Involvement of mitogen-activated protein kinases and reactive oxygen species in the inotropic action of ouabain on cardiac myocytes. A potential role for mitochondrial KATP channels |
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Authors: | Tian Jiang Liu Jiang Garlid Keith D Shapiro Joseph I Xie Zijian |
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Institution: | (1) Departments of Pharmacology and Medicine, Medical College of Ohio, Toledo, OH, USA;(2) Department of Biochemistry and Molecular Biology, OGI School of Science and Engineering, Oregon Health & Sciences University, Beaverton, OR, USA;(3) Department of Pharmacology, Medical College of Ohio, 3035 Arlington Avenue, Toledo, OH 43614-5804, USA |
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Abstract: | Binding of ouabain to Na+/K+-ATPase activated multiple signal transduction pathways including stimulation of Src, Ras, p42/44 MAPKs and production of reactive oxygen species (ROS) in rat cardiac myocytes. Inhibition of either Src or Ras ablated ouabain-induced increase in both Ca2+]i and contractility. While PD98059 abolished the effects of ouabain on Ca2+]i, it only caused a partial inhibition of ouabain-induced increases in contractility. On the other hand, pre-incubation of myocytes with N-acetyl cysteine (NAC) reduced the effects of ouabain on contractility, but not Ca2+]i. Furthermore, 5-hydroxydecanoate (5-HD) blocked ouabain-induced ROS production and partially inhibited ouabain-induced increases in contractility in cardiac myocytes. Pre-incubation of myocytes with both 5-HD and PD98059 completely blocked ouabain's effect on contractility. Finally, we found that opening of mitochondrial KATP channel by diazoxide increased intracellular ROS and significantly raised contractility in cardiac myocytes. These new findings indicate that ouabain regulates cardiac contractility via both Ca2+]i and ROS. While activation of MAPKs leads to increases in Ca2+]i, opening of mitochondrial KATP channel relays the ouabain signal to increased ROS production in cardiac myocytes. |
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Keywords: | Na+/K+-ATPase ouabain contractility [Ca2+]i Ras/MAPK mitochondrial KATP channel reactive oxygen species |
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