Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

Abstract

Abstract-We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (nϭ11 healthy and nϭ60 CAD) or placebo (nϭ11 healthy and nϭ10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (PϽ0.0001 for both). However, interleukin 6 was inversely correlated with FMD (PϽ0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (rϭ0.515; PϽ0.0001) compared with CAD (rϭ0.289; Pϭ0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (PϽ0.0001) and ADMA (Pϭ0.004) but lower FMD (Pϭ0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (PϽ0.001) and CAD (PϽ0.001) subjects. FMD was reduced in healthy subjects (PϽ0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (PϽ0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans. (Hypertension. 2011;58:93-98.) • Online Data Supplement Key Words: ADMA Ⅲ endothelium Ⅲ inflammation Ⅲ interleukin 6 Ⅲ atherosclerosis Ⅲ coronary artery disease T he development of endothelial dysfunction is considered to be the initial step in atherogenesis. 1 A healthy endothelium is responsible for NO generation through oxidation of L-arginine by endothelial NO synthase (eNOS). 1 NO maintains vascular tone and acts, per se, as an important intracellular messenger, inducing divergent anti-inflammatory, antithrombotic, and antiapoptotic effects. 1 Asymmetrical dimethylarginine (ADMA), an endogenous L-arginine analog, has been associated with impaired endothelial function in humans. 2 ADMA has also been associated with eNOS uncoupling that results in increased eNOSderived superoxide production in human vessels. 2 Clinical evidence suggests that ADMA plasma levels are associated with endothelial function, particularly in patients with coronary atherosclerosis 3 or atherosclerosis risk factors, 4 whereas this association is significant but weak in healthy individuals. 5 Furthermore, in prospective studies, plasma ADMA has been independently associated with clinical outcome and mortality in diabetic subjects and patients with atherosclerosis. 6 ADMA is derived from ...

Does cardiac resynchronization therapy restore peripheral circulatory homeostasis?

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