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of NO synthase, has been a subject of intensive research activity during last years. The ways of ADMA synthesis and degradation were studied. It was suggested that ADMA plays a considerable role in the realization of so called "Arginine paradox". This paradox refers to the dependence of cellular NO production on exogenous L-arginine despite the saturation of NOS enzymes with intracellular L-arginine. Close association was described between increase in blood ADMA level and endothelial dysfunction accompanied by related pathologies like atherosclerosis, renal insufficiency, hypertension and some others. Some studies have represented ADMA as a strong independent risk factor for cardiovascular complications. Possible reasons are discussed of some experimental data ambiguity as well as the limits of confidence in clinical ADMA analysis.
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PMID:[Asymmetric dimethylarginine: metabolism, arginine paradox, pathophysiology]. 1797 29

Insulin Resistance along with endothelial dysfunction give rise to a constellation of syndromes designated as IRS/MBS metabolic syndrome. Endothelial dysfunction starts early in life much before the development of structural atherosclerosis. Recent insights into vascular biology enable us to understand the molecular mechanisms underlying endothelial dysfunction, and the scope and need for prevention of "pre-clinical" coronary atherosclerosis through lifestyle modification; diet, exercise and stress management. Diminished production of nitric oxide (NO) and/or increased inactivation of NO through oxidative stress (reactive oxygen species ROS and reactive nitrogen species (RNS) are the basis of endothelial dysfunction hence increasing the bioavailability of NO and decreasing its inactivation is the aim of prevention and reversal of endothelial dysfunction. Insulin regulates constitutive NOS gene expression in endothelial cells in vivo; vasodilation is an important component of Insulin-stimulated whole body glucose uptake. Successful strategies are: PPAR alpha and gamma agonists which increase NO production in endothelium; anti-oxidants such as vit. E and C; supplementation with L-arginine, tetrahydrobiopterin-BH4 or sepiapterin (precursor of BH4), SOD mimetic tempol, statins which apart from lowering cholesterol improve NO production, selective beta1 adrenoreceptor antagonists such as nebivolol; suppression of angiotensin-mediated endothelin production by ACE inhibitors and ATR blockers; CB1 receptor blockers, PKCb inhibitors, nitric oxide donors (glyceryl trinitrate and isosorbide dinitrate), dietary supplements of EPA/DHA and regular physical exercise and control of mental stress.
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PMID:Causation, prevention and reversal of vascular endothelial dysfunction. 1805 38

Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme responsible for the metabolism of nitric oxide (NO) synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA), and DDAH2 is the predominant isoform in vascular endothelium. Lysophosphatidylcholine (LPC) and ADMA are implicated in endothelial dysfunction of atherosclerosis. This study was to examine changes in DDAH/ADMA/NOS/NO pathway in endothelial cells after exposure to LPC and investigate whether DDAH2 gene transfer could reverse LPC-induced changes. Human endothelial cell line ECV304 cells were transfected with recombinant pcDNA3.1-hDDAH2 plasmid and incubated with 3 micromol/L LPC for 48 h. Cells were harvested for assays of DDAH transcription, DDAH and NOS activities. The culture medium was collected for measurements of ADMA and nitrite/nitrate concentrations. LPC treatment suppressed DDAH2 transcription and DDAH activity in parallel with increased ADMA concentration, inhibited NOS activity and decreased NO metabolites content. DDAH2 gene transfer not only prevented the suppression of DDAH activity and the elevation of endogenous ADMA, but also attenuated the inhibition of NOS activity and the reduction of NO level induced by LPC in endothelial cells. These results suggest that LPC induces impairments of DDAH/ADMA/NOS/NO pathway, and DDAH2 gene transfer could improve the LPC-elicited impairments in endothelial cells.
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PMID:Gene transfer of dimethylarginine dimethylaminohydrolase-2 improves the impairments of DDAH/ADMA/NOS/NO pathway in endothelial cells induced by lysophosphatidylcholine. 1834 5

Recent studies have demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 interaction regulates multiple cell signal pathways and a variety of cellular functions such as cell migration, proliferation, survival and angiogenesis. In present study, we aimed to determine the effect of SDF-1alpha on endothelial progenitor cells (EPCs) apoptosis induced by serum deprivation and the implication of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling in this effect. EPCs were isolated and characterized. SDF-1alpha decreased EPCs apoptosis induced by serum deprivation in a dose-dependent manner and the inhibitory effect was CXCR4 dependent as confirmed by the total abolishment by AMD3100, a CXCR4-specific peptide antagonist. SDF-1alpha treatment also significant decreased caspase-3 expression and activity. The inhibitory effect of SDF-1alpha on EPCs apoptosis was nearly completely abolished by PI3K inhibitors (either Wortmannin or LY294002) and partially abolished by NOS inhibitor, N(G)-nitro-arginine methyl ester, whereas inhibitors of MAPKs had no significant effect on this inhibitory effect. The treatment of EPCs with SDF-1alpha resulted in time-dependent Akt, eNOS, extracellular-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) phosphorylations. These findings suggest that PI3K/Akt/eNOS activation, but not MAPKs activation, is required for the inhibitory effect of SDF-1alpha on EPCs apoptosis.
Atherosclerosis 2008 Nov
PMID:SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. 1838 92

Oxidative modification of low density lipoproteins is thought to play a pivotal role in the development and exacerbation of atherosclerosis and atherogenesis, and is believed to be closely associated with alterations in the vascular production of nitric oxide (NO). Previous work has shown that several products emerging from lipid peroxidation (e.g. lipid hydroperoxides, lysophospholipids, oxidized cholesterol) are able to reduce NO production in macrophages. The naturally occurring oxidant hypochlorite has been shown to be responsible for the in vivo formation of hypochlorite-oxidized LDL and such OxLDL are known to lack lipid peroxidation products. In this work we demonstrate that hypochlorite-oxidized LDL mediate profound effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages. By means of the membrane-permeable NO indicator 4,5-diaminofluorescein diacetate, we are able to show decreased levels of intracellular authentic nitric oxide following incubation with hypochlorite-oxidized LDL. The observed effects are dose-dependent and comparable to results obtained in the presence of the NOS inhibitor NG-monomethyl-L-arginine. This marked reduction of intracellular NO is accompanied by a dose-dependent inhibition of inducible nitric oxide synthase (iNOS) protein and mRNA expression. Furthermore, hyp-OxLDL lead to the generation of peroxynitrite, thereby also reducing bioavailability of NO. By mediating these effects on production and bioavailability of NO, hyp-OxLDL might also contribute to atherogenesis by reducing the antiatherogenic effects of nitric oxide.
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PMID:Hypochlorite-oxidized low density lipoproteins reduce production and bioavailability of nitric oxide in RAW 264.7 macrophages by distinct mechanisms. 1855 12

Asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, is also an important inflammatory factor contributing to the development of atherosclerosis (AS). The present study was to test the effect of ADMA on angiotensin (Ang) II-induced monocytic adhesion. Human monocytoid cells (THP-1) or isolated peripheral blood monocyte cells (PBMCs) were incubated with Ang II (10(-6)M) or exogenous ADMA (30 microM) for 4 or 24h in the absence or presence of losartan or antioxidant PDTC. In cultured THP-1 cells, Ang II (10(-6)M) for 24h elevated the level of ADMA in the medium, upregulated the protein expression of protein arginine methyltransferase (PRMT) and decreased the activity of dimethylarginine dimethylaminohydrolase (DDAH). Both of Ang II and ADMA increased monocytic adhesion to human umbilical vein endothelial cells (HUVECs), elevated the levels of monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha and upregulated CCR(2) and CXCR(2) mRNA expression, concomitantly with increase in reactive oxygen species (ROS) generation and activation of nuclear factor (NF)-kappaB. Pretreatment with losartan (10 microM) or PDTC (10 microM) abolished the effects mediated by Ang II or ADMA. In isolated PBMCs from healthy individuals, ADMA upregulated the expression of CXCR(2) mRNA, which was attenuated by losartan (10 microM), however, ADMA had no effect on surface protein expression of CCR(2). The present results suggest that ADMA may be involved in monocytic adhesion induced by Ang II via activation of chemokine receptors by ROS/NF-kappaB pathway.
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PMID:ADMA induces monocyte adhesion via activation of chemokine receptors in cultured THP-1 cells. 1861 18

Inflammation is an important event in the development of vascular diseases such as hypertension, atherosclerosis, and restenosis. In addition, the stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces the release of critical proinflammatory cytokines that activate potent immune responses. In this study, LPS was found to induce TLR4 expression and increased nitric oxide (NO) production by increasing the expression of inducible nitric oxide synthase (iNOS). Furthermore, LPS was found to induce interleukin (IL)-8 and vascular endothelial growth factor (VEGF) production, as well as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Taken together, these results indicate that LPS induces inflammatory responses in HASMC. Moreover, NOS inhibitor (L-NAME) and anti-TLR 4mAb reduced the LPS-induced NO, IL-8 and VEGF production and ICAM-1 expression. Additionally, TLR4 expression was reduced by NOS inhibitor. Taken together, these results indicate that LPS-induced inflammatory responses are regulated by TLR4 expression and NO production.
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PMID:LPS induces inflammatory responses in human aortic vascular smooth muscle cells via Toll-like receptor 4 expression and nitric oxide production. 1867 2

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

The development of the atherosclerosis is based on multifactorial causes. In addition to the traditional risk factors, gene polymorphisms can play a role in the disease. Therefore in this study we investigated whether the eNOS and MTHFR gene polymorphisms is associated with myocardial infarction and stroke in patients with or without diabetes. We have identified polymorphisms in the NOS 3 gene and one of these polymorphisms, Glu(298-->)Asp, was found to be a major risk factor for carotid artery disease and myocardial infarction. Our results indicate that the MTHFR G677T allele is significantly associated with MI. MTHFR 677 G/T genotyping may be of clinical importance as a prognostic and therapeutic marker, although further studies are needed to substantiate this hypothesis.
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PMID:Methylentetrahydrofolate reductase and nitric oxide synthase polymorphism in patients with atherosclerosis and diabetes. 1933 Apr 66


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