EXCEED THE SPACE PROVIDED. Cardiovascular events such as myocardial infarction and stroke that result from atherosclerosis of major vessels remains the leading cause of death in the U.S. It has become clear that increased vascular reactive oxygen species (ROS; i.e., H202, 02-, and ..OH) represents a common pathogenic mechanism for atherosclerosis. A particularly important mechanism for ROS-mediated cardovascular disease appears to be via stimulation of pro-inflammatory events. In the proposed research we will investigate the role of a newly discovered class of ROS mediators that we term SOXF for Secreted Oxidative stress induced Factors. This proposal is the competing renewal for NIH RO1 HL49192 which has funded several studies of the role of ROS in cardiovascular physiology. The current proposal to focus on SOXF represents a logical and important extension of or previous studies. SOXF expression is induced by ROS, and SOXF are secreted in response to ROS. Our exciting preliminary data suggest that intracellular and extracellular SOXF contribute to atherosclerosis and inflammation via their abilities to promote EC apoptosis and EC _expression of leukocyte adhesion molecules, to stimulate monocyte and lymphocyte migration, and to increase proliferation of macrophages and vascular smooth muscle cells (VSMC). SOXF include cyclophilin A (CyPA), cyclophilin B (CyPB), and heat shock protein 90 (HSP90). We have focused on CyPA because of its strong regulation by ROS, its role as a leukocyte chemotactic factor and pro-inflammatory cytokine, and substantial prelinimary data that indicate CyPA is highly expressed in the vasculal lture, especially in atherosclerotic plaques. We have obtained CyPA knockout mice that will facilitate in vivo studies of the role CyPA in atherogenesis. Our major hypothesis is that ROS stimulation of CyPA expression and secretion contributes to the development and progresion of atherosclerosis.
Three aims are proposed. 1. Determine the mechanisms for secretion of CyPA from VSMC and EC. 2. Determine the effect of CyPA2 on atherosclerosis by evaluating the effect of CyPA overexpression on the pathology of the ApoE deficient mouse. 3. Determine the role of CyPA in atherosclerosis development and progression by evaluating the effect of EC and VSMC CyPA deficiency on atherosclerosis in the ApoE deficient mouse. These studies will provide new insight into the mechanisms by which ROS regulate vascular function and the specific role of CyPA in atherosclerosis. PERFORMANCE SITE ========================================Section End===========================================
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