Long-term expression of protein kinase C in adult mouse hearts improves postischemic recovery

Activation of protein kinase C (PKC) protects the heart from ischemic injur y; however, its mechanism of action is unknown, in part because no model fo r chronic activation of PKC has been available. To test whether chronic, mi ld elevation of PKC activity in adult mouse hearts results in myocardial pr otection during ischemia or reperfusion, hearts isolated from transgenic mi ce expressing a low level of activated PKC beta throughout adulthood (beta- Tx) were compared with control hearts before ischemia, during 12 or 28 min of no-flow ischemia, and during reperfusion. Left-ventricular-developed pre ssure in isolated isovolumic hearts, normalized to heart: weight, was simil ar in the two groups at baseline. However, recovery of contractile function was markedly improved in beta-Tx hearts after either 12 (97 +/- 3% vs. 69 +/- 4%) or 28 min of ischemia (76 +/- 8% vs. 48 +/- 3%), Chelerythrine, a P KC inhibitor, abolished the difference between the two groups, indicating t hat the beneficial effect was PKC-mediated. P-31 NMR spectroscopy was used to test whether modification of intracellular pH and/or preservation of hig h-energy phosphate levels during ischemia contributed to the cardioprotecti on of beta-Tx hearts. No difference in intracellular pH or high-energy phos phate levels was found between the beta-Tx and control hearts at baseline o r during ischemia, Thus, long-term modest increase in PKC activity in adult mouse hearts did not alter baseline function but did lead to improved post ischemic recovery, Furthermore, our results suggest that mechanisms other t han reduced acidification and preservation of high-energy phosphate levels during ischemia contribute to the improved recovery.