Asymmetric Dimethylarginine (ADMA) and Endothelial Dysfunction: Implications for Atherogenesis

Abstract

Atherosclerotic coronary heart disease is the leading cause of morbidity and mortality in industrialized countries, and endothelial dysfunction is considered a precursor phenomenon. The nitric oxide produced by the endothelium under the action of endothelial nitric oxide synthase has important antiatherogenic functions. Its reduced bioavailabilty is the beginning of the atherosclerotic process. The addition of two methyl radicals to arginine, through the action of methyltransferase nuclear proteins, produces asymmetric dimethylarginine, which competes with L-arginine and promotes a reduction in nitric oxide formation in the vascular wall. The asymmetric dimethylarginine, which is itself considered a mediator of the vascular effects of the several risk factors for atherosclerosis, can be eliminated by renal excretion or by the enzymatic action of the dimethylarginine dimethylaminohydrolases. Several basic science and clinical research studies suggest that the increase in asymmetric dimethylarginine occurs in the context of chronic renal insufficiency, dyslipidemia, high blood pressure, diabetes mellitus, and hyperhomocysteinemy, as well as with other conditions. Therapeutic measures to combat atherosclerosis may reverse these asymmetric dimethylarginine effects or at least reduce the concentration of this chemical in the blood. Such an effect can be achieved with competitor molecules or by increasing the expression or activity of its degradation enzyme. Studies are in development to establish the true role of asymmetric dimethylarginine as a marker and mediator of atherosclerosis, with possible therapeutic applications. The main aspects of the formation and degradation of asymmetric dimethylarginine and its implication in the atherogenic process will be addressed in this article.

Proximal Tubule Dysfunction Is Dissociated from Endothelial Dysfunction in Normoalbuminuric Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study

“…Even when these concentrations are only slightly increased, ADMA is associated with high cardiovascular and cerebrovascular risks in the general population [38,39], as well as in type 1 and type 2 DM, a setting in which resistance to insulin is a core determinant of plasma ADMA concentrations [40]. …”

Asymmetric dimethylarginine regulates the lipopolysaccharide-induced nitric oxide production in macrophages by suppressing the activation of NF-kappaB and iNOS expression

“…Although considerable data concerning the role of naturally occurring methylarginines (N G -methyl-L-arginine, L-NMMA; N G , N G ′-dimethyl-L-arginine-symmetric dimethylarginine, SDMA; and N G , N G -dimethyl-L-arginine-asymmetric dimethylarginine, ADMA), especially ADMA, in regulation of endothelial cell responses have been published (Bogle et al, 1995;Fickling et al, 1999;Landim et al, 2009;Leiper et al, 2007;Palm et al, 2007), there still exists only incomplete information about the mechanism by which methylarginines regulate the activation of immune cells. We hypothesized that increased concentration of methylarginines could significantly affect the production of NO and at the same time increase the oxidative stress, which could negatively affect their normal functions.…”

A systematic review and meta-analysis on the effect of statins on plasma asymmetric dimethylarginine concentrations

“…The Hoorn Study showed that systemic inflammation was associated with decreased arginine and increased ADMA plasma levels resulting in an unfavorable NOS substrate-to-inhibitor ratio 12 . The interplay of inflammation, endothelial dysfunction, and oxidative stress might play a crucial role in ADMA pathophysiology, and reduction of ADMA levels might be a significant target for preventing endothelial dysfunction 13 . Statins may provide an effective response to reverse endothelial dysfunction via reduction of ADMA levels; however, the available evidence is not conclusive.…”