Abstract 382: Transgenic Overexpression of Dimethylarginine Dimethylaminohydrolase 1 Protects From Angiotensin II-induced Cardiac Hypertrophy

Abstract

Background: ADMA (asymmetric dimethylarginine) is an endogenous inhibitor of nitric oxide synthase. ADMA can be metabolized to citrulline by dimethylarginine dimethylaminohydrolase (DDAH). DDAH1 overexpression lowers ADMA and protects from angiotensin II - induced renal interstitial fibrosis and vascular oxidative stress. The goal of the current study was to test the hypothesis that transgenic overexpression of DDAH1 protects from angiotensin II-induced cardiac hypertrophy. Methods and Results: DDAH1 transgenic mice grew and developed normally and had decreased plasma ADMA levels. Angiotensin II was infused for four weeks in the dose of 0.75 mg/kg/day in DDAH1 transgenic mice and wild type littermates via osmotic minipumps. Echocardiography was performed in the first and fourth week after start of the infusion on anaesthetized mice. After 4 weeks of angiotensin II infusion wild type mice developed cardiac hypertrophy. The DDAH1 transgenic mice had higher left ventricular lumen to wall ratio compared to the wild type mice (1.76 ± 0.18 vs 1.15 ± 0.22, P<0.01). They also had lower left ventricular posterior wall thickness in systole and diastole as compared to the wild type controls (1.18 ± 0.03 mm vs 1.95 ± 0.16 mm, P<0.001 and 0.81 ± 0.03 mm vs 1.62 ± 0.25 mm, P<0.001, respectively). Conclusion: We demonstrated that upregulation of DDAH1 protects from angiotensin II-induced cardiac hypertrophy. Our findings suggest that ADMA plays a role in angiotensin II - induced myocardial remodeling. Upregulation of DDAH1 might be a potential approach for protection from angiotensin II - induced end organ damage.