title: KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3β, Calcineurin/NFATc4 and RhoA/ROCK Pathways.
abstract: The signaling cascades of the mitogen activated protein kinase (MAPK) family, calcineurin/NFATc4, and PI3K/Akt/GSK3, are believed to participate in endothelin-1 (ET-1)-induced cardiac hypertrophy. The aim of this study was to investigate whether KMUP-1, a synthetic xanthine-based derivative, prevents cardiomyocyte hypertrophy induced by ET-1 and to elucidate the underlying mechanisms. We found that in H9c2 cardiomyocytes, stimulation with ET-1 (100 nM) for 4 days induced cell hypertrophy and enhanced expressions of hypertrophic markers, including atrial natriuretic peptide and brain natriuretic peptide, which were all inhibited by KMUP-1 in a dose-dependent manner. In addition, KMUP-1 prevented ET-1-induced intracellular reactive oxygen species generation determined by the DCFH-DA assay in cardiomyocytes. KMUP-1 also attenuated phosphorylation of ERK1/2 and Akt/GSK-3β, and activation of calcineurin/NFATc4 and RhoA/ROCK pathways induced by ET-1. Furthermore, we found that the expression of heme oxygenase-1 (HO-1), a stress-response enzyme implicated in cardio-protection, was up-regulated by KMUP-1. Finally, KMUP-1 attenuated ET-1-stimulated activator protein-1 DNA binding activity. In conclusion, KMUP-1 attenuates cardiomyocyte hypertrophy induced by ET-1 through inhibiting ERK1/2, calcineurin/NFATc4 and RhoA/ROCK pathways, with associated cardioprotective effects via HO-1 activation. Therefore, KMUP-1 may have a role in pharmacological therapy of cardiac hypertrophy.
authors.affiliation: Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Liou
authors.affiliation: Department of Paediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Department of Paediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Jong-Hau
authors.initials: JH
authors.lastname: Hsu
authors.affiliation: Department and Graduate Institute of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: You-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Department and Graduate Institute of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.affiliation: Department and Graduate Institute of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. jwulai@kmu.edu.tw.|Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan. jwulai@kmu.edu.tw.
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006984:Hypertrophy; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1; D014970:Xanthines / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D050778:NFATC Transcription Factors; D010880:Piperidines; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014970:Xanthines; C439304:KMUP 1; D051547:Heme Oxygenase-1; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D020742:rhoA GTP-Binding Protein
keywords: KMUP-1; cardiac hypertrophy; endothelin-1; heme oxygenase-1; reactive oxygen species