The prevalence of Type 2 diabetes mellitus increases dramatically with age. Atherosclerosis accounts for about 80% of all deaths from Type 2 diabetes. The explanation of the enhanced susceptibility to atherfosclerotic disease in diabetes remains a matter of contention. Unfortunately, interventional strategies to reduce or prevent macrovascular complications have only recently received the needed attention and will require considerable effort and resources to improve the clinical outcomes and life expectancies for these patients. Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor superfamily of transcription factors that controls the expression of a large array of genes implicated in the development of both diabetes and atherosclerosis. Although it has been demonstrated that activation of PPAR-gamma lowers blood lipids, improves insulin sensitivity, and improves glucose homeostasis, accumulating evidence suggests that PPAR-gamma may also play an important role in reducing vascular inflammation. The objective of this study is to determine actions of PPAR-gamma on the inflammatory response in artery wall associated with diabetes. To achieve this objective, we will test the following overall hypothesis: PPAR-gamma prevents or attenuates vascular inflammation in diabetic vasculopathy. To test this hypothesis, we will pursue the following two specific aims: 1) Assess the effects of PPAR -gamma agonists on vascular endothelial cell activation by determining (a) expression of vascular endothelial cell adhesion molecules and (b) activation of NF-KB in a Type 2 diabetic model; 2) Determine the effects of PPAR-gamma agonists on vascular endothelial layer permeability in a Type 2 diabetic model. We expect to find that up-regulation of PPAR-gamma will prevent or attenuate the endothelial inflammatory response by negatively interfering with the NF-KB signaling pathway, thereby decreasing production of endothelial cell adhesion molecules. Reduction in endothelial cell activation also will decrease vascular endothelial layer permeability. Our long-term goal is to identify the early factors involved in the development of atherosclerosis associated with diabetes. The exact role of PPAR-gamma agonists on vascular inflammation is currently unknown. Insights into these mechanisms may provide possible therapeutic interventions for diabetic vasculopathy and other vascular diseases.
