Calmodulin Kinase II Inhibition Enhances Ischemic Preconditioning by Augmenting ATP-Sensitive K+Current
Mice with genetic inhibition (AC3-I) of the multifunctional Ca 2+ /calmodulin dependent protein kinase II (CaMKII) have improved cardiomyocyte survival after ischemia. Some K + currents are up-regulated in AC3-I hearts, but it is unknown if CaMKII inhibition increases the ATP sensitive K + current (I KATP ) that underlies ischemic preconditioning (IP) and confers resistance to ischemia. We hypothesized increased I KATP was part of the mechanism for improved ventricular myocyte survival during
... e survival during ischemia in AC3-I mice. AC3-I hearts were protected against global ischemia due to enhanced IP compared to wild type (WT) and transgenic control (AC3-C) hearts. I KATP was significantly increased, while the negative regulatory dose-dependence of ATP was unchanged in AC3-I compared to WT and AC3-C ventricular myocytes, suggesting that CaMKII inhibition increased the number of functional I KATP channels available for IP. We measured increased sarcolemmal Kir6.2, a pore-forming I KATP subunit, but not a change in total Kir6.2 in cell lysates or single channel I KATP opening probability from AC3-I compared to WT and AC3-C ventricles, showing CaMKII inhibition increased sarcolemmal I KATP channel expression. There were no differences in mRNA for genes encoding I KATP channel subunits in AC3-I, WT and AC3-C ventricles. The I KATP opener pinacidil (100 mM) reduced MI area in WT to match AC3-I hearts, while the I KATP antagonist HMR1098 (30 mM) increased MI area to an equivalent level in all groups, indicating that increased I KATP and augmented IP are important for reduced ischemic cell death in AC3-I hearts. Our study results show CaMKII inhibition enhances beneficial effects of IP by increasing I KATP .