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: Shu-Fen Liou, Jong-Hau Hsu, You-Ting Chen, Ing-Jun Chen, Jwu-Lai Yeh
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 20 Issue 6 Pg. 10435-49 (Jun 05 2015) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 26056815 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• NFATC Transcription Factors
• Piperidines
• Reactive Oxygen Species
• Transcription Factor AP-1
• Xanthines
• KMUP 1
• Heme Oxygenase-1
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• rho-Associated Kinases
• Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3
• Calcineurin
• rhoA GTP-Binding Protein

Topics

• Animals
• Calcineurin (metabolism)
• Endothelin-1 (metabolism)
• Enzyme Activation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Heme Oxygenase-1 (metabolism)
• Hypertrophy
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• NFATC Transcription Factors (metabolism)
• Piperidines (pharmacology)
• Protein Binding
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor AP-1
• Xanthines (pharmacology)
• rho-Associated Kinases (metabolism)
• rhoA GTP-Binding Protein (metabolism)