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J. Biol. Chem., Vol. 281, Issue 32, 22943-22952, August 11, 2006

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Switch from Caspase-dependent to Caspase-independent Death during Heart Development

ESSENTIAL ROLE OF ENDONUCLEASE G IN ISCHEMIA-INDUCED DNA PROCESSING OF DIFFERENTIATED CARDIOMYOCYTES^*

From the Laboratori d'Investigació, Hospital Arnau de Vilanova, Department of Ciències Mèdiques Bàsiques, Universitat de Lleida, Av. Rovira Roure, 80.25198 Lleida, Spain

Differentiated cardiomyocytes are resistant to caspase-dependent cell death; however, the mechanisms involved are still uncertain. We previously reported that low Apaf1 expression partially accounts for cardiomyocyte resistance to apoptosis. Here, we extend the knowledge on the molecular basis of cardiac resistance to caspase activation by showing that the whole caspase-dependent pathway is silenced during heart development. Experimental ischemia triggers caspase activation in embryonic cardiomyocytes and proliferating fibroblasts, but not in neonatal and adult cardiomyocytes. Ischemia induces the release of the proapoptotic factors cytochrome c, truncated-AIF, and EndoG from mitochondria in postnatal cardiomyocytes in the absence of caspase activation. On the one hand, lentiviral-driven knockdown of EndoG shows that this gene is essential for ischemia-induced DNA degradation in neonatal cardiomyocytes, but not in proliferating fibroblasts; on the other hand, the AIF gene is essential for high molecular DNA cleavage in fibroblasts, but not in postmitotic cardiomyocytes, where it plays a prosurvival role during reoxygenation. These results show the switch from caspase-dependent to caspase-independent death pathways after cardiac cell differentiation, and disclose the relevance of EndoG in the caspase-independent DNA processing of differentiated cardiomyocytes.

Received for publication, February 2, 2006 , and in revised form, June 1, 2006.

^* This work was supported in part by a Grant from the Spanish Ministry of Health (Fondo de Investigaciones Sanitarias Grant PI020106, to D. S.), a Grant from the Sociedad Española de Cardiología (to D. S.), a Grant from La Marató de TV3 (to J. X. C.), and Suport als Grups de Recerca from the Government of Catalonia. 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 supplemental Table S1 and Figs. S1-S3.

¹ Recipient of a predoctoral fellowship from the Departament d'Universitats, Recerca i Societat de la Informació (Government of Catalonia).

² A predoctoral fellow supported by FIS Grant PI020106 (to D. S.).

³ Ramón y Cajal fellow of the Spanish Ministry of Education and Science.

⁴ Both authors are co-senior authors.

⁵ To whom correspondence should be addressed: Cell Signaling & Apoptosis Group, Laboratori d'Investigació HUAV-Dept. CMB UdL. Av. Rovira Roure, 80 25198 Lleida, Spain. Tel.: 34-973-70-22-15; Fax: 34-973-70-22-13; E-mail: daniel.sanchis{at}cmb.udl.es.

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