Abstract 1394: Calmodulin Kinase II Inhibition Protects Against Ischemia-reperfusion Injury By Up-regulating ATP-sensitive K+ Channels
The multifunctional Ca2+/calmodulin dependent protein kinase II (CaMKII) is activated by cellular Ca2+ and contributes to action potential prolongation, apoptosis and adverse left ventricular remodeling after myocardial infarction (MI). Mice with genetic myocardial-specific CaMKII inhibition (Inh) are resistant to adverse remodeling after MI and have shortened action potentials due to up-regulation of repolarizing K+ currents. The ATP sensitive K+ current (IKATP) couples metabolic changes to repolarization and confers resistance to myocardial necrosis after ischemia-reperfusion injury (IR) by enabling a protective process termed ischemic preconditioning (IP). We studied the responses of Langendorff-perfused hearts from Inh, wild type (WT) and transgenic control (Con) mice to IR, in the presence and absence of IP. Inh mice had significantly lower MI area (P<0.001), based on tissue viability staining using triphenyl-tetrazolium chloride (TTC), compared to WT and Con hearts after IR with IP. IKATP was significantly up-regulated in Inh compared to Con and WT ventricular myocytes (P<0.001). This increased IKATP was due to the higher membrane surface expression of Kir6.2 in the Inh sarcolemma, without an increase in total Kir6.2 measured in whole cell lysates. There were no differences in mRNA expression levels of IKATP encoding genes in any of the groups. The IKATP opener pinacidil (100 μM) eliminated the differences in MI area between Inh and WT hearts and the IKATP antagonist HMR1098 (30 μM) increased MI area to an equivalent level in all groups, suggesting that increased IKATP is the mechanism for enhanced IP in Inh mice. In contrast to the beneficial effects of CaMKII inhibition in reducing MI size there was no significant improvement in myocardial function in any groups. These data identify CaMKII as a signal for increasing MI area during IR and show that CaMKII inhibition enhances the beneficial effects of IP for reducing MI size by increasing IKATP.