PKC Activation and Cardiovascular Disease in Diabetes

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DESCRIPTION (provided by applicant): Risk factors for cardiovascular disease (CVD) in type 1 diabetic patients (T1DM) include hyperglycemia, hyperlipidemia, renal dysfunction, oxidants, glycated lipids and proteins and other metabolic abnormalities. The pathologies of CVD in T1DM are similar to those of nondiabetic subjects, suggesting the risk factors accelerating CVD also present in T1DM. Activation of monocytes, endothelial cells (EC) and smooth muscle cells (SMC) are shown to be important for the development of atherosclerosis both in T1DM and nondiabetic patients. Protein kinase C (PKC) activation is important for promoting these cells into pro-atherogenic state. Many of the risk factors stated above, will activate PKC in monocytes and vascular cells. Thus, we propose that abnormal metabolites of glucose and lipids due to insulin deficiency will activate PKC, especially the beta isoforms, in monocytes, EC and SMC. This will result in the expression and secretion of proteins in favor of the formation of macrophages/foam cells, endothelial dysfunction, and SMC migration and proliferation. These alterations will further accelerate atherosclerosis in T1DM. To test this hypothesis definitively, we propose: l) to characterize the role of PKC alpha, beta, and delta isoforms in glucose-induced activation of monocytes, arterial EC and SMC. 2) to assess the role of PKC beta isoform activation in the development of atherosclerosis in apoE-KO mice by comparing the atherosclerotic lesions in :a) diabetic or nondiabetic apoE-KO mice with or without PKC beta inhibitor; b) offsprings (PKC beta 2 V-TgXapoE-KO) of mice with vascular-specific overexpression of PKC beta 2 (PKC beta 2 V-Tg) crossbred with apoE KO-mice; c) offsprings of PKC beta null mice (PKC beta-KO) crossbred with apoE-KO mice. 3) to make and characterize mice overexpressing PKC beta 2 isoform in monocytes using a monocyte CD68 promoter (PKC beta 2 M-Tg) with respect to retinal, renal and cardiac abnormalities in nondiabetic and diabetic state. We will crossbreed PKC beta 2 M-Tg mice with apoE KO mice to determine its effect on the development of atherosclerosis.