Dipeptidyl petidase-IV inhibitor (gemigliptin) inhibits tunicamycin-induced endoplasmic reticulum stress, apoptosis and inflammation in H9c2 cardiomyocytes

Hwan Jin Hwang, Tae Woo Jung, Ja Young Ryu, Ho Cheol Hong, Hyuk Soon Choi, Ji A Seo, Sin Gon Kim, Nan Hee Kim, Kyung Mook Choi, Dong Seop Choi, Sei-Hyun Baik, Hye Jin Yoo

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

The direct effects of dipeptidyl peptidase-IV (DPP-IV) inhibitors on endoplasmic reticulum (ER) stress-induced apoptosis and inflammation in cardiomyocytes have not been elucidated. H9c2 cell viability, which was reduced by tunicamycin, was increased after DPP-IV inhibitor gemigliptin treatment. Gemigliptin significantly decreased the tunicamycin-mediated increase in glucose regulated protein 78 (GRP78) expression and ER stress-mediated signaling molecules such as protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C-EBP homologous protein (CHOP) and inositol-requiring enzyme 1α (IRE1α)/c-Jun N-terminal kinase (JNK)-p38. Furthermore, gemigliptin effectively induced A. kt phosphorylation in a dose-dependent manner. Using flow cytometry and Hoechst staining, we showed that treatment with A. kt inhibitor significantly blocked the anti-apoptotic effects mediated by gemigliptin. The reduction in tunicamycin-induced GRP78 level and PERK/CHOP pathway activity by gemigliptin was reversed after treatment with A. kt inhibitor. In conclusion, gemigliptin effectively inhibited ER stress-induced apoptosis and inflammation in cardiomyocytes via A. kt/PERK/CHOP and IRE1α/JNK-p38 pathways, suggesting its direct protective role in cardiovascular diseases.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalMolecular and Cellular Endocrinology
Volume392
Issue number1-2
DOIs
Publication statusPublished - 2014 Jul 5

Bibliographical note

Funding Information:
Dr. S.H. Baik and Dr. K.M. Choi were supported by the Brain Korea 21 Project of the Ministry of Education and Human Resources Development, Republic of Korea ( A102065-1011-1070100 ). Dr. K.M. Choi received support from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2012006363 ). Dr. H.J. Yoo was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2012R1A1A1005257 ) and by a Korea University grant ( K1325151 ). Gemigliptin was provided by LG Life Sciences Ltd., Seoul, Korea.

Keywords

  • Apoptosis
  • Cardiomyocytes
  • Dipeptidyl peptidase-IV inhibitors
  • Inflammation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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