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(Circulation Research. 2005;97:372.)
© 2005 American Heart Association, Inc.

Integrative Physiology

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

Sheng Zhong Duan, Christine Y. Ivashchenko, Mark W. Russell, David S. Milstone, Richard M. Mortensen

From the Department of Pharmacology (S.Z.D., R.M.M.), Department of Molecular and Integrative Physiology (S.Z.D., C.Y.I., R.M.M.), Department of Pediatrics and Communicable Diseases (M.W.R.), and the Metabolism Endocrinology and Diabetes Division (R.M.M.), Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; and the Vascular Research Division (D.S.M.), Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Richard M. Mortensen, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109. E-mail rmort{at}umich.edu; or Dr David S. Milstone, E-mail milstone@rascal.med.harvard.edu

Peroxisome proliferator–activated receptor (PPAR)- 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- 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-, we have developed a cardiomyocyte-specific PPAR-–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 ß-myosin heavy chain) and elevated nuclear factor B activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-, whereas rosiglitazone induced phosphorylation of extracellular signal–related kinase 1/2 in the heart dependent of PPAR-. 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- suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor B activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR- in cardiomyocytes and through different mechanisms from CM-PGKO.

Key Words: peroxisome proliferator–activated receptor- • thiazolidinediones • cardiac hypertrophy • cardiomyocytes • knockout

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