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Studies on the role of apoptosis after transient myocardial ischemia: genetic deletion of the executioner caspases-3 and -7 does not limit infarct size and ventricular remodeling

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Abstract

Although it is widely accepted that apoptosis may contribute to cell death in myocardial infarction, experimental evidence suggests that adult cardiomyocytes repress the expression of the caspase-dependent apoptotic pathway. The aim of this study was to analyze the contribution of caspase-mediated apoptosis to myocardial ischemia-reperfusion injury. Cardiac-specific caspase-3 deficient/full caspase-7-deficient mice (Casp3/7DKO) and wild type control mice (WT) were subjected to in situ ischemia by left anterior coronary artery ligation for 45 min followed by 24 h or 28 days of reperfusion. Heart function was assessed using M-mode echocardiography. Deletion of caspases did not modify neither infarct size determined by triphenyltetrazolium staining after 24 h of reperfusion (40.0 ± 5.1 % in WT vs. 36.2 ± 3.6 % in Casp3/7DKO), nor the scar area measured by pricosirius red staining after 28 days of reperfusion (41.1 ± 5.4 % in WT vs. 44.6 ± 8.7 % in Casp3/7DKO). Morphometric and echocardiographic studies performed 28 days after the ischemic insult revealed left ventricular dilation and severe cardiac dysfunction without statistically significant differences between WT and Casp3/7DKO groups. These data demonstrate that the executioner caspases-3 and -7 do not significantly contribute to cardiomyocyte death induced by transient coronary occlusion and provide the first evidence obtained in an in vivo model that argues against a relevant role of apoptosis through the canonical caspase pathway in this context.

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Acknowledgments

This study was supported by the Spanish Ministry of Science (RETICS-RECAVA) Grants RD06/0014/0025 and RD12/0042/0035, Red de Investigación Cardiovascular, RIC to D.S; Grant 2009SGR-346 from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) to D.S., Instituto de Salud Carlos III (PI-12/01738) and Ministerio de Economía y Competitividad (MINECO) (Grants SAF2010_19125 and SAF2013_44942 to D.S.). We thank Cristina Girón (D.S. lab) for their skilful technical assistance.

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    1. Laboratory of Experimental Cardiology, Department of Cardiology, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

      Javier Inserte, Marcos Poncelas-Nozal, Víctor Hernando, Úrsula Vilardosa, David Aluja & David Garcia-Dorado

    2. Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile

      Victor M. Parra

    3. Cell Signalling and Apoptosis group, Departament Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Av Rovira Roure, 80, 25198, Lleida, Spain

      Maria Cardona & Daniel Sanchis

    4. Servicio de Cardiologia, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain

      David Garcia-Dorado

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    J. Inserte, M. Cardona and M. Poncelas-Nozal contributed equally to this work.

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    Inserte, J., Cardona, M., Poncelas-Nozal, M. et al. Studies on the role of apoptosis after transient myocardial ischemia: genetic deletion of the executioner caspases-3 and -7 does not limit infarct size and ventricular remodeling. Basic Res Cardiol 111, 18 (2016). https://doi.org/10.1007/s00395-016-0537-6

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