Dominant negative PPAR? promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle.

ABSTRACT: Agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?) have potent insulin-sensitizing effects and inhibit atherosclerosis progression in patients with Type II diabetes. Conversely, missense mutations in the ligand-binding domain of PPAR? that render the transcription factor dominant negative (DN) cause early-onset hypertension and Type II diabetes. We tested the hypothesis that DN PPAR?-mediated interference of endogenous wild-type PPAR? in the endothelium and vascular smooth muscle exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. Endothelium-specific expression of DN PPAR? on the ApoE(-/-) background unmasked significant impairment of endothelium-dependent relaxation in aortic rings, increased systolic blood pressure, altered expression of atherogenic markers (e.g., Cd36, Mcp1, Catalase), and enhanced diet-induced atherosclerotic lesion formation in aorta. Smooth muscle-specific expression of DN PPAR?, which induces aortic dysfunction and increased systolic blood pressure at baseline, also resulted in enhanced diet-induced atherosclerotic lesion formation in aorta on the ApoE(-/-) background that was associated with altered expression of a shared, yet distinct, set of atherogenic markers (e.g., Cd36, Mcp1, Osteopontin, Vcam1). In particular, induction of Osteopontin expression by smooth muscle-specific DN PPAR? correlated with increased plaque calcification. These data demonstrate that inhibition of PPAR? function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease.

SUBMITTER: Pelham CJ 

PROVIDER: S-EPMC3652079 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature