Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice

Three forms of PPARs are expressed in the heart. In animal models, PPAR gamma agonist treatment improves lipotoxic cardiomyopathy; however, PPAR gamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPAR gamma on heart function, we created transgenic mice expressing PPAR gamma 1 in the heart via the cardiac cc-myosin heavy chain (alpha-MHC) promoter. PPAR gamma 1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPAR alpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPAR gamma 1-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 PPAR gamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.