Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The generation of nitric oxide is regulated by several factors, including the substrates and cofactors supplementation. Decreased expression and activity of nitric oxide synthase as well as diminished amount of L-arginine or enzyme cofactors results in the inhibition of nitric oxide generation in vascular wall cells. GTP cyclohydrolase 1 is a key enzyme involved in the synthesis of tetrahydrobiopterin, one of the most important cofactors of NO synthases. We have demonstrated that oxidized LDL inhibit not only inducible nitric oxide synthase gene expression but also GTP cyclohydrolase I gene expression in interleukin-1 beta activated rat vascular smooth muscle cells in vitro. It is postulated that diminished availability of tetrahydrobiopterin may additionally impair the generation of nitric oxide in atherosclerosis.
 ...
PMID:Regulation of inducible nitric oxide synthase (iNOS) and GTP cyclohydrolase I (GTP-CH I) gene expression by ox-LDL in rat vascular smooth muscle cells. 944 17

Tetrahydrobiopterin ((6R)-L-erythro-tetrahydrobiopterin, BH4) is de novo synthesized from GTP. Enzymes involved in its synthesis are the rate limiting enzyme GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase (PTPS) and sepiapterin reductase. Abnormalities in the metabolism of BH4 have been demonstrated in some diseases affecting the central nervous systems such as atypical phenylketonuria, hereditary progressive dystonia (Segawa's disease). Furthermore, BH4 has been shown to be involved in vascular protection. It is suggested that the dysfunction of endothelial BH4 leads to atherosclerosis. Recently we established BH4-deficient mice by disrupting the PTPS gene to investigate the effects of BH4 depletion on the animals and the involvement of BH4 in regulating biological functions including neural systems. Investigation utilizing this model animal can contribute to the development of new therapeutic strategies toward various diseases involving neurological and vascular systems. Pterin derivatives other than biopterin may also be involved in the regulation of a variety of biological functions. We found that ciliated protozoan Tetrahymena pyriformis synthesizes tetrahydromonapterin, isomer of BH4, and its levels alter according to the progress of the cell cycle. How pterin derivatives are related to the human physiology and diseases is an interesting subject of investigation.
 ...
PMID:[Perspectives on tetrahydrobiopterin research]. 1177 54

Vascular smooth muscle cell (VSMC) proliferation is pivotal in the progression of hypertension, atherosclerosis, and restenosis. Resveratrol is a grape polyphenol that is implicated as an important contributor to red wine's vascular protective effects. Its antimitogenic action on VSMC is attributed to an array of pleiotropic effects, including modulation of the estrogen receptor (ER). To elucidate the mechanisms underlying resveratrol-mediated ER modulation and its inhibition of VSMC proliferation, we treated VSMC with resveratrol with or without the ER antagonist ICI 182,780 and measured cell proliferation and nitric oxide (NO) production. Resveratrol dose-dependently decreased VSMC DNA synthesis, with a half maximal inhibitory concentration (IC50) of 3.73+/-0.57 microM, and dramatically slowed cell growth, but did not induce VSMC apoptosis. Resveratrol-mediated decrease in proliferation was reversed by cotreatment with ICI 182,780, and resveratrol effectively competed with 17beta-estradiol for binding to the ER, exhibiting an IC50 of 8.92+/-0.14 microM. Resveratrol induced a sustained increase in ER-dependent NO production. Further, resveratrol-mediated decrease in VSMC proliferation was blunted by cotreatment with the general nitric oxide synthase (NOS) inhibitor N5-(1-Iminomethyl)-L-ornithine, dihydrochloride or with the inducible NOS (iNOS)-selective inhibitor S,S'-1,4-phenylene-bis (1,2-ethanediyl)bis-isothiourea, dihydrobromide, but not with the neuronal NOS-selective inhibitor 7-nitroindazole. Though resveratrol did not alter iNOS protein levels, it dose-dependently increased levels of iNOS activity, of the iNOS cofactor tetrahydrobiopterin (BH4), and of guanosine triphosphate cyclohydrolase I protein, the rate-limiting enzyme in BH4 biosynthesis. In addition, all of these effects were abolished by cotreatment with ICI 182,780. Thus, the antimitogenic effects of resveratrol on VSMC may be mediated by an ER-induced increase in iNOS activity.
 ...
PMID:Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production. 1766 20

Sphingosine 1-phosphate (S1P) is a lipid mediator that exerts potent and diverse biological effects on several cardiovascular cells. We investigated the effect of S1P on interleukin (IL)-1beta-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression in rat vascular smooth muscle cells (VSMCs). S1P inhibited NO production at concentrations higher than 0.1 muM; this was associated with the inhibition of iNOS protein and mRNA expression. S1P also inhibited IL-1beta-induced GTP cyclohydrolase I (GTPCH) mRNA expression. Pertussis toxin (PTX) partially attenuated the inhibitory effects of S1P on NO production and iNOS protein induction, whereas it completely blocked the inhibitory effects on iNOS and GTPCH mRNA expression. S1P inhibited iNOS expression in Ca(2+)-depleted conditions; PTX did not modify this effect. The Rho kinase inhibitor Y 27632 partially but significantly attenuated the inhibitory effect of S1P on iNOS expression in Ca(2+)-depleted condition but did not affect it in the presence of Ca(2+). S1P significantly inhibited IL-1beta-induced persistent activation of extracellular signal-regulated kinase (ERK) but had no effect in Ca(2+)-depleted conditions. Thus, S1P inhibits IL-1beta induction of NO production and iNOS expression in rat VSMCs through multiple mechanisms involving both PTX-sensitive and -insensitive G proteins coupled to S1P receptors. Furthermore, Ca(2+)-dependent ERK inhibition and Ca(2+)-independent Rho kinase activation might be involved in the inhibitory mechanism of iNOS expression. Through its action on NO production by VSMCs, S1P may play an important role in the progression of local vascular injury associated with thrombosis, atherosclerosis, and hypertension.
 ...
PMID:Sphingosine 1-phosphate inhibits nitric oxide production induced by interleukin-1beta in rat vascular smooth muscle cells. 1817 8

Previous studies have shown a link between inhaled particulate matter (PM) exposure in urban areas and susceptibility to cardiovascular diseases. Although an oxidative stress pathway is strongly implicated, the locus of generation of reactive oxygen species (ROS) and the mechanisms by which these radicals exert their effects remain to be characterized. To test the hypothesis that exposure to environmentally relevant inhaled concentrated ambient PM (CAPs) enhances atherosclerosis through induction of vascular ROS and reactive nitrogen species. High-fat chow fed apolipoprotein E(-/-) mice were exposed to CAPs of less than 2.5 microm (PM(2.5)) or filtered air (FA), for 6 h/day, 5 days/week, for 4 months in Manhattan, NY. Atherosclerotic lesions were analyzed by histomorphometricly. Vascular reactivity, superoxide generation, mRNA expression of NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase subunits, inducible nitric oxide synthase, endothelial nitric oxide synthase, and GTP cyclohydrolase I were also assessed. Manhattan PM(2.5) CAPs were characterized by higher concentrations of organic and elemental carbon. Analysis of vascular responses revealed significantly decreased phenylephrine constriction in CAPs-exposed mice, which was restored by a soluble guanine cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. Vascular relaxation to A23187, but not to acetylcholine, was attenuated in CAPs mice. Aortic expression of NADPH oxidase subunits (p47(phox) and rac1) and iNOS were markedly increased, paralleled by increases in superoxide generation and extensive protein nitration in the aorta. The composite plaque area of thoracic aorta was significantly increased with pronounced macrophage infiltration and lipid deposition in the CAPs mice. CAPs exposure in Manhattan alters vasomotor tone and enhances atherosclerosis through NADPH oxidase dependent pathways.
 ...
PMID:Ambient particulates alter vascular function through induction of reactive oxygen and nitrogen species. 1918 7

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) represents an anti-atherosclerotic principle. NO bioavailability is decreased in atherosclerosis due to increased NO inactivation by reactive oxygen species and reduced NO synthesis. Various types of vascular pathophysiology are associated with oxidative stress, with NADPH oxidases as the major source of reactive oxygen species. These inactivate NO. Also, oxidative stress is likely to be the main cause for oxidation of the essential NOS cofactor, tetrahydrobiopterin (BH(4)). A lack of BH(4) leads to eNOS uncoupling (i.e., uncoupling of oxygen reduction from NO synthesis in eNOS). Based on these pathomechanisms, the therapeutic potential of a number of compounds is discussed in this review: (1) NO donors; (2) L-arginine; (3) folic acid; (4) BH(4) and its precursor sepiapterin; (5) compounds that upregulate eNOS and concomitantly maintain eNOS activity (e.g. midostaurin, betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds that enhance the de novo synthesis of BH(4) by stimulating expression or activity of GTP cyclohydrolase I; and (7) 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins) and drugs interrupting the renin-angiotensin-aldosterone system. Statins, angiotensin II type 1 receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, the aldosterone antagonist eplerenone and the renin inhibitor aliskiren enhance NO bioactivity and reduce atherosclerosis progression through multiple mechanisms.
 ...
PMID:Prevention of atherosclerosis by interference with the vascular nitric oxide system. 1975 87

BH4 (tetrahydrobiopterin) supplementation improves endothelial function in models of vascular disease by maintaining eNOS (endothelial nitric oxide synthase) coupling and NO (nitric oxide) bioavailability. However, the cellular mechanisms through which enhanced endothelial function leads to reduced atherosclerosis remain unclear. We have used a pharmaceutical BH4 formulation to investigate the effects of BH4 supplementation on atherosclerosis progression in ApoE-KO (apolipoprotein E-knockout) mice. Single oral dose pharmacokinetic studies revealed rapid BH4 uptake into plasma and organs. Plasma BH4 levels returned to baseline by 8 h after oral dosing, but remained markedly increased in aorta at 24 h. Daily oral BH4 supplementation in ApoE-KO mice from 8 weeks of age, for a period of 8 or 12 weeks, had no effect on plasma lipids or haemodynamic parameters, but significantly reduced aortic root atherosclerosis compared with placebo-treated animals. BH4 supplementation significantly reduced VCAM-1 (vascular cell adhesion molecule 1) mRNA levels in aortic endothelial cells, markedly reduced the infiltration of T-cells, macrophages and monocytes into plaques, and reduced T-cell infiltration in the adjacent adventitia, but importantly had no effect on circulating leucocytes. GCH (GTP cyclohydrolase I)-transgenic mice, with a specific increase in endothelial BH4 levels, exhibited a similar reduction in vascular immune cell infiltration compared with BH4-deficient controls, suggesting that BH4 reduces vascular inflammation via endothelial cell signalling. In conclusion, BH4 supplementation reduces vascular immune cell infiltration in atherosclerosis and may therefore be a rational therapeutic approach to reduce the progression of atherosclerosis.
 ...
PMID:Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice. 2033 96

Tetrahydrobiopterin (BH(4)) is a critical cofactor for the nitric oxide synthases. In the absence of BH(4), these enzymes become uncoupled, fail to produce nitric oxide, and begin to produce superoxide and other reactive oxygen species (ROS). BH(4) levels are modulated by a complex biosynthetic pathway, salvage enzymes, and by oxidative degradation. The enzyme GTP cyclohydrolase-1 catalyzes the first step in the de novo synthesis of BH(4) and new evidence shows that this enzyme is regulated by phosphorylation, which reduces its interaction with its feedback regulatory protein (GFRP). In the setting of a variety of common diseases, such as atherosclerosis, hypertension, and diabetes, reactive oxygen species promote oxidation of BH(4) and inhibit expression of the salvage enzyme dihydrofolate reductase (DHFR), promoting accumulation of BH(2) and NOS uncoupling. There is substantial interest in therapeutic approaches to increasing tissue levels of BH(4), largely by oral administration of this agent. BH(4) treatment has proved effective in decreasing atherosclerosis, reducing blood pressure, and preventing complications of diabetes in experimental animals. While these basic studies have been very promising, there are only a few studies showing any effect of BH(4) therapy in humans in treatment of these common problems. Whether BH(4) or related agents will be useful in treatment of human diseases needs additional study.
 ...
PMID:Regulation of endothelial cell tetrahydrobiopterin pathophysiological and therapeutic implications. 2108 Dec 17