DDAH1 effects on endogenous NOS inhibitors and vascular endothelial function

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DESCRIPTION (provided by applicant): Accumulation of the endogenous NO synthase (NOS) inhibitors asymmetric dimethyl arginine (ADMA) and Ng-monomethyl-L-arginine (L-NMMA) is a major risk factor for cardiovascular diseases including hypertension, coronary artery disease, stroke, diabetes and atherosclerosis. These endogenous NOS inhibitors compete with L-arginine to inhibit NO production by NOS. ADMA and L-NMMA are eliminated principally by dimethylarginine dimethylaminohydrolase (DDAH) with a small contribution from renal excretion. It is reported that ADMA and L-NMMA are degraded by both DDAH1 and DDAH2, but the relative contributions of DDAH1 and DDAH2 have been controversial. Furthermore, whether DDAH1 can exert effects on vascular function beyond regulation of NO production is unknown. Using novel tissue specific DDAH1 deficient mice and global DDAH1 gene deficient mice generated in our laboratory, our preliminary data demonstrate that DDAH1 plays an essential role in degrading the endogenous NOS inhibitors, and that DDAH1 distributed in endothelial cells plays an important role in regulating vascular endothelial NO production and endothelial cell growth and injury repair. Most interestingly, our preliminary data further demonstrated that DDAH1 also regulates endothelial cell function through a novel molecular pathway independent of degradation the of endogenous NOS inhibitors. Based on these new findings, we propose to test two hypotheses. First, we hypothesize that DDAH1 is the principal enzyme responsible for degrading ADMA and L-NMMA. Second, we hypothesize that DDAH1 exerts additional actions beyond its role in degrading ADMA and L-NMMA that regulate vascular endothelial cell growth and injury repair. To test these hypotheses, we have generated a novel tissue specific endothelial-DDAH1 KO (endo-DDAH1 KO) mouse strain and a global DDAH1 KO mouse strain. The proposed studies will utilize in vitro and in vivo approaches to provide new insight into the function of the endogenous NOS inhibitors, as well as novel molecular mechanisms by which DDAH1 acts to maintain vascular endothelial cell growth and injury repair. PUBLIC HEALTH RELEVANCE: Accumulation of the endogenous nitric oxide synthase (NOS) inhibitors asymmetric dimethyl arginine (ADMA) and Ng-monomethyl-L-arginine (L-NMMA) is a major risk factor for cardiovascular diseases including hypertension, coronary artery disease, stroke, diabetes and atherosclerosis. DDAH1 degrades ADMA and L-NMMA to increase nitric oxide production. The proposed studies will integrate in vitro and in vivo approaches to provide new insight into the function of the endogenous NOS inhibitors, as well as novel molecular mechanisms by which DDAH1 acts to maintain vascular endothelial cell growth and injury repair.