Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice.
Peroxisome proliferator-activated receptor (PPAR)-gamma 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-gamma 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-gamma, we have developed a cardiomyocyte-specific PPAR-gamma-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 beta-myosin heavy chain) and elevated nuclear factor kappaB activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-gamma, whereas rosiglitazone induced phosphorylation of extracellular signal-related kinase 1/2 in the heart dependent of PPAR-gamma. 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-gamma suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor kappaB activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR-gamma in cardiomyocytes and through different mechanisms from CM-PGKO.
Duan
Sheng Zhong
SZ
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ivashchenko
Christine Y
CY
Russell
Mark W
MW
Milstone
David S
DS
Mortensen
Richard M
RM
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D000077154:Rosiglitazone; D013599:Systole; D045162:Thiazolidinediones / Q000494:pharmacology*
D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains