Scavenger Receptor BI and Endothelial Nitric Oxide Synthase Work Cooperatively to Prevent Endothelial Cell Dysfunction

Mice deficient in scavenger receptor class BI (SR-BI) or endothelial nitric oxide synthase (eNOS) develop atherosclerosis, however mice over expressing SR-BI or eNOS also develop atherosclerosis, indicating that balanced expression of SR-BI or eNOS is essential for preventing atherosclerosis. We recently identify a novel apoptotic pathway in endothelial cells that is induced by SR-BI and specifically suppressed by eNOS. We also show that SR-BI stimulates eNOS to produce 5 folds more nitric oxide. The dramatic increase in nitric oxide level, especially in caveolae, can be a problem because nitric oxide can cause cell damage at high levels. Interestingly, our preliminary data show that SR-BI efficiently prevents nitric oxide-induced cell death. These data indicate that SR-BI and eNOS work together in a co-regulatory manner. The goal of this proposal is to elucidate how SR-BI and eNOS regulate each other, and their respective contribution in preventing endothelial cell dysfunction. Our hypothesis is: SR-BI and eNOS work cooperatively through a novel SR-BlleNOS apoptotic pathway and a SR-Bl/nitric oxide scavenger pathway to prevent vascular endothelial cell dysfunction. We will perform binding assays and apoptotic assays using in vitro cell lines expressing mutant SR-BI and primary endothelial cells from genetically manipulated mice. We will also perform in situ assays using aorta from genetically manipulated mice to test the following specific aims: Aim 1) To elucidate the mechanism of how eNOS turns off SR-BI-induced apoptosis in healthy cells; Aim 2) To elucidate the mechanism of how eNOS turns on SR-BI-induced apoptosis in damaged cells; Aim 3) To elucidate the mechanism of how SR-BI prevents nitric oxide-induced cell damage. Atherosclerosis is a multi-genes-controlled complex disease and vascular endothelial cell dysfunction is the earliest signs of developing atherosclerosis. The unique part of this proposal is that we provide evidence to show that two caveolae proteins, SR-BI and eNOS, are linked by two different pathways. Understanding the novel SR-BlleNOS apoptotic pathway and SR-Bllnitric oxide scavenger pathway will provide insight into the mechanisms of atherosclerosis and reveal novel targets for disease intervention.