In the past 10 years, specific roles of peroxisome proliferator-activated receptor (PPAR) alpha and PPAR-gamma have emerged as important determinants of vascular function and structure. Although PPAR-delta (also known as PPAR-beta and NUC-l) is widely expressed in many tissues, the role of PPAR-delta is poorly understood. Our preliminary studies have documented for the first time that PPAR-delta is expressed in vascular smooth muscle cells (VSMCs) and up-regulated after vascular injury. In addition, we demonstrated that stable over expression of PPAR-delta in rat VSMC promotes cell proliferation. Furthermore, we observed that PDGF and TNF-alpha up-regulate PPAR-delta gene expression in VSMC. These intriguing results indicate that the up-regulation of PPAR-delta gene expression may play an important role during vascular lesion formation. The proposed project will test the central hypothesis that cytokines and growth factors expressed in response to vascular injury induce an up-regulation of PPAR-delta expression; the increase in this transcription factor may promote neointima formation by increasing VSMC proliferation.
Our specific aims are: 1) Determine the transcriptional regulatory mechanisms by which TNF-alpha and PDGF induce PPAR-delta gene expression in VSMC, 2) Determine the mediator role of PPAR-delta in the regulation of VSMC proliferation in cell culture models, and 3) Determine the mediator role of PPAR-delta as an endogenous promoter of lesion formation in vivo.
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