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

Abstract

BackgroundAsymmetric 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 ResultsWe 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.ConclusionsWe 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.

The detrimental effect of asymmetric dimethylarginine on cholesterol efflux of macrophage foam cells: Role of the NOX/ROS signaling

“…Growing lines of evidence suggest that the NOX-ROS signaling pathway contributes to the ADMA-mediated pathological effects [41,48,49], so activation of this pathway might be required for the detrimental effects of ADMA on cholesterol metabolism in macrophage foam cells. Indeed, our findings that treatment with NAC or APO abrogated the ADMA-mediated deregulation of cholesterol metabolism in macrophages agree with our previous findings that ADMA abolished the beneficial effects of simvastatin by triggering NOX-ROS signaling [26].…”

“…We then determined the molecular mechanism by which ADMA interferes with cholesterol efflux in macrophages. The NOX-ROS signaling pathway has been reported to be involved in the detrimental effects of ADMA [26]. Our results demonstrated that ADMA (0.5 µg/ml) increased NOX activity as early as 2 min, with a peak level at 15 min (Fig.…”

Synergistic Effect of Atorvastatin and Folic Acid on Cardiac Function and Ventricular Remodeling in Chronic Heart Failure Patients with Hyperhomocysteinemia

“…We also found that atorvastatin and folic acid work together to inhibit ventricular remodeling. The statin class of drugs is now recognized to have therapeutic properties beyond cholesterol lowering, including anti-oxidation, anti-inflammation, upregulation of nitric oxide synthesis [ 45 ], and prevention of cardiovascular diseases [ 46 ]. In a former study on ventricular remodeling of spontaneously hypertensive rats, atorvastatin was proved to upregulate the p27 protein level and induce cell apoptosis, by which way the ventricular remodeling was frustrated [ 47 ].…”

The Endothelial Nitric Oxide Synthase Gene Polymorphism is Associated with the Susceptibility to Immunoglobulin a Nephropathy in Chinese Population

“…The phosphorylation and dephosphorylation of serine and threonine are important in the regulation of eNOS expression [23]. Statins, widely used in the treatment of cardiovascular diseases, were found to provide protection against cardiovascular diseases by increasing the bioavailability of NO via enhancing eNOS gene function [24]. NO can relax the efferent and afferent artery, increase glomerular filtration rate, and regulate renal sodium excretion [16, 25].…”