Methylarginines and Vascular Injury

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The long term objective of this proposal is to establish Dimethyarginie Dimethylaminohydrolase (DDAH), the enyme responsible for methylarginine (MA) metabolism, as a key regulator of vascular function and the response to injury. Altered nitric oxide (NO) biosynthesis has been implicated in the pathogenesis of restenosis injury and it appears that accumulation of the endogenous nitric oxide synthase inhibitors, ADMA and NMMA, are responsible for the reduced NO generation observed in these conditions. We have shown that in both rabbit and rat models of balloon- mediated restenosis injury, vascular DDAH expression is significantly decreased with a concomitant increase in cellular MA levels. The overall hypothesis of this proposal is that the loss of DDAH expression/activity results in MA accumulation and decreased NO bioavailabilty with subsequent loss of the anti-proliferative anti-atherogenic properties afforded to the vascular wall by NO. To test this hypotheis we will pursue the following aims. In aim 1, we will define how modulation of DDAH affects methylarginine levels and subsequent NOS-derived NO and superoxide generation. In aim 2. we will determine the modulation of DDAH in vascular injury and its role in arterial remodeling. These studies will examine the effects of loss of DDAH expression on smooth muscle cell proliferation, migration and endothelial regeneration. In addition, using and AAV vector carrying the DDAH gene, we will determine whether DDAH over expression can modulate the vascular remodelling process and improve vascular function. The final aim will determine the role methylarginines in atherogenesis. Because DDAH is regulated by LDL, we will study the effects of DDAH over expression on the initiation and progression of atherosclerosis in the hyperlipidemic state. We believe that this project will establish DDAH as a critical component in the vascular response to injury and may serve as a novel therapeutic target in the treatment of vasculoproliferative disorders.