EndoG links Bnip3-induced mitochondrial damage and caspase-independent DNA fragmentation in ischemic cardiomyocytes
Zhang, Jisheng (Institut de Recerca Biomèdica de Lleida)
Ye, Junmei (Institut de Recerca Biomèdica)
Altafaj, Albert (Parc Científic de Barcelona)
Cardona, Maria (Institut de Recerca Biomèdica)
Bahi, Núria (Institut de Recerca Biomèdica)
Llovera, Marta (Institut de Recerca Biomèdica)
Cañas, Xavier (Parc Científic de Barcelona)
Cook, Stuart A. (Medical Research Council Clinical Sciences Centre (Londres, Regne Unit))
Comella i Carnicé, Joan Xavier, 1963- (Hospital Universitari Vall d'Hebron)
Sanchis, Daniel (Institut de Recerca Biomèdica)

Data:	2011
Resum:	Mitochondrial dysfunction, caspase activation and caspase-dependent DNA fragmentation are involved in cell damage in many tissues. However, differentiated cardiomyocytes repress the expression of the canonical apoptotic pathway and their death during ischemia is caspase-independent. The atypical BH3-only protein Bnip3 is involved in the process leading to caspase-independent DNA fragmentation in cardiomyocytes. However, the pathway by which DNA degradation ensues following Bnip3 activation is not resolved. To identify the mechanism involved, we analyzed the interdependence of Bnip3, Nix and EndoG in mitochondrial damage and DNA fragmentation during experimental ischemia in neonatal rat ventricular cardiomyocytes. Our results show that the expression of EndoG and Bnip3 increases in the heart throughout development, while the caspase-dependent machinery is silenced. TUNEL-positive DNA damage, which depends on caspase activity in other cells, is caspase-independent in ischemic cardiomyocytes and ischemia-induced DNA high and low molecular weight fragmentation is blocked by repressing EndoG expression. Ischemia-induced EndoG translocation and DNA degradation are prevented by silencing the expression of Bnip3, but not Nix, or by overexpressing Bcl-xL. These data establish a link between Bnip3 and EndoG-dependent, TUNEL-positive, DNA fragmentation in ischemic cardiomyocytes in the absence of caspases, defining an alternative cell death pathway in postmitotic cells.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; Versió publicada
Matèria:	Heart ; Molecular weight ; DNA damage ; Protein expression ; Mitochondria ; DNA fragmentation ; Apoptosis
Publicat a:	PloS one, Vol. 6, Issue 3 (March 2011) , p. e17998, ISSN 1932-6203

DOI: 10.1371/journal.pone.0017998
PMID: 21437288

10 p, 2.7 MB

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