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 PPARdelta 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 V SMC proliferation in cell culture models; 2). Define the essential role of the PPARdelta-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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