Korean Circulation Journal

  • 제43권6호
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  • Pages.400-407
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  • 2013
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  • 1738-5520(pISSN)
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  • 1738-5555(eISSN)
대한심장학회 (The Korean Society of Cardiology)
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Protective Effect of Survivin in Doxorubicin-Induced Cell Death in H9c2 Cardiac Myocytes

  • Lee, Beom Seob (Graduate Program in Science for Aging, Yonsei University) ;
  • Kim, Soo Hyuk (Graduate Program in Science for Aging, Yonsei University) ;
  • Jin, Taewon (Graduate Program in Science for Aging, Yonsei University) ;
  • Choi, Eun Young (Graduate Program in Science for Aging, Yonsei University) ;
  • Oh, Jaewon (Cardiology Division, Severance Cardiovascular Hospital and Cardiovascular Research Institute) ;
  • Park, Sungha (Cardiology Division, Severance Cardiovascular Hospital and Cardiovascular Research Institute) ;
  • Lee, Sang Hak (Cardiology Division, Severance Cardiovascular Hospital and Cardiovascular Research Institute) ;
  • Chung, Ji Hyung (Cardiology Division, Severance Cardiovascular Hospital and Cardiovascular Research Institute) ;
  • Kang, Seok-Min (Cardiology Division, Severance Cardiovascular Hospital and Cardiovascular Research Institute)
  • 발행 : 2013.06.30
⟨ 이전 논문 다음 논문 ⟩

초록

Background and Objectives: Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, which belongs to the inhibitor of apoptosis protein family, is associated with apoptosis and alteration of the cardiac myocyte molecular pathways. Therefore, we investigated the anti-apoptotic effect and cellular mechanisms of survivin using a protein delivery system in a doxorubicin-induced cardiac myocyte injury model. Materials and Methods: We constructed a recombinant survivin which was fused to the protein transduction domain derived from HIVTAT protein. In cultured H9c2 cardiac myocytes, TAT-survivin ($1{\mu}M$) was added for 1 hour prior to doxorubicin ($1{\mu}M$) treatment for 24 hours. Cell viability and apoptosis were evaluated by 2-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, caspase-3 activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay. We measured the expression levels of several apoptosis-related signal proteins. Results: The survivin level was significantly reduced in a dose dependent manner up to $1{\mu}M$ of doxorubicin in concentration. Purified recombinant TAT-survivin protein was efficiently delivered to H9c2 cardiac myocytes, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity and the apoptotic index, concomitantly with increased cell viability against doxorubicin injury. The phosphorylation of p38 mitogen-activated protein (MAP) kinase and the release of Smac from mitochondria were suppressed and the expression levels of Bcl-2 and cAMP response element-binding protein (CREB), the transcription factor of Bcl-2, were recovered following TAT-survivin transduction, indicating that survivin had an anti-apoptotic effect against doxorubicin injury. Conclusion: Our results suggest that survivin has a potentially cytoprotective effect against doxorubicin-induced cardiac myocyte apoptosis through mechanisms that involve a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl-2 and CREB.

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참고문헌

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