Dimethylarginine Dimethylaminohydrolase and Endothelial Dysfunction in the Failing Heart

Congestive heart failure (CHF) is associated with impaired endothelium-dependent nitric oxide (NO) mediated vasodilation (endothelial dysfunction). We hypothesized that coronary endothelial dysfunction in CHF may be due in part to decreased dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades endogenous inhibitors of NOS, including asymmetric dimethylarginine (ADMA). Coronary blood flow and the endotheliumdependent vasodilator response to acetylcholine were studied in dogs in which CHF was produced by rapid ventricular pacing for 4 weeks. Coronary flow and MVO2 at rest and during treadmill exercise were decreased after development of CHF, and the vasodilator response to acetylcholine (75 μg/min intracoronary) was decreased by 39±5 %. DDAH activity and DDAH isoform 2 (DDAH2) protein content were decreased by 53±13 % and 58±14 %, respectively, in hearts with CHF, while eNOS and DDAH isoform 1 (DDAH1) were increased. Caveolin-1 and protein arginine N-methyltransferase I (PRMT1), the enzyme that produces ADMA, were unchanged. Immunohistochemical staining showed DDAH1 strongly expressed in coronary endothelium and smooth muscle, and in the sarcolemma of cardiac myocytes. In cultured human endothelial cells DDAH1 was uniformly distributed in the cytosol and nucleus, while DDAH2 was found only in the cytosol. Decreased DDAH activity and DDAH2 protein expression may cause accumulation of endogenous inhibitors of eNOS, thereby contributing to endothelial dysfunction in the failing heart.