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

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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.

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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).

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Authors and Affiliations

  1. Department of Cardiology, Chinese PLA General Hospital, Medical School of Chinese PLA, Bei**g, 100853, China

    Hao Zhou, **jun Zhu & ** Wang

  2. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA

    Hao Zhou & Jun Ren

  3. Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN, 55812, USA

    Sam Toan

  4. Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jun Ren & Yingmei Zhang

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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.

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Correspondence to Hao Zhou, Jun Ren or Yingmei Zhang.

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Zhou, H., Toan, S., Zhu, P. et al. DNA-PKcs promotes cardiac ischemia reperfusion injury through mitigating BI-1-governed mitochondrial homeostasis. Basic Res Cardiol 115, 11 (2020). https://doi.org/10.1007/s00395-019-0773-7

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