Switch from caspase-dependent to caspase-independent death during heart development: essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes.
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.
Bahi
Núria
N
Laboratori d'Investigació, Hospital Arnau de Vilanova, Department of Ciències Mèdiques Bàsiques, Universitat de Lleida, Av. Rovira Roure, 80.25198 Lleida, Spain.
Zhang
Jisheng
J
Llovera
Marta
M
Ballester
Manel
M
Comella
Joan X
JX
Sanchis
Daniel
D
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D004247:DNA / Q000737:chemistry*; D053938:DNA Fragmentation; D004706:Endodeoxyribonucleases / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D008928:Mitochondria / Q000378:metabolism; D017202:Myocardial Ischemia; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004247:DNA; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases