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

Molecules

Shu-Fen Liou¹  Jong-Hau Hsu²  You-Ting Chen³  Ing-Jun Chen³  Jwu-Lai Yeh³ 

[1]Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan

[2]Department of Paediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

[3]Department and Graduate Institute of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

关键词: KMUP-1;    endothelin-1;    cardiac hypertrophy;    reactive oxygen species;    heme oxygenase-1;   

DOI  :  10.3390/molecules200610435

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.