Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

• Published in: Journal of the American Heart Association Vol. 5; no. 4; pp. e003327 - n/a
• Main Authors: Hsu, Chiao‐Po, Zhao, Jin‐Feng, Lin, Shing‐Jong, Shyue, Song‐Kun, Guo, Bei‐Chia, Lu, Tse‐Min, Lee, Tzong‐Shyuan
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.04.2016; Wiley
• Subjects: Aged; Animals; Arginine - analogs & derivatives; Arginine - blood; asymmetric dimethylarginine; Cardiovascular Diseases - prevention & control; endothelial nitric oxide synthase; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme Activation - drug effects; Female; Humans; Male; Mice; NADPH oxidase; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type III - drug effects; Nitric Oxide Synthase Type III - metabolism; Original Research; reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; simvastatin; Simvastatin - therapeutic use; simvastatin; endothelial nitric oxide synthase; NADPH oxidase; asymmetric dimethylarginine; reactive oxygen species
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.116.003327

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 μmol/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 simvastatin‐induced 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.