Mice with genetic inhibition (AC3-I) of the multifunctional Ca2+/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 (IKATP) that underlies ischemic preconditioning (IP) and confers resistance to ischemia. We hypothesized increased IKATP was part of the mechanism for improved ventricular myocyte 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. IKATP 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 IKATP channels available for IP. We measured increased sarcolemmal Kir6.2, a pore-forming IKATP subunit, but not a change in total Kir6.2 in cell lysates or single channel IKATP opening probability from AC3-I compared to WT and AC3-C ventricles, showing CaMKII inhibition increased sarcolemmal IKATP channel expression. There were no differences in mRNA for genes encoding IKATP channel subunits in AC3-I, WT and AC3-C ventricles. The IKATP opener pinacidil (100 mM) reduced MI area in WT to match AC3-I hearts, while the IKATP antagonist HMR1098 (30 mM) increased MI area to an equivalent level in all groups, indicating that increased IKATP 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 IKATP.
- ATPdependent potassium channel
- Calmodulin kinase II
- Ischemic preconditioning