Protection against cardiac injury by small Ca(2+)-sensitive K(+) channels identified in guinea pig cardiac inner mitochondrial membrane.

David F Stowe, Ashish K Gadicherla, Yifan Zhou, Mohammed Aldakkak, Qunli Cheng, Wai-Meng Kwok, Ming Tao Jiang, James S Heisner, Meiying Yang, Amadou K S Camara

Biochimica et biophysica acta 2013 Feb

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We tested if small conductance, Ca(2+)-sensitive K(+) channels (SK(Ca)) precondition hearts against ischemia reperfusion (IR) injury by improving mitochondrial (m) bioenergetics, if O(2)-derived free radicals are required to initiate protection via SK(Ca) channels, and, importantly, if SK(Ca) channels are present in cardiac cell inner mitochondrial membrane (IMM). NADH and FAD, superoxide (O(2)(-)), and m[Ca(2+)] were measured in guinea pig isolated hearts by fluorescence spectrophotometry. SK(Ca) and IK(Ca) channel opener DCEBIO (DCEB) was given for 10 min and ended 20 min before IR. Either TBAP, a dismutator of O(2)()(-), NS8593, an antagonist of SK(Ca) isoforms, or other K(Ca) and K(ATP) channel antagonists, were given before DCEB and before ischemia. DCEB treatment resulted in a 2-fold increase in LV pressure on reperfusion and a 2.5 fold decrease in infarct size vs. non-treated hearts associated with reduced O(2)(-) and m[Ca(2+)], and more normalized NADH and FAD during IR. Only NS8593 and TBAP antagonized protection by DCEB. Localization of SK(Ca) channels to mitochondria and IMM was evidenced by a) identification of purified mSK(Ca) protein by Western blotting, immuno-histochemical staining, confocal microscopy, and immuno-gold electron microscopy, b) 2-D gel electrophoresis and mass spectroscopy of IMM protein, c) [Ca(2+)]-dependence of mSK(Ca) channels in planar lipid bilayers, and d) matrix K(+) influx induced by DCEB and blocked by SK(Ca) antagonist UCL1684. This study shows that 1) SK(Ca) channels are located and functional in IMM, 2) mSK(Ca) channel opening by DCEB leads to protection that is O(2)(-) dependent, and 3) protection by DCEB is evident beginning during ischemia. Copyright © 2012 Elsevier B.V. All rights reserved.

Citation

David F Stowe, Ashish K Gadicherla, Yifan Zhou, Mohammed Aldakkak, Qunli Cheng, Wai-Meng Kwok, Ming Tao Jiang, James S Heisner, Meiying Yang, Amadou K S Camara. Protection against cardiac injury by small Ca(2+)-sensitive K(+) channels identified in guinea pig cardiac inner mitochondrial membrane. Biochimica et biophysica acta. 2013 Feb;1828(2):427-42