Journal Article

The relative order of mK<sub>ATP</sub> channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart

Yuankun Yue, Qining Qin, Michael V Cohen, James M Downey and Stuart D Critz

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 55, issue 3, pages 681-689
Published in print August 2002 | ISSN: 0008-6363
Published online August 2002 | e-ISSN: 1755-3245 | DOI: http://dx.doi.org/10.1016/S0008-6363(02)00452-2
The relative order of mKATP channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart

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Abstract

Objectives: Ischemic preconditioning (PC) reduces myocardial infarction by a mechanism that involves opening of mitochondrial ATP-dependent potassium channels (mKATP), reactive oxygen species (ROS), and possibly activation of p38 mitogen-activated protein kinase (p38 MAPK). The actual order of these steps, however, is a matter of current debate. This study examined whether protection afforded by menadione, which protects by causing mitochondria to produce ROS, requires mKATP opening. In addition, we tested whether protection from anisomycin, a p38 MAPK activator, is dependent on ROS production. Methods and Results: Isolated, buffer-perfused rat hearts were pretreated with menadione, and infarction was assessed after 30 min of regional ischemia and 120 min of reperfusion. Menadione reduced infarction in a dose-dependent manner with an EC50 of 270 nM. Menadione's infarct-limiting effect was insensitive to 200 μM 5-hydroxydecanoate (5HD), an mKATP channel blocker, whereas protection by diazoxide and PC were blocked by 5HD. Anisomycin caused hearts to resist infarction and this protective effect was abrogated by SB203580, a p38 MAPK inhibitor, and 2-mercaptopropionylglycine (MPG), a free radical scavenger. Conclusions: These results indicate that mKATP opening occurs upstream of mitochondrial ROS generation in the protective pathway. Furthermore, protection afforded by anisomycin was p38 MAPK- and ROS-dependent.

Keywords: Free radicals; Infarction; Ischemia; Mitochondria; Preconditioning; Signal transduction

Journal Article.  5570 words.  Illustrated.

Subjects: Cardiovascular Medicine

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