Interference with PPAR [gamma] Function in Smooth Muscle Causes Vascular Dysfunction and Hypertensio.pdf

Cell Metabolism ArticleInterference with PPARg Function in Smooth Muscle Causes Vascular Dysfunction and Hypertension Carmen M. Halabi,1 Andreas M. Beyer,1 Willem J. de Lange,2 Henry L. Keen,2 Gary L. Baumbach,4 Frank M. Faraci,2,3 and Curt D. Sigmund2,5,6,* 1Genetics Program 2Department of Internal Medicine 3Department of Pharmacology 4Department of Pathology 5Department of Molecular Physiology and Biophysics 6Center for Functional Genomics of Hypertension Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA *Correspondence: curt-sigmund@ DOI 10.1016/j.cmet.2007.12.008SUMMARY Peroxisome proliferator-activated receptor g (PPARg) is a ligand-activated transcription factor that plays a critical role in metabolism. Thiazolidinediones, high-affinity PPARg ligands used clinically to treat type II diabetes, have been reported to lower blood pressure and provide other cardiovascular benefits. Some mutations in PPARg (PPARG) cause type II diabetes and severe hypertension. Here we tested the hypothesis that PPARg in vascular muscle plays a role in the regulation of vascular tone and blood pressure. Transgenic mice expressing dominant- negative mutations in PPARg under the control of a smooth-muscle-specific promoter exhibit a loss of responsiveness to nitric oxide and striking alterations in contractility in the aorta, hypertrophy and inward remodeling in the cerebral microcirculation, and sys- tolic hypertension. These results identify PPARg as pivotal in vascular muscle as a regulator of vascular structure, vascular function, and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones. INTRODUCTION The incidence of obesity and diabetes and their consequent cardiovascular sequelae has reached epidemic proportions, jus- tifying the enormous effort to identify pathways and molecules involved in their pathogenesis. One molecule that has emerged at the crossroads of metabolic and cardiovascular