DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel inducer to promote mitochondrial apoptosis and suppress tumor growth in a variety of cells although its role in cardiovascular diseases remains obscure. This study was designed to examine the role of DNA-PKcs in cardiac ischemia reperfusion (IR) injury and mitochondrial damage. Cardiomyocyte-specific DNA-PKcs knockout (DNA-PKcsCKO) mice were subjected to IR prior to assessment of myocardial function and mitochondrial apoptosis. Our data revealed that IR challenge, hypoxia-reoxygenation (HR) or H2O2-activated DNA-PKcs through post-transcriptional phosphorylation in murine hearts or cardiomyocytes. Mice deficient in DNA-PKcs in cardiomyocytes were protected against cardiomyocyte death, infarct area expansion and cardiac dysfunction. DNA-PKcs ablation countered IR- or HR-induced oxidative stress, mPTP opening, mitochondrial fission, mitophagy failure and Bax-mediated mitochondrial apoptosis, possibly through suppression of Bax inhibitor-1 (BI-1) activity. A direct association between DNA-PKcs and BI-1 was noted where DNA-PKcs had little effect on BI-1 transcription but interacted with BI-1 to promote its degradation. Loss of DNA-PKcs stabilized BI-1, thus offering resistance of mitochondria and cardiomyocytes against IR insult. Moreover, DNA-PKcs ablation-induced beneficial cardioprotection against IR injury was mitigated by concurrent knockout of BI-1. Double deletion of DNA-PKcs and BI-1 failed to exert protection against global IR injury and mitochondrial damage, confirming a permissive role of BI-1 in DNA-PKcs deletion-elicited cardioprotection against IR injury. DNA-PKcs serves as a novel causative factor for mitochondrial damage via suppression of BI-1, en route to the onset and development of cardiac IR injury.
Bibliographical noteFunding Information:
This work was supported in part by National Key R&D Program of China (2017YFA0506000), China Postdoctoral Science Foundation (2019TQ0128) and the NSFC (81900252, 81770261, 81870249, 81900254 and 91749128).
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
- Dna-pkcs. apoptosis
- IR injury
- Mitochondria, Heart/enzymology
- Signal Transduction
- Mice, Inbred C57BL
- Cells, Cultured
- Membrane Proteins/genetics
- Myocytes, Cardiac/enzymology
- Myocardial Infarction/enzymology
- Mice, Knockout
- DNA-Activated Protein Kinase/deficiency
- DNA-Binding Proteins/deficiency
- Myocardial Reperfusion Injury/enzymology
- Protein Stability
- Disease Models, Animal
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article