title: Dipeptidyl petidase-IV inhibitor (gemigliptin) inhibits tunicamycin-induced endoplasmic reticulum stress, apoptosis and inflammation in H9c2 cardiomyocytes.
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 Akt phosphorylation in a dose-dependent manner. Using flow cytometry and Hoechst staining, we showed that treatment with Akt 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 Akt inhibitor. In conclusion, gemigliptin effectively inhibited ER stress-induced apoptosis and inflammation in cardiomyocytes via Akt/PERK/CHOP and IRE1α/JNK-p38 pathways, suggesting its direct protective role in cardiovascular diseases.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Hwan-Jin
authors.initials: HJ
authors.lastname: Hwang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Jung
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Ryu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Ho Cheol
authors.initials: HC
authors.lastname: Hong
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Hae Yoon
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Ji A
authors.initials: JA
authors.lastname: Seo
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Sin Gon
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Nan Hee
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Kyung Mook
authors.initials: KM
authors.lastname: Choi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Dong Seop
authors.initials: DS
authors.lastname: Choi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Baik
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea. Electronic address: deisy21@naver.com.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yoo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D004722:Endoribonucleases / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004722:Endoribonucleases; D018836:Inflammation Mediators; D009097:Multienzyme Complexes; D010881:Piperidones; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D012333:RNA, Messenger; D014415:Tunicamycin; D019892:eIF-2 Kinase; C575026:Ern1 protein, rat; C534891:LC15-0444
keywords: Apoptosis; Cardiomyocytes; Dipeptidyl peptidase-IV inhibitors; Inflammation