KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3 beta, Calcineurin/NFATc4 and RhoA/ROCK Pathways

doi:10.3390/molecules200610435

CNU IR > Pharmacy and Science > Dept. of Pharmacy > Periodical Articles > Item 310902800/29634

Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/29634

Title:	KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3 beta, Calcineurin/NFATc4 and RhoA/ROCK Pathways
Authors:	Liou, Shu-Fen Hsu, Jong-Hau Chen, You-Ting Chen, Ing-Jun Yeh, Jwu-Lai
Contributors:	藥學系
Keywords:	KMUP-1 endothelin-1 cardiac hypertrophy reactive oxygen species heme oxygenase-1
Date:	2015-06
Issue Date:	2016-04-19 19:02:46 (UTC+8)
Publisher:	Mdpi Ag
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-3, 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.
Relation:	Molecules, v.20 n.6, pp.10435-10449
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

Files in This Item:

File	Description	Size	Format
29634.pdf		3096Kb	Adobe PDF	334	View/Open
index.html		0Kb	HTML	1334	View/Open

Loading...