KMUP-1 attenuates isoprenaline-induced cardiac hypertrophy in rats through NO/cGMP/PKG and ERK1/2/calcineurin A pathways

doi:10.1111/j.1476-5381.2009.00587

CNU IR > Pharmacy and Science > Dept. of Pharmacy > Periodical Articles > Item 310902800/25394

Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/25394

Title:	KMUP-1 attenuates isoprenaline-induced cardiac hypertrophy in rats through NO/cGMP/PKG and ERK1/2/calcineurin A pathways
Authors:	Jwu-Lai Yeh Jong-Hau Hsu Ping-Ju Wu Shu-Fen Liou Chung-Pin Liu Ing-Jun Chen Bin-Nan Wu Zen-Kong Dai Jiunn-Ren Wu
Contributors:	藥學系
Keywords:	KMUP-1 cardiac hypertrophy isoprenaline nitric oxide calcineurin A
Date:	2010-03
Issue Date:	2012-06-05 10:10:33 (UTC+8)
Publisher:	Wiley
Abstract:	Background and purpose: To determine whether KMUP-1, a novel xanthine-based derivative, attenuates isoprenaline (ISO)-induced cardiac hypertrophy in rats, and if so, whether the anti-hypertrophic effect is mediated by the nitric oxide (NO) pathway. Experimental approach: In vivo, cardiac hypertrophy was induced by injection of ISO (5 mg·kg−1·day−1, s.c.) for 10 days in Wistar rats. In the treatment group, KMUP-1 was administered 1 h before ISO. After 10 days, effects of KMUP-1 on survival, cardiac hypertrophy and fibrosis, the NO/guanosine 3′5′-cyclic monophosphate (cGMP)/protein kinase G (PKG) and hypertrophy signalling pathways [calcineurin A and extracellular signal-regulated kinase (ERK)1/2] were examined. To investigate the role of nitric oxide synthase (NOS) in the effects of KMUP-1, a NOS inhibitor, Nω-nitro-L-arginine (L-NNA) was co-administered with KMUP-1. In vitro, anti-hypertrophic effects of KMUP-1 were studied in ISO-induced hypertrophic neonatal rat cardiomyocytes. Key results: In vivo, KMUP-1 pretreatment attenuated the cardiac hypertrophy and fibrosis and improved the survival of ISO-treated rats. Plasma NOx (nitrite and nitrate) and cardiac endothelial NOS, cGMP and PKG were all increased by KMUP-1. The activation of hypertrophic signalling by calcineurin A and ERK1/2 in ISO-treated rats was also attenuated by KMUP-1. All these effects of KMUP-1 were inhibited by simultaneous administration of L-NNA. Similarly, in vitro, KMUP-1 attenuated hypertrophic responses and signalling induced by ISO in neonatal rat cardiomyocytes. Conclusions and implications: KMUP-1 attenuates the cardiac hypertrophy in rats induced by administration of ISO. These effects are mediated, at least in part, by NOS activation. This novel agent, which targets the NO/cGMP pathway, has a potential role in the prevention of cardiac hypertrophy.
Relation:	British journal of pharmacology 159(5)：p.1151-1160
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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