Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current.

Abstract

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 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 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 microM) reduced MI area in WT to match AC3-I hearts, while the I(KATP) antagonist HMR1098 (30 microM) 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).

• Authors: Jingdong Li, Celine Marionneau, Olha Koval, Leonid Zingman, Peter J Mohler, Jeanne M Nerbonne, Mark E Anderson
• Journal: Channels (Austin, Tex.) (Channels (Austin)) 2007 Sep-Oct Vol. 1 Issue 5 Pg. 387-94 ISSN: 1933-6969 [Electronic] United States
• PMID: 18690039 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Kir6.2 channel
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• RNA, Messenger
• Adenosine Triphosphate
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Adenosine Triphosphate (chemistry)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors)
• Electrophysiology
• Female
• Ischemia
• Ischemic Preconditioning
• Male
• Mice
• Models, Biological
• Patch-Clamp Techniques
• Perfusion
• Potassium Channels (chemistry)
• Potassium Channels, Inwardly Rectifying (chemistry)
• RNA, Messenger (metabolism)