Abstract 15948: Transgenic Overexpression of Dimethylarginine Dimethylaminohydrolase 1 Protects From Angiotensin II - Induced Cardiac Hypertrophy and Vascular Remodeling

BackgroundDimethylarginine dimethylaminohydrolase 1 (DDAH1) hydrolyzes the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA). In animal models DDAH1 overexpression has been shown to lower ADMA levels and to protect from renal interstitial fibrosis and vascular oxidative stress in angiotensin-II-induced hypertension. DDAH1 is also suggested to have ADMA-independent effects. The current study was designed to test the hypothesis that DDAH1 overexpression protects from angiotensin II-induced cardiac hypertrophy and vascular remodeling.Methods and ResultsAngiotensin II (AngII) was infused in two doses (0.75 and 1.5 mg/kg/day) in DDAH1 transgenic mice (TG) and wild type (WT) littermates via osmotic minipumps. Echocardiography was performed in the first and fourth week of the infusion, systolic blood pressure was measured by the tail-cuff method and cardiac hypertrophy and vascular remodeling was assessed by histology after 4 weeks of AngII infusion. TG mice had decreased plasma and tissue ADMA levels. Infusion of AngII resulted in an increase in systolic blood pressure, which was similar between TG and WT mice at week 1, however, TG mice were protected from a further increase in blood pressure. 4 weeks of AngII infusion resulted in significantly higher left ventricular lumen to wall ratio, smaller size of cardiomyocytes and reduced amount of myocardial collagen in the TG mice as compared to WT littermates. TG mice had lower left ventricular posterior wall thickness in systole and diastole as compared to WT controls. The vasomotor function of aortic rings in response to acetylcholine was improved in the TG mice as compared to the WT mice. TG mice had less aortic hypertrophy and fibrosis and more elastin in aorta as compared to WT mice. Aortic infiltration of CD45, CD3, CD8 and CD4 T-cells was significantly lower in TG than in WT mice.ConclusionThis study shows that upregulation of DDAH1 protects from AngII-induced cardiac hypertrophy and vascular remodeling. Upregulation of DDAH1 might be a potential therapeutic approach for protection from AngII - induced end organ damage. We are currently investigating, whether protective effects of DDAH1 are ADMA-dependent, ADMA-independent or both.