Cardiomyocyte-Specific Knockout and Agonist of Peroxisome Proliferator–Activated Receptor-γ Both Induce Cardiac Hypertrophy in Mice

Abstract

Peroxisome proliferator–activated receptor (PPAR)-γ is required for adipogenesis but is also found in the cardiovascular system, where it has been proposed to oppose inflammatory pathways and act as a growth suppressor. PPAR-γ agonists, thiazolidinediones (TZDs), inhibit cardiomyocyte growth in vitro and in pressure overload models. Paradoxically, TZDs also induce cardiac hypertrophy in animal models. To directly determine the role of cardiomyocyte PPAR-γ, we have developed a cardiomyocyte-specific PPAR-γ–knockout (CM-PGKO) mouse model. CM-PGKO mice developed cardiac hypertrophy with preserved systolic cardiac function. Treatment with a TZD, rosiglitazone, induced cardiac hypertrophy in both littermate control mice and CM-PGKO mice and activated distinctly different hypertrophic pathways from CM-PGKO. CM-PGKO mice were found to have increased expression of cardiac embryonic genes (atrial natriuretic peptide and β-myosin heavy chain) and elevated nuclear factor κB activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-γ, whereas rosiglitazone induced phosphorylation of extracellular signal–related kinase 1/2 in the heart dependent of PPAR-γ. Phosphorylation of c-Jun N-terminal kinases was not affected by rosiglitazone or CM-PGKO. Surprisingly, despite hypertrophy, Akt phosphorylation was suppressed in CM-PGKO mouse heart. These data show that cardiomyocyte PPAR-γ suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor κB activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR-γ in cardiomyocytes and through different mechanisms from CM-PGKO.