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

Jingdong Li; Celine Marionneau; Olha Koval; Leonid Zingman; Peter J Mohler; Jeanne M Nerbonne; Mark E Anderson

doi:10.4161/chan.5449

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

Journal article

Open access

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

Jingdong Li, Celine Marionneau, Olha Koval, Leonid Zingman, Peter J Mohler, Jeanne M Nerbonne and Mark E Anderson

Channels (Austin, Tex.), Vol.1(5), pp.387-394

09/2007

DOI: 10.4161/chan.5449

PMID: 18690039

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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).

Electrophysiology

Ischemic Preconditioning

Male

Potassium Channels, Inwardly Rectifying - chemistry

RNA, Messenger - metabolism

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors

Patch-Clamp Techniques

Animals

Ischemia

Models, Biological

Perfusion

Female

Potassium Channels - chemistry

Mice

Adenosine Triphosphate - chemistry

Details

Title: Subtitle: Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current
Creators: Jingdong Li - Departments of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1081, USA
Celine Marionneau
Olha Koval
Leonid Zingman
Peter J Mohler
Jeanne M Nerbonne
Mark E Anderson
Resource Type: Journal article
Publication Details: Channels (Austin, Tex.), Vol.1(5), pp.387-394
DOI: 10.4161/chan.5449
PMID: 18690039
ISSN: 1933-6950
eISSN: 1933-6969
Grant note: HL070250 / NHLBI NIH HHS HL083422 / NHLBI NIH HHS HL066388 / NHLBI NIH HHS HL034161 / NHLBI NIH HHS HL046681 / NHLBI NIH HHS HL062494 / NHLBI NIH HHS HL084583 / NHLBI NIH HHS
Language: English
Date published: 09/2007
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094646402771

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