| First Author | Zhou H | Year | 2020 |
| Journal | Basic Res Cardiol | Volume | 115 |
| Issue | 2 | Pages | 11 |
| PubMed ID | 31919590 | Mgi Jnum | J:332587 |
| Mgi Id | MGI:6754716 | Doi | 10.1007/s00395-019-0773-7 |
| Citation | Zhou H, et al. (2020) DNA-PKcs promotes cardiac ischemia reperfusion injury through mitigating BI-1-governed mitochondrial homeostasis. Basic Res Cardiol 115(2):11 |
| abstractText | 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-PKcs(CKO)) 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. |
