This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/4/372    most recent 01.RES.0000179226.34112.6dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Duan, S. Z. Articles by Mortensen, R. M. Search for Related Content PubMed PubMed Citation Articles by Duan, S. Z. Articles by Mortensen, R. M. Related Collections Cardiovascular Pharmacology Animal models of human disease Hypertrophy Type 2 diabetes

(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

This article has been cited by other articles:

				E. Caglayan, B. Stauber, A. R. Collins, C. J. Lyon, F. Yin, J. Liu, S. Rosenkranz, E. Erdmann, L. E. Peterson, R. S. Ross, et al. Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator-Activated Receptor {gamma} in Cardiac Fibrosis Diabetes, September 1, 2008; 57(9): 2470 - 2479. [Abstract] [Full Text] [PDF]

				C. Fang, J. Gu, F. Xie, M. Behr, W. Yang, E. D. Abel, and X. Ding Deletion of the NADPH-Cytochrome P450 Reductase Gene in Cardiomyocytes Does Not Protect Mice against Doxorubicin-Mediated Acute Cardiac Toxicity Drug Metab. Dispos., August 1, 2008; 36(8): 1722 - 1728. [Abstract] [Full Text] [PDF]

				C. P. Alibin, M. A. Kopilas, and H. D. I. Anderson Suppression of Cardiac Myocyte Hypertrophy by Conjugated Linoleic Acid: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS {alpha} AND {gamma} J. Biol. Chem., April 18, 2008; 283(16): 10707 - 10715. [Abstract] [Full Text] [PDF]

				S. Sena, I. R. Rasmussen, A. R. Wende, A. P. McQueen, H. A. Theobald, N. Wilde, R. O. Pereira, S. E. Litwin, J. P. Berger, and E. D. Abel Cardiac Hypertrophy Caused by Peroxisome Proliferator- Activated Receptor-{gamma} Agonist Treatment Occurs Independently of Changes in Myocardial Insulin Signaling Endocrinology, December 1, 2007; 148(12): 6047 - 6053. [Abstract] [Full Text] [PDF]

				G. Ding, M. Fu, Q. Qin, W. Lewis, H. W. Kim, T. Fukai, M. Bacanamwo, Y. E. Chen, M. D. Schneider, D. J. Mangelsdorf, et al. Cardiac peroxisome proliferator-activated receptor {delta} is essential in protecting cardiomyocytes from oxidative damage Cardiovasc Res, November 1, 2007; 76(2): 269 - 279. [Abstract] [Full Text] [PDF]

				C. Y. Ivashchenko, S. Z. Duan, M. G. Usher, and R. M. Mortensen PPAR-{gamma} knockout in pancreatic epithelial cells abolishes the inhibitory effect of rosiglitazone on caerulein-induced acute pancreatitis Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G319 - G326. [Abstract] [Full Text] [PDF]

				B. N. Finck and D. P. Kelly Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1 (PGC-1) Regulatory Cascade in Cardiac Physiology and Disease Circulation, May 15, 2007; 115(19): 2540 - 2548. [Full Text] [PDF]

				J. T. Crossno Jr., C. V. Garat, J. E. B. Reusch, K. G. Morris, E. C. Dempsey, I. F. McMurtry, K. R. Stenmark, and D. J. Klemm Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L885 - L897. [Abstract] [Full Text] [PDF]

				B. N. Finck The PPAR regulatory system in cardiac physiology and disease Cardiovasc Res, January 15, 2007; 73(2): 269 - 277. [Abstract] [Full Text] [PDF]

				A. J. Gilde, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A24 - A32. [Abstract] [Full Text] [PDF]

				S. S. Wang, S. Davis, J. R. Cerhan, P. Hartge, R. K. Severson, W. Cozen, Q. Lan, R. Welch, S. J. Chanock, and N. Rothman Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma Carcinogenesis, September 1, 2006; 27(9): 1828 - 1834. [Abstract] [Full Text] [PDF]

				M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]