期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 50, 期 5, 页码 884-893出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2011.02.005
关键词
Receptor, adrenergic, beta; Endothelin-1; Contractility; Reactive oxygen species; Signal transduction
资金
- Academy of Finland (Center of Excellence)
- Sigrid Juselius Foundation
- Finnish Foundation for Cardiovascular Research
- Hungarian Scientific Research Fund [K69118]
- National Development Agency of Hungary [TAMOP-4.2.2-08/1/KMR-2008-0004]
- Aarne Koskelo Foundation
- Orion-Farmos Research Foundation
- Ida Montin Foundation
Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of contractile dysfunction in heart failure. However, it is unclear whether ROS can regulate physiological cellular processes in the myocardium. Here, we characterized the role of endogenous ROS production in the acute regulation of cardiac contractility in the intact rat heart. In isolated perfused rat hearts, endothelin-1 (ET-1, 1 nmol/L) stimulated ROS formation in the left ventricle, which was prevented by the antioxidant N-acetylcysteine and the NAD(P)H oxidase inhibitor apocynin. N-acetylcysteine, the superoxide dismutase mimetic MnTMPyP, and apocynin significantly attenuated ET-1-mediated inotropic effect, which was accompanied by inhibition of extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Moreover, the mitochondrial K-ATP channel blocker 5-HD, and the mitochondrial large conductance calcium activated potassium channel blocker paxilline, but not the sarcolemmal K-ATP channel blocker HMR 1098 attenuated the inotropic response to ET-1. However, ET-1-induced ROS generation was not abolished by inhibiting mitochondria! K-ATP channel opening. In contrast to ET-1 stimulation, the positive inotropic effect of beta(1)-adrenergic receptor agonist dobutamine (250 nmol/L) was significantly augmented by N-acetylcysteine and apocynin. Moreover, dobutamine-induced phospholamban phosphorylation was markedly enhanced by apocynin. In conclusion, NAD(P)H oxidase-derived ROS play a physiological role in the acute regulation of cardiac contractility in the intact rat heart. Our results reveal that ET-1-induced increase in cardiac contractility is partially dependent on enhanced ROS generation, which in turn, activates the ERK1/2 pathway. On the other hand, beta-adrenergic receptor-induced positive inotropic effect and phospholamban phosphorylation is enhanced by NAD(P)H oxidase inhibition. (C) 2011 Elsevier Ltd. All rights reserved.
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