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

Abstract

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.

Role of apoptosis in cardiovascular disease

“…exchanger-1 (NHE-1) inhibitor, reduced release of Endo G and I/R injury, suggesting that attenuation of Endo G release is cardioprotective. In addition, Bahi et al [118] demonstrated that Endo G was released from mitochondria and induced DNA damage, and importantly when Endo G was downregulated using siRNA, DNA damage was significantly reduced in adult cardiomyocytes during I/R. Collectively, these studies suggest that Endo G is a critical contributor to DNA degradation during I/R.…”

The Drosophila melanogaster Gene cg4930 Encodes a High Affinity Inhibitor for Endonuclease G

“…EndoG knock-out mice have no defect in apoptotic DNA degradation (16,17), but this might be due to redundancy with CAD and additional nucleases (1,2,18). RNA interference experiments and genetic data in Saccharomyces cerevisiae support a role of EndoG in apoptosis (8,19,20). EndoG is also thought to function in a non-apoptotic form of programmed cell death (21).…”

AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia

“…It is reported that AIF causes high molecular weight DNA fragmentation and chromatin condensation in cells and isolated nuclei in a caspase-independent manner [9,10]. Previous research by Bahi and coworkers has demonstrated that the release of EndoG together with AIF from mitochondria to cytosol in rat postnatal differentiated cardiomyocytes is induced by experimental ischemia and causes DNA degradation in cardiomyocytes thereafter [11]. However, the involvement of EndoG and AIF in cardiomyocytes with AKT2 inhibition during ischemia still remains unclear.…”