Identification and Function of PPARy and PPARy Target Genes in the Blood Vessel

University Of Iowa, Iowa City IA

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Abstract

PPARgamma is a transcription factor of the nuclear hormone receptor subfamily that has been postulated to[unreadable] participate in a diverse range of diseases. PPARgamma is highly expressed in the adipocyte and its role in[unreadable] metabolism, particularly with regard to diabetes mellitus and insulin resistance has been extensively studied.[unreadable] However, an important role for PPARgamma in the blood vessel wall has only recently begun to emerge and be[unreadable] appreciated. PPARgamma agonists lower blood pressure, reduce expression of pro-inflammatory molecules in the[unreadable] vessel wall, and improve endothelial function suggests that PPARgamma normally exhibits an important vascular[unreadable] protective function. PPARgamma has also been implicated to play an important role in atherosclerosis. The central[unreadable] hypothesis of this proposal is that PPARgamma plays an important role in the regulation of vascular function, blood[unreadable] pressure and atherosclerosis through the activation and repression of target genes in the blood vessel wall.[unreadable] These target genes include, but are not restricted to genes encoding vasoactive substances, redox[unreadable] substances, and inflammatory molecules. We will take advantage of a robust experimental platform[unreadable] consisting of both bioinformatics and a series of novel genetic models to: 1) discover PPARgamma target genes in[unreadable] the vasculature, and 2) examine the protective role of PPARgamma expression in vascular smooth muscle and[unreadable] endothelial cells in atherosclerosis. To accomplish these goals we proposed the following specific aims: 1) to[unreadable] identify novel targets of PPARgamma in the vascular wall by using an integrated approach for prioritizing target[unreadable] gene selection that combines gene expression analysis using oligonucleotide microarrays with bioinformatics[unreadable] and computational analysis, and 2) to examine, the protective role of PPARgamma in endothelial and smooth[unreadable] muscle cells during the progression of atherosclerosis using genetic models generated in our laboratory[unreadable] targeting either wildtype or dominant negative mutants of PPARgamma to the vessel wall. Development of[unreadable] atherosclerosis and vessel dysfunction will be assessed in ApoE-/- mice and in response to angiotensin-ll in[unreadable] ApoE-/- mice. The establishment of these unique transgenic models will provide tools which will allow us for[unreadable] the first time to not only examine the importance of the PPARgamma pathway in the blood vessel wall to[unreadable] atherosclerosis, but also separate the effects of PPARgamma in the endothelium and vascular smooth muscle.