Novel mechanisms of vascular-specific peroxisome proliferator-activated receptor gamma in hypertension and atherosclerosis

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor of increasing importance in cardiovascular physiology. Treatment of type II diabetes patients with thiazolidinediones (TZD), synthetic ligands of PPARγ, improves insulin sensitivity and also lowers blood pressure despite increased water and salt retention by the kidneys. In 1999, Stephen O’Rahilly’s group reported that patients carrying mutations in PPARγ exhibit severe type II diabetes and early-onset hypertension. The missense mutations in PPARγ (e.g. V290M, P467L) affect the ligand-binding domain and render the transcription factor dominant negative (DN). These findings suggested that PPARγ activation plays a vital role in cardiovascular regulation but they did not differentiate whether the cardiovascular protective effects of TZDs result from systemic metabolic changes or direct actions of PPARγ in the vasculature. To answer this, our group generated transgenic mice that express DN PPARγ specifically in vascular endothelial or vascular smooth muscle cell types. Herein we are reporting the molecular and physiological mechanism linking mutation of PPARγ to impaired vascular function leading to hypertension. Smooth muscle-specific expression of DN PPARγ in transgenic mice causes increased arterial pressure and enhanced agonist-mediated contraction and blunting of nitric oxidemediated relaxation in aorta via a RhoA/Rho-kinase-dependent mechanism. Our results demonstrate that interference with PPARγ in smooth muscle impairs Cullin-3 RING E3 ubiquitin ligase-mediated regulation of RhoA/Rho-kinase signaling and identify Cullin-3 as a novel regulator of vascular function.