The problem of obesity is reaching epidemic proportions in both children and adults in the United States and poses a major public health problem by predisposing individuals to cardiovascular disease. However, the molecular determinants that mediate obesity-related vascular disease remain to be further defined. Emerging data suggest that transcription factors such as the peroxisome proliferator-activated receptors (PPARs), provide a molecular link between fatty acids within the cellular environment and the regulation of gene transcription. Although the """"""""vasculo-protective"""""""" effects of PPARalpha and PPARgamma activation are relatively well defined, the role of PPAR delta in vascular biology is poorly understood. Our preliminary data documents that PPARdelta expression is up-regulated in arteries of genetically obese mice in association with hypertrophic vascular remodeling. Moreover, we have demonstrated that growth-stimulatory and antiapoptotic factors such as PDGF and angiotensin II stimulate PPARdelta gene expression in vascular smooth muscle cells (VSMC). In contrast to the """"""""vasculo-protective"""""""" role of PPARalpha and PPARgamma, our preliminary data supports the working hypothesis that PPARdelta functions as a countervailing PPAR transcriptional factor that promotes obesity-induced hypertrophic vascular remodeling by stimulating VSMC growth and inhibiting VSMC apoptosis. This hypothesis will be tested by systematically implementing both a loss- and gain-of-function strategy in both in vitro and in vivo model systems. The proposed project will exploit our access to a unique set of pharmacologic probes and genetic model systems to achieve vascular-selective up-regulation or deletion of the PPARdelta transcriptional pathway in VSMC. This experimental approach will enable us to characterize the role of the PPARdelta pathway as an essential mediator of obesity-induced vascular disease. Specifically, we will: 1). Determine the essential mediator role of PPARdelta in the regulation of VSMC proliferation in cell culture models; 2). Define the essential role of the PPARdleta-ILK/PDK1-Akt pathway in the regulation of VSMC apoptosis in cell culture models; 3). Define the essential role of PPARdelta as a """"""""vasculopathic"""""""" determinant in obesity-related vascular disease in vivo. ? ?
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