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)

Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA). ADMA is a naturally occurring amino acid found in plasma and various types of tissues. Recently, it has been demonstrated that plasma levels of ADMA are elevated in patients with diabetes. It has also been reported that elevated plasma levels of ADMA are associated with increased risks of nonfatal stroke and myocardial infarction in patients with early diabetic nephropathy. These findings suggest that the elevated ADMA in diabetes could contribute to acceleration of atherosclerosis in this population. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs are involved in the development and progression of atherosclerosis in patients with diabetes. Since ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase (DDAH), it is conceivable that the impairment of DDAH actions by AGEs could be one possible molecular mechanism of the ADMA elevation in diabetic patients. In this paper, we would like to propose the possible ways of testing our hypotheses. Does treatment with metformin, which has a potential effect on the inhibition of glycation reactions in vivo, decrease the levels of ADMA in diabetic patients? If the answer is yes, is this beneficial effect of metformin superior to that of other anti-diabetic agents with equihypoglycemic properties? Does treatment with pyridoxamine, a post-Amadori inhibitor (so-called Amadorins) of AGE formation, also reduce the levels of ADMA and subsequently improve endothelial dysfunction in diabetic patients? Are the ADMA-lowering effects of these agents associated with an increase of DDAH expression and/or activity in endothelial cells? These clinical studies could clarify whether AGEs are involved in the elevation of ADMA in patients with diabetes via suppression of DDAH expression and/or activity, thus providing a novel molecular mechanism for accelerated atherosclerosis in diabetes.
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PMID:A possible involvement of crosstalk between advanced glycation end products (AGEs) and asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor in accelerated atherosclerosis in diabetes. 1736 60

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

Nitric oxide (NO) is a well-recognized anti-atherogenic factor; it inhibits the inflammatory-proliferative processes in atherosclerosis. Indeed, endothelial dysfunction due to reduced synthesis and/or bioavailability of NO is thought to be an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA), a naturally occurring amino acid found in plasma and various types of tissues. Recently, it has been demonstrated that plasma levels of ADMA are elevated in patients with diabetes. These findings suggest that the elevated ADMA in diabetes could contribute to acceleration atherosclerosis in this population. Further, since ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase (DDAH), it is conceivable that the inhibition of ADMA via up-regulation of DDAH may be a novel therapeutic target for the prevention of CVD in patients with diabetes. In this paper, we review the pathophysiological role of ADMA and DDAH system for accelerated atherosclerosis in diabetes and the therapeutic utility of ADMA suppression in CVD in diabetes.
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PMID:Role of asymmetric dimethylarginine (ADMA) in diabetic vascular complications. 1899 78

Asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits the activity of the enzyme endothelial nitric oxide synthase, with consequent reduced synthesis of nitric oxide. ADMA is metabolised to L-citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The modulation of DDAH activity and expression plays a pivotal role in regulating intracellular ADMA concentrations, with important effects on vascular homeostasis. For example, impairment in DDAH activity, resulting in elevated ADMA concentrations and reduced nitric oxide synthesis, can promote the onset and progression of atherosclerosis in experimental models. This review discusses the current role of ADMA and DDAH in vascular health and disease, the techniques used to assess DDAH activity and expression, and the results of recent studies on pharmacological and biological agents modulating DDAH activity and expression. Suggestions for future basic and clinical research directions are also discussed.
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PMID:Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease. 1933 93

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is mainly metabolized by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH). We investigated whether altered cavernosal ADMA-DDAH metabolism might cause impairment of erection in rat model of atherosclerosis (AS). Male Sprague-Dawley rats (3 months old) were divided into an AS group and a normal control (Con) group (n=20 in each group). The AS rats received AS-prone treatment (6 weeks of 1% cholesterol diet plus early 2 weeks of N(G)-nitro-L-arginine methyl ester (3 mg ml(-1) per day) treatment). After 6 weeks, rats underwent cavernosometry measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios as a surrogate marker of erectile function. The amount of cavernosal ADMA was assessed by immunoblot analysis and correlated with the ICP/MAP. Isoform-specific DDAH expression was compared by immunohistochemistry. Cavernosal DDAH and NOS activity were measured. Cavernosal malondialdehyde levels were assayed to determine the degree of lipid peroxidation. Compared to the controls, the AS rats had signs of impaired erectile function. Higher cavernosal ADMA was observed in the AS rats. The cavernosal ADMA had a moderately negative correlation with the ICP/MAP. Immunohistochemistry revealed the expression of both isoforms was not affected by the presence of AS. However, significantly diminished DDAH as well as NOS activity was observed in the AS group. In addition, elevated cavernosal malondialdehyde levels were noted in the AS rats. Our study showed that decreased cavernosal DDAH activity is the cause of cavernosal ADMA accumulation leading to reduced cavernosal NOS activity and impairment of erectile function.
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PMID:Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis. 1960 41

Previous investigations have indicated that reduced erythrocyte deformability may be an important factor contributing to the development of atherosclerosis, and endogenous asymmetric dimethylarginine (ADMA) might be an important contributor to reduction of erythrocyte deformability in atherosclerosis. In this study, the effect of 3,4,5,6-tetrahydroxyxanthone (1), a kind of polyphenolic compound, on erythrocyte deformability in apolipoprotein E-deficient (apoE-/-) mice was evaluated. After treatment with compound 1 (10 or 20 mg/kg per day) for 4 weeks, erythrocyte deformability, antioxidant enzymes activity, erythrocyte dimethylarginine dimethylaminohydrolase (DDAH) activity, the plasma level of ADMA and malondialdehyde (MDA) level were determined. Treatment with compound 1 (10 or 20 mg/kg) increased erythrocyte deformability, antioxidant enzymes activity concomitantly, a decrease in the plasma levels of MDA and ADMA, and an increase in erythrocyte DDAH activity. The present result suggests that the beneficial effect of 1 on the erythrocyte deformability, besides inhibiting lipid peroxidation, may be related to reduction of ADMA concentration via an increase in DDAH activity.
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PMID:Effect of 3,4,5,6-tetrahydroxyxanthone on erythrocyte deformability in apolipoprotein E-deficient mice. 2018 1

N(omega)-Carboxymethyl-arginine (CMA), N(omega)-carboxyethyl-arginine (CEA) and N(delta)-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) have been identified as L-arginine-derived advanced glycation end products (AGEs) formed by non-enzymatic reactions between reducing sugars such as glucose and amino groups in proteins. These AGEs are structurally analogous to endogenous inhibitors of nitric oxide synthases (NOS) including N(G)-monomethyl-L-arginine (L-NMMA) and asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA). Increased plasma levels of these NOS inhibitors, and thus impaired generation of NO in vivo has been associated with the pathogenesis of vascular complications such as kidney failure and atherosclerosis. For these reasons we examined whether L-arginine-derived AGEs inhibit the activities of three L-arginine metabolizing enzymes including three isoforms of NOS (endothelium, neuronal and inducible NOS), dimethylarginine dimethylaminohydrolase (DDAH) that catalyzes the hydrolytic degradation of L-NMMA and ADMA to L-citrulline, and arginase that modulates intracellular L-arginine bioavailability. We found that AGEs inhibited the in vitro activities of endothelium type NOS weakly (IC(50) values of CMA, CEA and MG-H1 were 830, 3870 and 1280 microM, respectively) and were also potential endogenous inhibitors for arginase (IC(50) values of CMA and CML were 1470 and 1060 microM), but were poor inhibitors for DDAH. These results suggest that the tested L-arginine- and L-lysine-derived AGEs appear not to impair NO biosynthesis directly.
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PMID:Inhibition of L-arginine metabolizing enzymes by L-arginine-derived advanced glycation end products. 2021 51

An impaired nitric oxide (NO) bioavailability is well-recognized in the pathology of endothelial dysfunction or atherosclerosis, respectively, and characterized by a reduced NO biosynthesis, an accelerated inactivation and/or a decreased sensitivity to NO. Therefore, attempts to increase endogenous NO concentrations or to improve responses to NO stimulation have attracted great pharmaceutical interest for the treatment of several cardiovascular diseases. The biological system of the NO/cGMP cascade is very complex and highly regulated through diverse upstream and downstream molecular and cellular elements and feedback mechanisms. This review summarizes the current options to modulate NO bioavailability for the treatment of cardiovascular disease, with a special focus on targets upstream of cGMP. We also point at the many shortcomings that are associated with the established therapy with nitrates, thereby raising general questions regarding this pharmacological approach. In fact, it is highly desirable to more selectively affect the respective pathologically altered processes in endothelial dysfunction, which ensures a safer and more effective therapy. Approaches to modulate those enzymes that predominate in the regulation of endogenous NO levels represent promising means to achieve this goal: nitric oxide synthases, arginases and dimethylarginine dimethylaminohydrolase. The herein presented novel developments essentially imply a paradigm shift from purely symptomatic to more causative therapeutics which opens up opportunities to not only treat ischemic heart disease but many more cardiovascular diseases.
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PMID:Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease. 2022 11

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a novel biomarker in cardiovascular disease. To date, it remains unclear whether elevated ADMA levels are merely associated with cardiovascular risk or whether this molecule is of functional relevance in the pathogenesis of atherosclerotic vascular disease. To clarify this issue, we crossed dimethylarginine dimethylaminohydrolase (DDAH) transgenic mice that overexpress the human isoform 1 of the ADMA degrading enzyme DDAH into ApoE-deficient mice to generate ApoE(-/-)/hDDAH1(+/-) mice. In these mice, as well as ApoE(-/-) wild-type littermates, atherosclerosis within the aorta as well as vascular function of aortic ring preparations was assessed. We report here that overexpression of hDDAH1 reduces plaque formation in ApoE(-/-) mice by lowering ADMA. The extent of atherosclerosis closely correlated with plasma ADMA levels in male but not female mice fed either a standard rodent chow or an atherogenic diet. Functional analysis of aortic ring preparations revealed improved endothelial function in mice overexpressing hDDAH1. Our findings provide proof-of-principle that ADMA plays a causal role as a culprit molecule in atherosclerosis and support recent evidence indicating a functional relevance of DDAH enzymes in genetic mouse models. Together, these results demonstrate that pharmacological interventions targeting the ADMA/DDAH pathway may represent a novel approach in the prevention and management of cardiovascular diseases.
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PMID:Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine. 2034 44

Nitric oxide (NO) formed via endothelial NO synthase (eNOS) plays crucial roles in the regulation of coronary blood flow through vasodilatation and decreased vascular resistance and in the inhibition of platelet aggregation and adhesion, leading to the prevention of coronary circulatory failure, thrombosis, and atherosclerosis. NO restrains myocardial oxygen consumption, when coronary perfusion is restricted. Endothelial function is impaired by pathogenic factors including smoking, excess salt intake, obesity, aging, hypercholesterolemia, hyperglycemia, and hypertension. The mechanisms involved in endothelial dysfunction are reduced NOS expression and activity, decreased NO bioavailability, and increased production of oxygen radicals and endogenous NOS inhibitors. NADPH oxidase, xanthine oxidase, and NOS uncoupling are involved in increased superoxide generation. Plasma levels of asymmetric dimethylarginine, the endogenous NOS inhibitor, are increased by an impairment of enzymatic degradation by dimethylarginine dimethylaminohydrolase and alanine-glyoxylate aminotransferase 2. Impairment of coronary arteriolar dilatation induced by perivascular nitrergic nerve activation is involved in decreased coronary blood flow. NO derived from nNOS singly or in combination with eNOS protects against serious myocardial injury through ischemic insults. Ischemia-induced iNOS upregulation contributes to myocardial contractile dysfunction. Preventive and therapeutic measures, such as improvement of life-style and treatment with therapeutic agents, to eliminate pathogenic factors for endothelial dysfunction or nNOS-derived NO deprivation would be quite important for the prophylaxis and minimizing the development of coronary artery disease.
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PMID:Coronary hemodynamic regulation by nitric oxide in experimental animals: recent advances. 2174 64


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