β-Catenin Overexpression Reduces Myocardial Infarct Size through Differential Effects on Cardiomyocytes and Cardiac Fibroblasts

doi:10.1074/jbc.M603916200

β-Catenin Overexpression Reduces Myocardial Infarct Size through Differential Effects on Cardiomyocytes and Cardiac Fibroblasts^*

^{^‡}Department of Internal Medicine, Seoul National University College of Medicine and the ^{^§}National Research Laboratory for Cardiovascular Stem Cell, ^{^¶}Hormone Research Center, Seoul National University Hospital, Seoul 110-744, Korea

2 To whom correspondence should be addressed. Tel.: 82-2-2072-2226; Fax: 82-2-766-8904; E-mail: hyosoo{at}snu.ac.kr.

Abstract

β-Catenin is a transcriptional regulator of several genes involved in survival and proliferation. Although previous studies suggest that β-catenin may be involved in the process of preconditioning and healing after myocardial infarction (MI), little is known regarding the role of β-catenin in cardiomyocytes and cardiac fibroblasts. We investigated the role of β-catenin in cardiomyocytes and cardiac fibroblasts and whether β-catenin overexpression could reduce MI size. Adenovirus-mediated gene transfer of nonphosphorylatable constitutively active β-catenin (Ad-catenin) decreased apoptosis in cardiomyocytes and cardiac fibroblasts with increased expression of survivin and Bcl-2. Although Ad-catenin increased the percentage of cells in the S phase with enhanced expression of cyclin D1 and E2 in both cell types, the increase in cell number was only evident in cardiac fibroblasts, whereas hypertrophy and binuclear cells were more prominent in cardiomyocytes. All of these effects of β-catenin gene transfer were blocked by inhibition of its nuclear translocation. Furthermore, Ad-catenin enhanced the expression of vascular endothelial growth factor in both cells and induced differentiation of cardiac fibroblasts into myofibroblasts. In a rat MI model, injection of Ad-catenin into the infarct border zone resulted in a significantly decreased MI size with anti-apoptotic effect and cell cycle activation in both cardiomyocytes and myofibroblasts. β-Catenin may play an important role in the healing process after MI by promoting survival and cell cycle not only in cardiomyocytes but also in cardiac fibroblasts with its differentiation into myofibroblasts.

Footnotes

↵³ The abbreviations used are: GSK3β, glycogen-synthase kinase 3β; MI, myocardial infarction; GFP, green fluorescence protein; Ad-catenin, adenoviruses expressing triple mutant β-catenin construct; Ad-GFP, adenovirus encoding GFP; NCadΔC, dominant negative N-cadherin; DMEM, Dulbecco's modified Eagle's medium; WST, water-soluble tetrazolium salt; BrdUrd, bromodeoxyuridine; FACS, fluorescence-activated cell sorter; VEGF, vascular endothelium growth factor; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; ATW, anterior wall thickness; FS, fractional shortening; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling; PECAM, platelet-endothelial cell adhesion molecule; α-SMA, α-smooth muscle actin; PCNA, proliferating cell nuclear antigen; FBS, fetal bovine serum; LV, left ventricular.
↵^* This work was supported by a grant from the National Research Laboratory Program, KOSEF, the Korea Health 21R&D Project, Ministry of Health & Welfare Grant A050082, and Stem Cell Research Center Grant SC13122, Republic of Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵ The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.
↵¹ Both authors contributed equally to this work.
- Received April 24, 2006.
- Revision received August 10, 2006.
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