Survivin in Endothelial Hyperglycemia

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DESCRIPTION (provided by applicant): Dysfunction of the vascular endothelium is regarded as an important factor in the pathogenesis of diabetes. Hyperglycemia alters the features of endothelial cells by increasing the number of apoptotic cells and reducing their ability to proliferate. Survivin belongs to the inhibitor of apoptosis protein (IAP) family, which has been shown to be associated with anti-apoptosis, angiogenesis and carcinogenesis. Our laboratory and others have demonstrated that Survivin expression is attenuated by hyperglycemia in endothelial cells. We have recently identified Survivin binding proteins including sodium-glucose co-transporter-2 (SGLT-2), which binds to Survivin in endothelial cells under high-glucose condition. We hypothesize that attenuation of Survivin in hyperglycemic endothelial cells is caused by Survivin forming a complex with SGLT- 2 or other proteins. Two specific aims will be addressed: 1) To evaluate the role of Survivin and Survivin binding proteins in hyperglycemic endothelial cells by transducing adenoviral constructs with wild-type and dominant-negative Survivin, and to specify the Survivin binding proteins' potential ability to enhance apoptosis by interrupting Survivin. Specifically, to determine the mechanism of SGLT-2 binding and inhibiting expression and function of Survivin via blocking SGLT-2 by SGLT inhibitors and SGLT-2 SiRNA. 2) To examine the effect of attenuating Survivin on increasing apoptotic and decreasing angiogenic reactions in endothelial cells in a mouse model of diabetes (STZ-induced hyperglycemia in Survivin mice) and to evaluate effects of SGLT on Survivin's capacity by administering SGLT inhibitors. These studies will improve our understanding of the regulation and functional consequences of Survivin and have significant implications in protecting endothelial cells from hyperglycemia therapeutically.