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DNA-PKcs promotes cardiac ischemia reperfusion injury through mitigating BI-1-governed mitochondrial homeostasis

  • Hao ZhouEmail author
  • Sam Toan
  • Pingjun Zhu
  • Jin Wang
  • Jun RenEmail author
  • Yingmei ZhangEmail author
Original Contribution
  • 73 Downloads

Abstract

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.

Keywords

Dna-pkcs. apoptosis IR injury BI-1 Mitochondria 

Notes

Acknowledgements

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).

Author contributions

HZ, PJZ and JW were involved in conception and design, performance of experiments, data analysis and interpretation and manuscript writing; ST and PZ were involved in the development of methodology; HZ and PJZ were involved in the data acquisition; JR and YZ were involved data analysis and interpretation; and HZ, JR and YZ involved in study supervision and final approval of manuscript.

Compliance with ethical standards

Conflict of interest

The authors have declared that they have no conflicts of interest.

Supplementary material

395_2019_773_MOESM1_ESM.pdf (2.7 mb)
Supplementary file1 (PDF 2770 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of CardiologyChinese PLA General Hospital, Medical School of Chinese PLABeijingChina
  2. 2.Center for Cardiovascular Research and Alternative MedicineUniversity of Wyoming College of Health SciencesLaramieUSA
  3. 3.Department of Chemical EngineeringUniversity of Minnesota-DuluthDuluthUSA
  4. 4.Department of Cardiology and Shanghai Institute of Cardiovascular DiseasesZhongshan Hospital, Fudan UniversityShanghaiChina

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