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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL075397-04
Application #
7385784
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2007-04-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$346,658
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hamblin, Milton; Chang, Lin; Zhang, Hengmin et al. (2011) Vascular smooth muscle cell peroxisome proliferator-activated receptor-? mediates pioglitazone-reduced vascular lesion formation. Arterioscler Thromb Vasc Biol 31:352-9
Yin, Ke-Jie; Deng, Zhen; Hamblin, Milton et al. (2011) Vascular PPAR? protects against stroke-induced brain injury. Arterioscler Thromb Vasc Biol 31:574-81
Yin, Ke-Jie; Deng, Zhen; Hamblin, Milton et al. (2010) Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J Neurosci 30:6398-408
Schopfer, Francisco J; Cole, Marsha P; Groeger, Alison L et al. (2010) Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions. J Biol Chem 285:12321-33
Hamblin, Milton; Chang, Lin; Zhang, Hengmin et al. (2010) Vascular smooth muscle cell peroxisome proliferator-activated receptor-? deletion promotes abdominal aortic aneurysms. J Vasc Surg 52:984-93
Zhang, Jifeng; Villacorta, Luis; Chang, Lin et al. (2010) Nitro-oleic acid inhibits angiotensin II-induced hypertension. Circ Res 107:540-8
Guo, Xin; Xu, Kefeng; Zhang, Jifeng et al. (2010) Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor gamma activation in mice. J Biol Chem 285:23711-20
Chang, Lin; Villacorta, Luis; Zhang, Jifeng et al. (2009) Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension. Circulation 119:2161-9
Hamblin, Milton; Chang, Lin; Fan, Yanbo et al. (2009) PPARs and the cardiovascular system. Antioxid Redox Signal 11:1415-52
Villacorta, Luis; Schopfer, Francisco J; Zhang, Jifeng et al. (2009) PPARgamma and its ligands: therapeutic implications in cardiovascular disease. Clin Sci (Lond) 116:205-18

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