Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1828, Issue 2, Pages 427-442Publisher
ELSEVIER
DOI: 10.1016/j.bbamem.2012.08.031
Keywords
Cardiac mitochondria; Inner mitochondrial membrane; Cell signaling; Ischemia reperfusion injury; Oxidant stress; Small conductance Ca2+-sensitive K+ channel
Categories
Funding
- Veterans Administration [8204-05P]
- National Institutes of Health [R01 HL089514, R01 HL095122]
- American Heart Association [0355608Z, 0855940G]
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We tested if small conductance, Ca2+-sensitive K+ channels (SKCa) precondition hearts against ischemia reperfusion (IR) injury by improving mitochondrial (m) bioenergetics, if O-2-derived free radicals are required to initiate protection via SKCa, channels, and, importantly, if SKCa channels are present in cardiac cell inner mitochondrial membrane (IMM). NADH and FAD, superoxide (O-2(center dot-)), and m[Ca2+] were measured in guinea pig isolated hearts by fluorescence spectrophotometry. SKCa and IKCa channel opener DCEBIO (DCEB) was given for 10 min and ended 20 min before IR. Either TBAP, a dismutator of O-2(center dot-), NS8593, an antagonist of SKCa 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(center dot-) and m[Ca2+], and more normalized NADH and FAD during IR. Only NS8593 and TBAP antagonized protection by DCEB. Localization of SKCa 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) [Ca2+]-dependence of mSK(Ca) channels in planar lipid bilayers, and d) matrix K+ influx induced by DCEB and blocked by SKCa antagonist UCL1684. This study shows that 1) SKCa channels are located and functional in IMM, 2) mSK(Ca) channel opening by DCEB leads to protection that is O-2(center dot-) dependent, and 3) protection by DCEB is evident beginning during ischemia. (C) 2012 Elsevier B.V. All rights reserved.
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