Protein kinase C mediates Ca2(+)-induced cardioadaptation to ischemia-reperfusion injury.
Although protein kinase C (PKC)-mediated cardioadaptation to ischemia-reperfusion (IR) is accompanied by increased intracellular Ca2+ concentration, it is unknown whether a preischemia sarcoplasmic reticulum (SR) Ca2+ release affects PKC-mediated post-IR functional protection. To study this, crystalloid-perfused (Langendorff) Sprague-Dawley rat hearts were used to assess the effects of a ryanodine (Ry)-induced preischemia Ca2+ load (Ry, 5 nM/2 min, retrograde coronary) 10 min before global IR (20 min). Ry was administered with and without each of two different PKC inhibitors (20 microM chelerythrine and 150 nM bisindolylmaleimide I-HCl). Ry improved myocardial functional recovery (developed pressure, end-diastolic pressure, coronary flow, and creatine kinase activity), which was eliminated after PKC inhibition. Immunohistochemical staining for PKC isoforms demonstrated that Ry induces specific PKC translocation of alpha-, delta-, and zeta-isoforms. We conclude that 1) a preischemia Ca2+ load from the SR results in post-IR myocardial functional protection 2) Ca(2+)-induced functional protection is PKC regulated via the translocation of specific isoforms, and 3) Ca(2+)-induced cardioadaptation to IR injury may have important therapeutic implications prior to planned ischemic events such as cardiac allograft preservation and cardiac bypass surgery.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Cleveland
J C
JC
Mitchell
M B
MB
Sheridan
B C
BC
Gamboni-Robertson
F
F
Harken
A H
AH
Banerjee
A
A
D000222:Adaptation, Physiological / Q000502:physiology*; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001692:Biological Transport; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D003402:Creatine Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009124:Muscle Proteins / Q000502:physiology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel
D000470:Alkaloids; D053119:Benzophenanthridines; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D009124:Muscle Proteins; D010617:Phenanthridines; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; C016299:chelerythrine; D011493:Protein Kinase C; D003402:Creatine Kinase; C088060:bisindolylmaleimide; D002118:Calcium