Extensive characterization of the human DDAH1 transgenic mice.

Overview

PURPOSE OF THE RESEARCH: Overexpression of the human dimethylarginine dimethylaminohydrolase type 1 (hDDAH1) gene was reported to have beneficial cardiovascular effects in mice. To date, it is unclear whether these effects are related to enhanced metabolic clearance of asymmetric dimethylarginine (ADMA) and l-N(G)-mono-methyl-l-arginine (l-NMMA) or increased DDAH1 expression and activity in cardiovascular tissues of hDDAH1 transgenic mice. PRINCIPAL RESULTS: DDAH activity (DDAH1+DDAH2) was found to be markedly increased in aortic and heart tissues but unaltered in liver and kidney tissues of hDDAH1 transgenic as compared to wild-type (WT) mice. In WT mice, DDAH activity was more abundant in liver and kidney as compared to aorta and heart, suggesting a possible ceiling effect of activity which was unsurpassed by hDDAH1 overexpression. MAJOR CONCLUSIONS: Overexpression of hDDAH1 in healthy mice does not result in an improved DDAH-metabolic capacity of kidney and liver under normal, i.e. unchallenged conditions. The most likely explanation for low ADMA and l-NMMA concentrations in hDDAH1 transgenic mice is a decreased release of ADMA from aorta, heart, and possibly other organs. The protective cardiovascular effects seen in these animals may therefore be related to an improved activity of the DDAH enzyme in the cardiovascular system and not be related to improved renal and hepatic clearance of ADMA and l-NMMA.