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   Asymmetric dimethylarginine limits the efficacy of simvastatin activating endothelial nitric oxide synthase  
   
نویسنده hsu c.-p. ,zhao j.-f. ,lin s.-j. ,shyue s.-k. ,guo b.-c. ,lu t.-m. ,lee t.-s.
منبع journal of the american heart association - 2016 - دوره : 5 - شماره : 4
چکیده    Background-asymmetric dimethylarginine (adma),an endogenous inhibitor of endothelial nitric oxide synthase (enos),is considered a risk factor for the pathogenesis of cardiovascular diseases. simvastatin,a lipid-lowering drug with other pleiotropic effects,has been widely used for treatment of cardiovascular diseases. however,little is known about the effect and underlying molecular mechanisms of adma on the effectiveness of simvastatin in the vascular system. methods and results-we conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow-up period of 8 years. in patients with plasma adma level ≥0.49 lmol/l (a cut-off value from receiver operating characteristic curve),statin treatment had no significant effect on cardiovascular events. we also conducted randomized,controlled studies using in vitro and in vivo models. in endothelial cells,treatment with adma (≥0.5 μmol/l) impaired simvastatininduced nitric oxide (no) production,endothelial no synthase (enos) phosphorylation,and angiogenesis. in parallel,adma markedly increased the activity of nadph oxidase (nox) and production of reactive oxygen species (ros). the detrimental effects of adma on simvastatin-induced no production and angiogenesis were abolished by the antioxidant,n-acetylcysteine,nox inhibitor,or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (ddah-2). moreover,in vivo,adma administration reduced matrigel plug angiogenesis in wild-type mice and decreased simvastatin-induced enos phosphorylation in aortas of apolipoprotein e-deficient mice,but not endothelial ddah-2-overexpressed aortas. conclusions-we conclude that adma may trigger nox-ros signaling,which leads to restricting the simvastatin-conferred protection of enos activation,no production,and angiogenesis as well as the clinical outcome of cardiovascular events. © 2016 the authors.
کلیدواژه Asymmetric dimethylarginine; Endothelial nitric oxide synthase; NADPH oxidase; Reactive oxygen species; Simvastatin
آدرس faculty of medicine,school of medicine,national yang-ming university,taipei,taiwan,division of cardiovascular surgery,department of surgery,taipei veterans general hospital,taipei, Taiwan, department of physiology,genome research center,national yang-ming university,taipei, Taiwan, department of physiology,genome research center and institute of clinical medicine,national yang-ming university,taipei,taiwan,division of cardiovascular surgery,department of surgery and division of cardiology,department of internal medicine,taipei veterans general hospital,taipei, Taiwan, institute of biomedical sciences,academia sinica,taipei, Taiwan, department of physiology,genome research center,national yang-ming university,taipei, Taiwan, faculty of medicine,school of medicine,national yang-ming university,taipei,taiwan,division of cardiovascular surgery,department of surgery and division of cardiology,department of internal medicine,taipei veterans general hospital,taipei, Taiwan, department of physiology,genome research center,national yang-ming university,taipei, Taiwan
 
     
   
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