: It is postulated that pathological changes in vessel structure are regulated by transcription factors that govern cell growth, death, differentiation, inflammation and matrix production. Recent findings indicate that the ligand-activated nuclear transcriptional factor, peroxisome proliferator-activated receptor-y (PPARy), may provide a critical link between obesity, diabetes, hypertension and vascular complications. Indeed, the profound clinical implications of this pathway is indicated by the fact that the thiazolidinedione (TZD) class of antidiabetic drugs are now recognized as synthetic ligands of PPARy. Moreover, studies in our laboratory and others using these TZD ligands suggest that PPARy activation reduces vascular lesion formation by inhibiting growth promoting pathways as well as genes involved in matrix production. However, the actual role of PPARy as a determinant of vascular function and structure remains controversial based on data documenting PPARy independent effects of TZD administration. This proposal will address this controversy by using both novel pharmacologic probes and genetic approaches to elucidate the mediator role of PPARy in vascular disease. The proposed project will test the central hypothesis that the transcription factor PPARy governs a coordinated genetic program that functions as an endogenous inhibitor of vascular lesion formation. Specifically, it is postulated that cytokines expressed in response to vascular injury induce an up-regulation of PPARy expression and that PPARy mediates the transactivation of genes that exert a countervailing inhibitory effect on VSMC growth and matrix production.
Our specific aims are: 1) Determine the transcriptional regulatory mechanisms by which TNFa and PDGF induce PPARy1 gene expression in VSMC using a unique PPARy1 promoter fragment that we have cloned, 2) Determine the mediator role of PPARy in the regulation of VSMC proliferation and matrix production in cell culture models using novel pharmacologic probes and genetic strategies to selectively inhibit PPARy activation, and 3) Determine the mediator role of PPARy during lesion formation by studying transgenic mice with either vascular-specific, up-regulation or deletion of PPARy.
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