Abstract 1671: DDAH1 Overexpression Suppresses Plaque Formation in ApoE-Deficient Mice by Lowering ADMA Levels
To evaluate the impact of the endogenous nitric-oxide synthase inhibitor asymmetric dimethylarginine (ADMA) on atherosclerotic lesion formation, plaque burden was analyzed in ApoE-deficient mice with or without transgenic overexpression of the ADMA degrading enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1). Plaque formation within the entire aorta (Sudan IV stained en-face preparations) was analyzed in male and female ApoE-deficient mice with or without overexpression of the human DDAH1 transgene kept on a standard rodent chow (n = 57; sacrifice at 12 months) or on an atherosclerotic diet (currently n = 31; sacrifice at 7 months) to accelerate lesion formation. Plasma ADMA levels were significantly lower in DDAH1 transgenic mice (p < 0.01). Overexpression of DDAH1 was associated with reduced plaque formation in male ApoE-deficient mice on standard chow (7.6% vs. 12.4% of aortic surface, p = 0.002) and a trend towards reduced atherosclerosis in female mice (8.8% vs. 10.5%, p = 0.11). The degree of atherosclerosis significantly correlated with ADMA levels (r = 0.52, p = 0.004) and albuminuria (r = 0.58, p = 0.001) in male but not female mice kept on standard rodent chow. Under an atherogenic diet overexpression of DDAH1 also reduced plaque formation in female ApoE-deficient mice (16.8% vs. 22.8%, p = 0.005, examples see figure⇓). Overexpression of DDAH1 reduces plaque burden in ApoE-deficient mice. Our findings suggest a causal role for ADMA as a culprit in atherosclerotic vascular disease.