Adenoviral-mediated overexpression of DDAH improves vascular tone regulation

Dimethylarginine dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine (ADMA), an endogenously produced nitric oxide (NO) synthase inhibitor. In mammals, two isoforms of DDAH, DDAH1 and DDAH2, are expressed in the cardiovascular system, suggesting that ADMA concentrations are actively regulated in blood vessels, raising the possibility that cardiovascular metabolism of ADMA constitutes a novel mechanism for the regulation of NO production. The purpose of this study was to determine the role of DDAH-catalyzed asymmetric methylarginine metabolism in the regulation of vascular function. We developed adenoviral vectors for the expression of human DDAH1 and 2. Overexpression of DDAH1 or 2 in human umbilical vein endothelial cells (HUVEC) increases DDAH activity, reduces ADMA concentrations and increases NO production. Similarly, overexpression of DDAH1 or 2 in DDAH1+/ — mice carotid vessels increases NO production and attenuates the response to phenylephrine (PE), enhances acetylcholine (ACh) rela...