Endothelial nitric oxide synthase (eNOS) and cyclooxygenases (COX-1 and COX-2) are key enzymes that catalyze the synthesis of vasoprotective nitric oxide (NO) and prostacyclin (PGI2), respectively. our preliminary data show that lysophosphatidylcholine (lysoPC), induces the expression of eNOS and COX-2. We postulate that lysoPC induces these two different genes by distinct transcriptional mechanisms. We further postulate that the cardiovascular protective effects of estrogen are mediated by induction of eNOS and COX-2. Furthermore, the eNOS activity is regulated by vasoactive agents. To test these hypotheses, we propose three specific aims: (1) to elucidate differential transcriptional activation mechanisms by lysoPC; (2) to evaluate the effects of estrogen on eNOS and COX-2 expression; and (3) to determine eNOS structure-activity relationship and regulation. We will use strategies which strategies which encompass biochemical, cell and molecular biology, structural biology and molecular genetic approaches to achieve the goal of each specific aim. These experiments should yield important information regarding the fundamental processes of injury-coupled vasoprotection. They will enhance our understanding about the vasoprotective properties of estrogen. Furthermore, results from this project should shed light on the regulation of eNOS activity by biochemical processes that influence stability and calmodulin. Overall, this project should have a major impart on research pertaining to basic eNOS and COX research and vascular cerebral pathophysiology.
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