Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice

J Clin Invest. 2007 Oct;117(10):2791-801. doi: 10.1172/JCI30335.

Abstract

Three forms of PPARs are expressed in the heart. In animal models, PPARgamma agonist treatment improves lipotoxic cardiomyopathy; however, PPARgamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARgamma on heart function, we created transgenic mice expressing PPARgamma1 in the heart via the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. PPARgamma1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARalpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARgamma1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARgamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Animals
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology
  • Fatty Acids / metabolism
  • Gene Expression
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Glycogen / metabolism
  • Heart / physiopathology
  • Lipid Metabolism* / genetics
  • Mice
  • Mice, Transgenic
  • PPAR gamma / agonists
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Promoter Regions, Genetic / genetics
  • Rosiglitazone
  • Thiazolidinediones / pharmacology
  • Ventricular Myosins / genetics

Substances

  • Fatty Acids
  • Glucose Transporter Type 4
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone
  • Glycogen
  • Ventricular Myosins
  • Glucose