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Archives of Pharmacal Research

, Volume 40, Issue 5, pp 640–654 | Cite as

Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts

  • Eun-Seok Park
  • Do-Hyun Kang
  • Jun Chul Kang
  • Yong Chang Jang
  • Min-Ju Lee
  • Hun-Jong Chung
  • Kyu Yang Yi
  • Dae-Eun Kim
  • Bokyung Kim
  • Hwa-Sup ShinEmail author
Research Article

Abstract

Oxidative stress plays a critical role in cardiac injury during ischemia/reperfusion (I/R). Despite a potent cardioprotective activity of KR-33889, a novel poly (ADP-ribose) polymerase inhibitor, its underlying mechanism remains unresolved. This study was designed to investigate the protective effects of KR-33889 against oxidative stress-induced apoptosis in rat cardiomyocytes H9c2 cells and isolated rat hearts. H2O2 caused severe injury to H9c2 cells, mainly due to apoptosis, as revealed by TUNEL assay. However, KR-33889 pretreatment significantly attenuated H2O2-induced apoptosis of H9c2 cells, which was accompanied by decrease in expression of both cleaved caspase-3 and Bax and increase in Bcl-2 expression and the ratio of Bcl-2/Bax. KR-33889 also significantly enhanced the expression of anti-oxidant enzymes including heme oxygenase-1, Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase, thereby inhibiting production of intracellular ROS. Furthermore, KR-33889 reversed H2O2-induced decrease in phosphorylation of Akt, GSK-3β, ERK1/2, p38 MAPK, and SAPK/JNK during most H2O2 exposure time. In globally ischemic rat hearts, KR-33889 inhibited both I/R-induced decrease in cardiac contractility and apoptosis by increasing Bcl-2, decreasing both cleaved caspase-3 and Bax expression, and enhancing expression of anti-oxidant enzymes. Taken together, these results suggest that KR-33889 may have therapeutic potential to prevent I/R-induced heart injury in ischemic heart diseases mainly by reducing oxidative stress-mediated myocardial apoptosis.

Keywords

KR-33889 PARP inhibitor Apoptosis Ischemia/reperfusion Oxidative stress 

Notes

Acknowledgements

This study was supported by Konkuk University.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© The Pharmaceutical Society of Korea 2017

Authors and Affiliations

  • Eun-Seok Park
    • 1
    • 4
  • Do-Hyun Kang
    • 1
  • Jun Chul Kang
    • 1
  • Yong Chang Jang
    • 1
  • Min-Ju Lee
    • 1
  • Hun-Jong Chung
    • 2
  • Kyu Yang Yi
    • 3
  • Dae-Eun Kim
    • 4
  • Bokyung Kim
    • 5
  • Hwa-Sup Shin
    • 1
    Email author
  1. 1.Department of Biomedical Chemistry, College of Biomedical and Health SciencesKonkuk UniversityChungjuKorea
  2. 2.Industrial Medicine Department, Chungju Hospital, Konkuk Medical SchoolKonkuk UniversityChungjuKorea
  3. 3.Bio-Organic Science DivisionKorea Research Institute of Chemical TechnologyDaejeonKorea
  4. 4.Department of Biomedical Laboratory ScienceKyungbok UniversityPochenKorea
  5. 5.Department of Physiology, Konkuk Medical SchoolKonkuk UniversityChungjuKorea

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