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)

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

Hyperhomocyst(e)inemia, characterized by accelerated atherosclerosis, is believed to induce endothelial cell injury and promote atherothrombosis by supporting the generation of hydrogen peroxide. Earlier observations in our laboratory demonstrated that in vitro nitrosation of homocyst(e)ine (HCY) prevents the generation of hydrogen peroxide. We, therefore, hypothesized that stimulating the production of nitric oxide (NO) by endothelial cells would detoxify HCY by forming the corresponding S-nitrosothiol, S-nitroso-homocysteine. In an attempt to prove this hypothesis, media containing 1 mM L-arginine, 1 microM bradykinin, a known NO agonist, and one of the biologically relevant thiols (HCY, cysteine, or glutathione) at concentrations of 0, 0.05, 0.5 and 5.0 mM were incubated with bovine aortic endothelial cells (BAEC) for 0.5, 1 and 4 h. S-nitrosothiol (RSNO) concentrations were measured by photolysis-chemiluminescence. Nitric oxide synthase (eNOS or isoform 3) activity and Nos 3 steady-state mRNA levels were determined by the conversion of [3H]L-arginine to [3H]L-citrulline and Northern analysis, respectively. Results demonstrate that increasing concentrations of HCY, and not cysteine or glutathione, in the presence of bradykinin at 0.5, 1, and 4 h led to significant (P < 0.05 by ANOVA) time- and dose-dependent increases in RSNO produced by BAEC. Cells exposed to 1 microM calcium ionophore A23187 in the presence of 5.0 mM HCY also produced a time-dependent increase in RSNO compared to control (P < 0.05 by ANOVA). In an attempt to determine if de novo synthesis was occurring, BAEC were treated with bradykinin following a 4 h pretreatment with HCY. Pretreatment with HCY followed by stimulation also led to a time- and dose-dependent increase in RSNO production (P < 0.05 by ANOVA). Using high performance liquid chromatography with electrochemical detection, S-nitroso-homocysteine was identified following treatment of BAEC with HCY and bradykinin. The increase in RSNO production in the presence of bradykinin and HCY at 4 h occurred concomitantly with a 78% increase in eNOS activity and a 58% increase in steady-state Nos 3 mRNA, with no change in Nos 3 mRNA half-life, compared to control. A partial explanation for HCY's unique ability to support an increase in NO production was demonstrated by showing that the t1/2 of HCY in media was greater than that of cysteine or glutathione. These data show that, in the presence of an NO agonist, HCY increases RSNO production in a time- and dose-dependent fashion that is reflected by an increase in eNOS activity and Nos 3 transcription. These results suggest that stimulation of endogenous NO, or provision of an exogenous NO donor, may ameliorate endothelial cell injury and thereby decrease the atherothrombotic risk of hyperhomocyst(e)inemic states.
Atherosclerosis 1997 Jul 25
PMID:Stimulation of endothelial nitric oxide production by homocyst(e)ine. 924 63

Endothelium injury plays an important role in atherosclerosis. Damage to the endothelium results in vascular smooth muscle cell proliferation. Natriuretic peptides present a potent antimitogenic action, mediating their biological effects via the binding of guanylate cyclase-linked atrial natriuretic peptide (ANP) receptor and the production of cyclic GMP. In a previous study, we demonstrated that L-citrulline, the by-product of nitric oxide synthesis, could relax rabbit aortic rings by stimulating the guanylate cyclase-linked ANP receptor. In this work, we investigated the effect of L-citrulline on vascular smooth muscle cell proliferation. L-Citrulline (10(-8) M) significantly decreased rat aortic (A10 cell line) vascular smooth muscle proliferation. The percentage of inhibition exerted by L-citrulline on days 3, 5, and 7 of the proliferation curve was 20.0 +/- 0.5%, 37.5 +/- 8.3%, and 28. 5 +/- 7.2%, respectively. In addition, L-citrulline also inhibited serum-induced DNA synthesis, measured as 5-bromo-2'-deoxyuridine incorporation. 5-Bromo-2'-deoxyuridine incorporation into nuclei of vehicle-treated cells was 40.5 +/- 2.4%, whereas in L-citrulline-treated cells the percentage decreased to 36.0 +/- 4.1%, 29.1 +/- 2.0% (P <.01, n = 4), 30.5 +/- 2.4% (P <.05, n = 4), and 23.1 +/- 0.5% (P <.001, n = 4) for 10(-10), 10(-9), 10(-8), and 10(-7) M, respectively. Zaprinast, a phosphodiesterase type V inhibitor, enhanced 5-bromo-2'-deoxyuridine incorporation in serum-stimulated cells. Moreover, L-citrulline inhibition of serum-stimulated DNA synthesis was abolished by HS-142-1 (10(-5) M), an ANP receptor antagonist. In another group of experiments, L-citrulline was shown to increase intracellular cyclic GMP levels from 2.1 +/- 0.2 pmol of cGMP/mg protein to 4.1 +/- 0.1 for L-citrulline (10(-8) M) (P <.001, n = 3). These findings suggest that L-citrulline decreases vascular smooth muscle cell proliferation in the A10 cell line by acting on DNA synthesis by mechanisms that involve the ANP receptor.
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PMID:L-Citrulline, the by-product of nitric oxide synthesis, decreases vascular smooth muscle cell proliferation. 1038 92

In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.
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PMID:Endothelium-derived nitric oxide and vascular physiology and pathology. 1044 89

Patients with metabolic syndrome represent a group with extensive cardiovascular risk factors for the development of atherosclerosis, which may be preceded by an impairment of endothelial function. Endothelial dysfunction is characterized by a reduced availability of bioactive nitric oxide, the principal mediator of endothelium-dependent vasodilation. In the present study we assessed NO synthesis in vivo by measuring the NO-related amino acids L-arginine and L-citrulline and in particular the stable intermediate compound N(omega)-hydroxy-L-arginine (L-NHA) in patients with metabolic syndrome by using high-performance liquid chromatography (HPLC) analysis. As a prerequisite to our study, we measured the amino acid concentrations in 31 healthy volunteers to investigate gender and age differences. To prove whether blood drawn from peripheral veins reflects plasma concentrations of the whole vessel system, several blood samples from different regions were obtained from patients undergoing elective left and right heart catheterization. In the latter group, no significant differences were noted among the plasma concentrations between the different sample sites. In healthy volunteers, there were no significant differences in plasma concentrations of any one specific amino acid between males and females or age groups. The main finding of the study is that the intermediate product of NO synthesis, L-NHA, is significantly reduced in the plasma samples of patients with a metabolic syndrome as compared with samples from healthy control subjects. The plasma concentrations of the NO precursor L-arginine and the end product of NO synthesis, L-citrulline, were unchanged. In conclusion, our results suggest that plasma levels of L-NHA are independent of age and gender and are not different at various locations within the vascular system. In a group of patients at high risk for the development of atherosclerosis, we found reduced plasma concentrations of L-NHA, either caused by a decreased endothelial NO synthase activity or caused by an increased breakdown of L-NHA by pathways independent of NO synthase, resulting in a reduced availability of L-NHA for NO synthesis.
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PMID:Decreased plasma concentrations of L-hydroxy-arginine as a marker of reduced NO formation in patients with combined cardiovascular risk factors. 1081 Oct 58

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In addition, ADMA is degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine. Activity of DDAH is decreased by oxidized low density lipoprotein (LDL) or tumor necrosis factor-alpha (TNF-alpha) in vitro yielding increased levels of ADMA. Furthermore, plasma levels of ADMA are elevated in hyperhomocyst(e)inemia and in hypertensive patients on a high salt diet. Data from several experimental studies suggest that ADMA concentrations in a pathophysiologically high range (3 to 10 micromol/L) significantly inhibit vascular NO formation by NO synthase in the presence of L-arginine in isolated human blood vessels, cultured macrophages, and in cultured endothelial cells. It has been well demonstrated that ADMA accumulates in chronic renal failure. Although there is controversy concerning the absolute concentration of ADMA, all authors found a two- to sixfold increase in ADMA levels in patients in chronic renal failure as compared to controls. Different dialysis treatment strategies differentially affect ADMA levels. The presence of atherosclerosis is associated with higher ADMA levels in patients with normal renal function as well as in dialysis patients, but this phenomenon may be unrelated to renal handling of ADMA. Reduced NO elaboration secondary to accumulation of ADMA may be an important pathogenic factor for atherosclerosis in chronic renal failure and ADMA may be a new uremic toxin. Clinical studies on the effect of ADMA are needed to further elucidate its pathophysiological role in atherosclerosis and uremia.
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PMID:Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease. 1116 75

Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10(-)(9) to 10(-)(5) mol/L) and Ca(2+) ionophore (10(-)(9) to 10(-)(6) mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-)(10) to 10(-)(5) mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O(2)(-)) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn-superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10(-)(5) mol/L), reduced O(2)(-) production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [(14)C]L-Citrulline assay showed a decrease of Ca(2+)-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O(2)(-) and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O(2)(-) and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.
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PMID:Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice. 1139 13

Reactive oxygen species (ROS) hydrogen peroxide (H(2)O(2)) and hypochlorite (HOCl) participate in the pathogenesis of ischemia/reperfusion injury, inflammation, and atherosclerosis. Both NO and ROS are important modulators of vascular tone and architecture and of adhesive interactions between leukocytes, platelets, and vascular endothelium. We studied the effect of H(2)O(2) and HOCl on receptor-dependent (bradykinin [10(-6) mol/L] and ADP [10(-4) mol/L]) and receptor-independent mechanisms (calcium ionophore A23187 [10(-6) mol/L]) of NO production by porcine aortic endothelial cells (ECs). Changes in the level of EC cGMP (the second messenger of NO) were used as a surrogate of NO production. EC cGMP increased 300% in response to bradykinin and A23187 and 200% in response to ADP. Exposure of ECs to H(2)O(2) (50 micromol/L) for 30 minutes significantly impaired cGMP levels in response to ADP, bradykinin, and the receptor-independent NO agonist A23187. In contrast, preincubation with HOCl (50 micromol/L) impaired cGMP production only in response to ADP and bradykinin but not A23187. These concentrations of H(2)O(2) and HOCl did not result in increased EC lethality as assessed by lactate dehydrogenase release. Neither H(2)O(2) nor HOCl affected EC cGMP production in response to NO donor sodium nitroprusside, which suggests that guanylate cyclase is resistant to these oxidants. We also demonstrated that neither H(2)O(2) nor HOCl affects endothelial NO synthase (eNOS) catalytic activity as measured by conversion of L-arginine to L-citrulline in EC homogenates supplemented with eNOS cofactors. The present studies show that H(2)O(2) impairs NO production in response to both receptor-dependent and receptor-independent agonists and that these effects are due, at least in part, to inactivation of eNOS cofactors, whereas HOCl inhibits NO production by interfering with receptor-operated mechanisms at the level of the cell membrane. Concentrations of H(2)O(2) and HOCl used in the present studies have been shown to be generated in vivo during inflammation and ischemia/reperfusion. Therefore, we infer that these effects of H(2)O(2) and HOCl on EC NO production may contribute to disregulated vascular tone and altered leukocyte-EC interactions that occur in vascular injury as a result of those causes in which ROS generation is involved.
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PMID:Effects of the reactive oxygen species hydrogen peroxide and hypochlorite on endothelial nitric oxide production. 1164 2

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 micromol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor N(G)-monomethyl-L-arginine (500 micromol/L). Activity of iNOS, determined by the conversion of L-arginine to L-citrulline, increased 9-fold after atorvastatin treatment. Western blot and semiquantitative reverse transcriptase-polymerase chain reaction revealed that atorvastatin (34 to 68 micromol/L) strongly upregulated iNOS protein and mRNA levels, respectively. These concentrations of atorvastatin did not cause cytotoxicity, as judged by the cell survival rate. Similarly, simvastatin and lovastatin (34 micromol/L) caused robust upregulation of the iNOS protein level. Transfection experiments demonstrated that the -1034- to 88-bp human iNOS promoter was strongly induced by atorvastatin (34 micromol/L). Electromobility and supershift assays using a nuclear factor-kappaB (NF-kappaB) consensus oligonucleotide and nuclear extracts from VSM cells as well as transfection studies using an NF-kappaB reporter plasmid suggested that the transcriptional activation of the iNOS gene by atorvastatin is not mediated via the NF-kappaB pathway. We conclude that HMG-CoA reductase inhibitors potently upregulate iNOS expression and activity in VSM cells, at least in part, by transcriptional mechanisms that do not depend on transcription factor NF-kappaB. These effects might have important implications for the impact of HMG-CoA reductase inhibitors on atherosclerosis.
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PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells. 1171 92

Protein arginine N-methyltransferases (PRMTs) catalyse the methylation of guanidinonitrogen(s) of arginine to produce NG-monomethyl-L-arginine (L-NMMA), asymmetric NG,NG-dimethyl-L-arginine (ADMA) and symmetric NG,NG-dimethyl-L-arginine (SDMA), which are subsequently released into the cytoplasm following proteolysis. Free intracellular L-NMMA and ADMA, but not SDMA, are inhibitors of all three isoforms of nitric oxide synthases (nNOS, eNOS and iNOS). L-NMMA and ADMA, but not SDMA, are actively metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and methylamine (and dimethylamine). Free methylarginines are detectable in cell cytosol, plasma and tissues. Elevated ADMA has been detected in the plasma of patients or experimental animals with hypercholesterolemia, renal failure, atherosclerosis, hypertension, thrombotic microangiopathy, peripheral arterial occlusive disease and in the regenerated endothelial cells after angioplasty. Moreover, in the non-cardiovascular field, ADMA was increased in the urethral tissue following ischemia and in the plasma of patients with schizophrenia and multiple sclerosis. Altered biosynthesis of NO has been implicated in the pathogenesis of these diseases, and it is possible to consider that the accumulation of endogenous L-NMMA and ADMA underlies the impaired NO generation and increased O2- production. We described herein the biosynthesis, transmembrane transport, metabolic pathway and possible pathophysiological roles of endogenous methylarginines.
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PMID:[Biological and pathophysiological roles of endogenous methylarginines as inhibitors of nitric oxide synthase]. 1186 54


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