AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 294: H2637-H2645, 2008. First published April 11, 2008; doi:10.1152/ajpheart.91476.2007
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Differential loss of cytochrome-c oxidase subunits in ischemia-reperfusion injury: exacerbation of COI subunit loss by PKC-{varepsilon} inhibition

Qilin Yu,1,2 Tiffany Nguyen,1,2 Mourad Ogbi,1,2 Robert W. Caldwell,1 and John A. Johnson1,2

1Department of Pharmacology and Toxicology, School of Medicine, and 2The Program in Regenerative Medicine, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia

Submitted 14 December 2007 ; accepted in final form 4 April 2008

We have previously described a PKC-{varepsilon} interaction with cytochrome oxidase subunit IV (COIV) that correlates with enhanced CO activity and cardiac ischemic preconditioning (PC). We therefore investigated the effects of PC and ischemia-reperfusion (I/R) injury on CO subunit levels in an anesthetized rat coronary ligation model. Homogenates prepared from the left ventricular regions at risk (RAR) and not at risk (RNAR) for I/R injury were fractionated into cell-soluble (S), 600 g low-speed centrifugation (L), gradient-purified mitochondrial (M), and 100,000 g particulate (P) fractions. In RAR tissue, PC (2 cycles of 5-min ischemia and 5-min reperfusion) decreased the COI in the P fraction (~29% of total cellular COI), suggesting changes in interfibrillar mitochondria. After 30 min of ischemia and 120 min of reperfusion, total COI levels decreased in the RAR by 72%. Subunit Va was also downregulated by 42% following prolonged I/R in the RAR. PC administered before I/R reduced the loss of COI in the M and P fractions ~30% and prevented COVa losses completely. We observed no losses in subunits Vb and VIIa following I/R alone; however, significant losses occurred when PC was administered before prolonged I/R. Delivery of a cell-permeable PKC-{varepsilon} translocation inhibitor ({varepsilon}V1-2) to isolated rat hearts before prolonged I/R dramatically increased COI loss, suggesting that PKC-{varepsilon} protects COI levels. We propose that additional measures to protect CO subunits when coadministered with PC may improve its cardioprotection against I/R injury.

preconditioning; protein kinase C; cytochrome oxidase subunit; coronary ligation; mitochondria


Address for reprint requests and other correspondence: J. A. Johnson, Dept. of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912-2300 (e-mail: jjohnson{at}mail.mcg.edu)






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