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


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.
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.
Chiao-Po
CP
Hsu
Department of Physiology, Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
Jin-Feng
JF
Zhao
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Shing-Jong
SJ
Lin
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Song-Kun
SK
Shyue
Department of Physiology, Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
Bei-Chia
BC
Guo
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan tslee@ym.edu.tw tmlu@vghtpe.gov.tw.
Tse-Min
TM
Lu
Department of Physiology, Genome Research Center, National Yang-Ming University, Taipei, Taiwan tslee@ym.edu.tw tmlu@vghtpe.gov.tw.
Tzong-Shyuan
TS
Lee
D000368:Aged; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002318:Cardiovascular Diseases / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III
NADPH oxidase; asymmetric dimethylarginine; endothelial nitric oxide synthase; reactive oxygen species; simvastatin