Genetic variations in peroxisome proliferator-activated receptor gamma expression affect blood pressure

Metabolic syndrome, a clustering of conditions including obesity, insulin resistance, and hypertension, is a risk factor for cardiovascular morbidity and mortality. Because peroxisome proliferator-activated receptor gamma (PPARgamma) regulates adipocyte differentiation and lipid metabolism and is the molecular target of a class of insulin sensitizers, genetic variants that alter Pparg gene expression are potential contributors to the metabolic syndrome. To test this possibility, we generated mice having 182% of the normal steady-state level of PPARgamma mRNA by replacing the 3'-UTR of the natural Pparg gene with that of the beta-globin gene, thereby stabilizing the Pparg transcripts. This increase in PPARgamma mRNA level had no apparent consequences in various physiological parameters, except that the mice repeatedly showed a trend toward lower blood pressures (by about 3 mm Hg) than their WT littermates. In contrast, the opposite trend, toward increased blood pressure, was observed in mice with genetically reduced levels of PPARgamma mRNA as a consequence of insertion of an allele with an mRNA-destabilizing sequence into the endogenous 3'-UTR of the Pparg gene. By combining 12 sets of blood pressure measurements in more than 350 mutant mice having PPARgamma expression levels varying from 28% to 182% and more than 280 WT littermates, we show that a 2-fold genetic increase (or decrease) in PPARgamma expression levels decreases (or increases) blood pressure by about 2.8 mm Hg. Thus, our experiments demonstrate that quantitative variants causing decreased Pparg expression are a potential causative risk factor for essential hypertension.