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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

PKC- is upstream and PKC- is downstream of mitoK_ATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium

Integrative Human Cardiovascular Physiology and Cardiac Surgery Unit, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom

Submitted 16 March 2004 ; accepted in final form 8 July 2004

Protein kinase C (PKC) is involved in the process of ischemic preconditioning (IPC), although the precise mechanism is still a subject of debate. Using specific PKC inhibitors, we investigated which PKC isoforms were involved in IPC of the human atrial myocardium sections and to determine their temporal relationship to the opening of mitochondrial potassium-sensitive ATP (mitoK_ATP) channels. Right atrial muscles obtained from patients undergoing elective cardiac surgery were equilibrated and then randomized to receive any of the following protocols: aerobic control, 90-min simulated ischemia/120-min reoxygenation, IPC using 5-min simulated ischemia/5-min reoxygenation followed by 90-min simulated ischemia/120-min reoxygenation and finally, PKC inhibitors were added 10 min before and 10 min during IPC followed by 90-min simulated ischemia/120-min reoxygenation. The PKC isoforms inhibitors investigated were V1–2 peptide, GO-6976, rottlerin, and LY-333531 for PKC-, -, - and -, respectively. To investigate the relation of PKC isoforms to mitoK_ATP channels, PKC inhibitors found to be involved in IPC were added 10 min before and 10 min during preconditioning by diazoxide followed by 90-min simulated ischemia/120-min reoxygenation in a second experiment. Creatine kinase leakage and methylthiazoletetrazolium cell viability were measured. Phosphorylation of PKC isoforms after activation of the sample by either diazoxide or IPC was detected by using Western blot analysis and then analyzed by using Scion image software. PKC- and - inhibitors blocked IPC, whereas PKC- and - inhibitors did not. The protection elicited by diazoxide, believed to be via mitoK_ATP channels opening, was blocked by the inhibition of PKC- but not - isoforms. In addition, diazoxide caused increased phosphorylation of PKC- to the same extent as IPC but did not affect the phosphorylation of PKC-, a process believed to be critical in PKC activation. The results demonstrate that PKC- and - are involved in IPC of the human myocardium with PKC- being upstream and PKC- being downstream of mitoK_ATP channels.

cardioprotection; protein kinase C isoforms

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