Overexpression of dimethylarginine dimethylaminohydrolase inhibits asymmetric dimethylarginine-induced endothelial dysfunction in the cerebral circulation

Background and Purpose-Asymmetric dimethylarginine ( ADMA) is an endogenous inhibitor of nitric oxide synthase ( NOS). An elevation of plasma ADMA levels is associated with cardiovascular disease. ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1-Tg) mice inhibits the vascular effects of ADMA. Methods-Using nontransgenic (non-Tg) and DDAH-1-Tg mice, we compared responses of the carotid artery and aorta ( in vitro) and of the cerebral arterioles ( in vivo) in the absence or presence of ADMA. DDAH-1 expression and plasma levels of ADMA were also measured. Results-Western blotting indicated that vascular expression of DDAH-1 was increased markedly in DDAH-1-Tg mice. Plasma levels of ADMA were reduced by approximate to 50% in DDAH-1-Tg mice compared with non-Tg mice ( 0.19 +/- 0.02 vs 0.37 +/- 0.04 mu mol/L, P < 0.05). Contraction of the aorta to nitro-L-arginine methyl ester ( an inhibitor of NOS), an index of basal production of NO, was increased in DDAH-1-Tg mice compared with controls ( 50 +/- 4% vs 34 +/- 4%, P < 0.05). Relaxation of the carotid artery to acetylcholine ( an endothelium-dependent agonist) was enhanced in DDAH-1-Tg animals compared with control mice ( relaxation of 74 +/- 6% vs 59 +/- 5%, respectively, in response to 10 mu mol/L acetylcholine, P < 0.05). ADMA ( 100 mu mol/L) impaired the vascular response to acetylcholine in both non-Tg and DDAH-1-Tg mice, but the relative difference between the 2 strains remained. Responses to the endothelium-independent NO donor nitroprusside were similar in all groups. In vivo, ADMA ( 10 mu mol/L) reduced responses of the cerebral arterioles to acetylcholine by approximate to 70% in non-Tg mice ( P < 0.05), and this inhibitory effect was largely absent in DDAH-1-Tg mice. Conclusions-These findings provide the first evidence that overexpression of DDAH-1 increases basal levels of vascular NO and protects against ADMA-induced endothelial dysfunction in the cerebral circulation.