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J. Biol. Chem., Vol. 279, Issue 33, 34882-34889, August 13, 2004

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Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death^*

Maritza Mayorga, Núria Bahi¶, Manel Ballester||, Joan X. Comella**, and Daniel Sanchis, Supported by a postdoctoral grant from the Generalitat de Catalunya and by the Fondo de Investigaciones Sanitarias (01/3023)**

From the Group of Cell Signaling & Apoptosis, Departament de Ciències Mèdiques Bàsiques and ^||Departament de Medicina, Facultat de Medicina, Universitat de Lleida, 25008 Lleida, Spain and the Laboratori de Recerca, Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain

Cardiac fibroblasts play an essential role in the physiology of the heart. These produce extracellular matrix proteins and synthesize angiogenic and cardioprotective factors. Although fibroblasts of cardiac origin are known to be resistant to apoptosis and to remain metabolically active in situations compromising cell survival, the underlying mechanisms are unknown. Here, we report that cardiac fibroblasts were more resistant than dermal or pulmonary fibroblasts to mitochondria-dependent cell death. Cytochrome c release was blocked in cardiac fibroblasts but not in dermal fibroblasts treated with staurosporine, etoposide, serum deprivation, or simulated ischemia, precluding caspase-3 activation and DNA fragmentation. Resistance to apoptosis of cardiac fibroblasts correlated with the expression of the anti-apoptotic protein Bcl-2, whereas skin and lung fibroblasts did not express detectable levels of this protein. Bcl-x_L, Bax, and Bak were expressed at similar levels in cardiac, dermal, and lung fibroblasts. In addition, the death of cardiac fibroblasts during hypoxia was not associated with the cleavage of Bid but rather with Bcl-2 disappearance, suggesting the requirement of the mitochondrial apoptotic machinery to execute death receptor-induced programmed cell death. Knockdown of bcl-2 expression by siRNA in cardiac fibroblasts increased their apoptotic response to staurosporine, serum, and glucose deprivation and to simulated ischemia. Moreover, dermal fibroblasts overexpressing Bcl-2 achieved a similar level of resistance to these stimuli as cardiac fibroblasts. Thus, our data demonstrate that Bcl-2 is an important effector of heart fibroblast resistance to apoptosis and highlight a probable mechanism for promoting survival advantage in fibroblasts of cardiac origin.

Received for publication, April 26, 2004 , and in revised form, May 28, 2004.

^* The present work has been supported by grants from the Fundació Marató de TV3 (to J. X. C. and M. B.) and the Fondo de Investigaciones Sanitarias (01/3023 and PI020116, to D. S. and PI020051, to J. X. C.). 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.

Supported by a Young Researcher Award from the Generalitat de Catalunya (to J. X. C.).

^¶ Supported by a grant from the Fondo de Investigaciones Sanitarias (PI020116, to D. S.).

^** Both authors are co-senior authors.

To whom correspondence should be addressed: Group of Cell Signaling & Apoptosis, Facultat de Medicina, Universitat de Lleida, Montserrat Roig, 2 25008 Lleida, Spain. Tel.: 34-973-70-24-14; Fax: 34-973-70-24-38; E-mail: daniel.sanchis{at}cmb.udl.es.

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