Abnormal endothelial function plays a key role in the pathophysiology of several vascular diseases. The overall 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 non-macrophage vascular cells, and transduce immune responses to several inflammatory mediators. Fourth, impairment of antioxidant mechanisms, including extracellular and manganese superoxide dismutases, may be of great importance in vascular disease. Fifth, accelerated thrombosis in atherosclerotic mice is produced by oxidative inactivation of thrombomodulin and decreased activation of the anticoagulant protein C. Sixth, peroxisome proliferator activated receptor gamma may modulate vascular function and atherogenesis through activation and repression of target genes in the blood vessel wall. The Program consists of four projects and an administration core, which includes a bioinformatics section. The investigators integrate pharmacological approaches, state-of-the-art molecular approaches, sophisticated physiological measurements in mice, 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 of the Program is to contribute to better understanding of oxidative and inflammatory mechanisms of vascular diseases, to allow translation into improved treatment of atherosclerosis and other vascular diseases.
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