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January 2009 - March 2010

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University of Minnesota Twin Cities
Medical School
Department of Medicine

PI: Yingjie Chen

Effect of Endothelial DDAH1 Gene Deletion on the Development of Left Ventricular Disfunction

The asymmetric methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethylarginine (L-NMMA), are endogenous inhibitors of nitric oxide (NO) synthases (NOS) that competitively repress NO production. In addition, asymmetric methylarginines can cause NOS to produce superoxide anion rather than NO, a phenomenon described as NOS uncoupling, and thereby cause increased oxidative stress. High plasma asymmetric methylarginine levels are associated with cardiovascular disorders including hypertension, congestive heart failure, stroke, coronary disease, and atherosclerosis, and thus represent an important risk factor for cardiovascular disease. Elimination of asymmetric methylarginines from the body is mainly through metabolism by dimethylarginine dimethylaminohydrolase (DDAH). Two DDAH isoforms have been identified (DDAH1 and DDAH2), but most recent studies indicate that overall DDAH activity is mainly determined by DDAH1. Interestingly, it has been reported that global DDAH1 deletion is lethal. These researchers recently demonstrated that DDAH1 is predominantly expressed in vascular endothelial cells. In order to assess the effect of accumulation of asymmetric methylarginines on cardiovascular function, the researchers have developed an endothelial specific DDAH1 knockout mouse strain (endo-DDAH1-/-). The endo-DDAH1-/- mice have abolished DDAH1 expression in several tissues, increased plasma ADMA levels, and increased blood pressure at 3 months of age. The group is using this mouse model to test their hypothesis that chronic accumulation of asymmetric methylarginines caused by reduced DDAH activity contributes to aging-related cardiac hypertrophy and dysfunction. Recent studies have identified two important factors that appear to contribute to heart failure in response to pressure overload. One is impaired myocardial angiogenesis in the overloaded heart; the second is NOS uncoupling that increases myocardial oxidative stress. Both of these factors could be influenced by high levels of endogenous NOS inhibitors. Therefore, the group is evaluating the hypothesis that accumulation of asymmetric methylarginines in the endo-DDAH1-/- mice will attenuate NO signaling and impair myocardial angiogenesis, and will also induce NOS uncoupling and increase oxidative stress, and thereby exacerbate left ventricular dysfunction and heart failure in the pressure-overloaded heart.

Group Members

Xinli Hu, Research Associate
Zhongbing Lu, Research Associate