Asymmetrical dimethylarginine: the Uber marker?

Abstract

The traditional risk factors of hypercholesterolemia, hypertension, diabetes mellitus, and tobacco exposure identify a subset of patients at greater cardiovascular risk. A variety of clinical phenotypes, biochemical markers, and genetic polymorphisms have been proposed to explain the variance in risk not explained by the traditional factors. Notably, all of the traditional risk factors, as well as the great majority of new risk markers, are associated with endothelial vasodilator dysfunction. Because the end points (endothelial dysfunction leading to plaque formation, progression, and rupture) are the same, it follows that diverse risk factors ultimately share common pathways(s) of pathobiology. We and others have provided evidence for a ubiquitous mechanism of endothelial pathobiology shared by all risk factors and markers examined to date. This mechanism of endothelial derangement is mediated by an endogenous inhibitor of nitric oxide synthase (NOS), a molecule known as asymmetrical dimethylarginine (ADMA). Risk factors impair endothelial vasodilator function by causing the accumulation of ADMA. Furthermore, by blocking NO generation, ADMA initiates and promotes processes involved in atherogenesis, plaque progression. and plaque rupture. This review examines the burgeoning body of literature that supports ADMA as an “Uber marker,” a biochemical factor mediating the adverse vascular effects of many other risk factors and markers. Endothelial NOS converts the amino acid l-arginine into l-citrulline and NO. The importance of NO in vascular homeostasis has been discussed elsewhere.1 In addition to its vasodilator activity, NO inhibits key processes involved in vascular disease, including leukocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation. In animal models, alterations in vascular NO synthesis profoundly influence the progression of atherosclerosis and restenosis.2–6 These experimental observations have gained greater significance with recent reports that impairment of the NOS pathway independently predicts cardiovascular events.7–11 Major causes of impairment of the NOS pathway are …