Published Online
on January 7, 2008

A more recent version of this article appeared on February 1, 2008

This Article Full Text (PDF) All Versions of this Article: 51/2/560    most recent HYPERTENSIONAHA.107.102590v1 Alert me when this article is cited Alert me if a correction is posted 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 Qian, J.-Y. Articles by LaPointe, M. C. Search for Related Content PubMed PubMed Citation Articles by Qian, J.-Y. Articles by LaPointe, M. C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Attack Related Collections Remodeling Animal models of human disease Hypertrophy Physiological and pathological control of gene expression

Submitted on October 9, 2007
Revised on November 7, 2007

Reduced Cardiac Remodeling and Function in Cardiac-Specific EP₄ Receptor Knockout Mice With Myocardial Infarction

Jian-Yong Qian; Pamela Harding; Yunhe Liu; Ed Shesely; Xiao-Ping Yang; and Margot C. LaPointe^*

From the Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich.

^* To whom correspondence should be addressed. E-mail: mlapoin1{at}hfhs.org.

Abstract—We have shown previously that cyclooxygenase-2 inhibition reduces cardiac hypertrophy and fibrosis postmyocardial infarction (MI) in a mouse model and that prostaglandin E₂ stimulates cardiomyocyte hypertrophy in vitro through its EP₄ receptor. Because the role of cardiac myocyte EP₄ in cardiac function and hypertrophy in vivo is unknown, we generated mice lacking EP₄ only in cardiomyocytes (CM- EP₄ knockout [KO]). Twelve- to 14-week–old mice were evaluated using echocardiography and histology. There were no differences in ejection fraction, myocyte cross-sectional area, and interstitial collagen fraction between KO mice and littermate controls. To test the hypothesis that EP₄ is involved in cardiac remodeling after MI, we induced MI by ligating the left anterior descending coronary artery. Two weeks later, the mice were subjected to echocardiography, and hearts were removed for histology and Western blot. There was no difference in infarct size between KO mice and controls; however, KO mice showed less myocyte cross-sectional area and interstitial collagen fraction than controls. Also, CM-EP4 KO mice had reduced ejection fraction. Because the transcription factor Stat-3 is involved in hypertrophy and protection from ischemic injury, we tested whether it was activated in control and KO mouse hearts after MI. Western blot indicated that Stat-3 was activated in control hearts after MI but not in KO hearts. Thus, CM-EP4 deletion decreased hypertrophy, fibrosis, and activation of Stat-3. However, cardiac function was unexpectedly worsened in these mice. We conclude that cardiac myocyte EP₄ plays a role in hypertrophy via activation of Stat-3, a process that seems to be cardioprotective.

Key words: PG receptor • hypertrophy • EP₄ • PGE • MI, remodeling

This article has been cited by other articles:

				D. Wang, V. V. Patel, E. Ricciotti, R. Zhou, M. D. Levin, E. Gao, Z. Yu, V. A. Ferrari, M. M. Lu, J. Xu, et al. Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function PNAS, May 5, 2009; 106(18): 7548 - 7552. [Abstract] [Full Text] [PDF]

				E. M. Smyth, T. Grosser, M. Wang, Y. Yu, and G. A. FitzGerald Prostanoids in health and disease J. Lipid Res., April 1, 2009; 50(Supplement): S423 - S428. [Abstract] [Full Text] [PDF]

				J. Meyer-Kirchrath, M. Martin, C. Schooss, C. Jacoby, U. Flogel, A. Marzoll, J. W. Fischer, J. Schrader, K. Schror, and T. Hohlfeld Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart Cardiovasc Res, February 1, 2009; 81(2): 310 - 318. [Abstract] [Full Text] [PDF]

				M. A. Frias, S. Somers, C. Gerber-Wicht, L. H. Opie, S. Lecour, and U. Lang The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis Cardiovasc Res, October 1, 2008; 80(1): 69 - 77. [Abstract] [Full Text] [PDF]