Calcium preconditioning elicits strong protection against ischemic injury via protein kinase C signaling pathway.
We tested the hypothesis that elevation of [Ca2+]i during Ca2+ preconditioning (CPC) is a strong activator of protein kinase C (PKC) and confers unique protection against ischemic injury. CPC consisted of three cycles of Ca2+ depletion (1 minute each) and Ca2+ repletion (5 minutes each). Langendorff-perfused rat hearts were subjected to 40 minutes of global ischemia followed by 30 minutes of reperfusion. Significant functional recovery and decreased lactate dehydrogenase release were observed in CPC hearts compared with ischemic control hearts. In addition, ATP contents were significantly higher and cell structure was better preserved in CPC hearts than in ischemic control hearts. Administration of chelerythrine, a specific PKC inhibitor, completely abolished the CPC-induced cardioprotection. In other groups, in which Ca2+ influx during CPC was inhibited with verapamil, amiloride, and low Na+ perfusion, cardioprotection was significantly reduced. The prominent increase in the membrane PKC activity after CPC was in agreement with immunolocalization of PKC-alpha and PKC-delta in the cell membrane of CPC hearts. These results demonstrate that (1) a transient increase in [Ca2+]i is a prominent feature of CPC and is a strong stimulus for the activation of PKC, (2) the elevation of [Ca2+]i likely occurs via an L-type Ca2+ channel and Na(+)-Ca2+ exchanger, and (3) PKC plays a crucial role in the subcellular mechanisms of protection by CPC.
Miyawaki
H
H
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, OH 45267-0529, USA.
Zhou
X
X
Ashraf
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D066298:In Vitro Techniques; D008297:Male; D008854:Microscopy, Electron; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014018:Tissue Distribution; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D014700:Verapamil; D011493:Protein Kinase C; D002118:Calcium