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Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts

¹Departments of Medicine and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota; and ²Department of Nutritional Science, Okayama Prefectural University, Okayama, Japan

Submitted 8 March 2005 ; accepted in final form 11 June 2005

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 NO synthase (NOS), including asymmetric dimethylarginine. Coronary blood flow and the endothelium-dependent vasodilator response to acetylcholine were studied in dogs in which CHF was produced by rapid ventricular pacing for 4 wk. Coronary flow and myocardial O₂ consumption at rest and during treadmill exercise were decreased after development of CHF, and the vasodilator response to intracoronary acetylcholine (75 µg/min) was decreased by 39 ± 5%. DDAH activity and DDAH isoform 2 (DDAH-2) protein content were decreased by 53 ± 13% and 58 ± 14%, respectively, in hearts with CHF, whereas endothelial NOS and DDAH isoform 1 (DDAH-1) were increased. Caveolin-1 and protein arginine N-methyltransferase 1, the enzyme that produces asymmetric dimethylarginine, were unchanged. Immunohistochemical staining showed DDAH-1 strongly expressed in coronary endothelium and smooth muscle and in the sarcolemma of cardiac myocytes. In cultured human endothelial cells, DDAH-1 was uniformly distributed in the cytosol and nucleus, whereas DDAH-2 was found only in the cytosol. Decreased DDAH activity and DDAH-2 protein expression may cause accumulation of endogenous inhibitors of endothelial NOS, thereby contributing to endothelial dysfunction in the failing heart.

nitric oxide; pacemaker; heart failure; exercise

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