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.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Zhou H,Toan S,Zhu P,Wang J,Ren J,Zhang Ydoi
10.1007/s00395-019-0773-7subject
Has Abstractpub_date
2020-01-09 00:00:00pages
11issue
2eissn
0300-8428issn
1435-1803pii
10.1007/s00395-019-0773-7journal_volume
115pub_type
杂志文章abstract::A rapid change in length of cat papillary muscle induces two reciprocal diastolic and systolic processes: stretching causes a viscoelastic relaxation of the muscle. The opposite behavior is observed after abrupt releases when - subsequent to an increase in resting tension - diastolic force attains its new equilibrium....
journal_title:Basic research in cardiology
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journal_title:Basic research in cardiology
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journal_title:Basic research in cardiology
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journal_title:Basic research in cardiology
pub_type: 杂志文章,评审
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journal_title:Basic research in cardiology
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doi:
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01910408
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF00788941
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journal_title:Basic research in cardiology
pub_type: 杂志文章,评审
doi:10.1007/BF00795368
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01908204
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-004-0482-7
更新日期:2004-09-01 00:00:00
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-010-0143-y
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-018-0671-4
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-012-0289-x
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01907365
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF02001397
更新日期:1980-01-01 00:00:00
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF02650352
更新日期:1989-01-01 00:00:00
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-006-0592-5
更新日期:2006-07-01 00:00:00
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doi:10.1007/s00395-016-0552-7
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journal_title:Basic research in cardiology
pub_type: 临床试验,杂志文章
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journal_title:Basic research in cardiology
pub_type: 杂志文章,随机对照试验
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journal_title:Basic research in cardiology
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/978-3-662-11038-6_28
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abstract::Therapeutic angiogenesis improves tissue ischemia by supplementing and supporting the intrinsic process of angiogenesis. Besides direct administration of angiogenic growth factor proteins, injection of naked DNA, non-viral vectors and viral vector constructs carrying angiogenic genes have been used. A novel approach i...
journal_title:Basic research in cardiology
pub_type: 杂志文章,评审
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journal_title:Basic research in cardiology
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abstract::The mitochondrial electrochemical gradient (Δp), which comprises the pH gradient (ΔpH) and the membrane potential (ΔΨ), is crucial in controlling energy transduction. During myocardial ischemia and reperfusion (IR), mitochondrial dysfunction mediates superoxide (·O2-) and H2O2 overproduction leading to oxidative injur...
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journal_title:Basic research in cardiology
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journal_title:Basic research in cardiology
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