In patients with coronary artery disease and plasma ADMA levels ≥0.49 μmol/L, statin treatment had no significant effect on cardiovascular events over an 8-year follow-up.
Cohort (n=648)
Does elevated asymmetric dimethylarginine (ADMA) limit the efficacy of statin treatment in patients with coronary artery disease and in preclinical models?
Elevated ADMA levels may attenuate the cardiovascular protective effects of statins by triggering NOX-ROS signaling and restricting eNOS activation.
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.
Hsu et al. (Sun,) conducted a cohort in coronary artery disease (n=648). Statin treatment was evaluated on cardiovascular events. In patients with coronary artery disease and plasma ADMA levels ≥0.49 μmol/L, statin treatment had no significant effect on cardiovascular events over an 8-year follow-up.