PPG - Oxidative Mechanisms in Vascular Disease

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DESCRIPTION (provided by applicant): Abnormal endothelial function plays a key role in the pathophysiology of several vascular diseases. Theoverall theme of this Program is mechanisms of endothelial dysfunction in atherosclerosis and hypertension,with emphasis on the balance between oxidative and antioxidant mechanisms, and between inflammation and anti-inflammatory mechanisms. Better understanding of oxidative injury and inflammation will be needed before these exciting areas of research can be translated into effective treatment for atherosclerosis and other vascular diseases.Studies are proposed to examine several novel hypotheses. The goals are tightly focused and cohesive.First, angiotensin II may contribute to hypertension, in substantial part, by oxidative and inflammatory mechanisms. Second, interleukin-10 is an important anti-inflammatory cytokine which may protect against vascular disease, including hypertension. Third, an innate immune response may be generated by nonmacrophagevascular cells, and transduce immune responses to several inflammatory mediators. Fourth, impairment of antioxidant mechanisms, including extracellular and manganese superoxide dismutases and glutathione peroxidase, may be of great importance in vascular disease. Fifth, accelerated thrombosisin atherosclerotic mice is produced by decreased bioavailability of endothelium-derived nitric oxide and decreased activation of the anticoagulant protein C. Sixth, peroxisome proliferator activated receptor(PPARv) may modulate vascular function and atherogenesis through activation and repression of target genes in the blood vessel wall. The Program consists of five projects and an administrative core. The investigators integrate pharmacological approaches, state-of-the-art molecular approaches, sophisticated physiological measurements inmice, and novel genetically altered mice in each project. There is a sustained record of excellent productivity with close collaboration among the investigators, within an outstanding environment. The long-term goal oft he Program is to contribute to better understanding of oxidative and inflammatory mechanisms in vascular diseases, to allow translation into improved treatment of atherosclerosis and other vascular diseases. (End of Abstract).