Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury.

Abstract

The search for new approaches to treatment and prevention of heart failure is a major challenge in medicine. The adenosine triphosphate-sensitive potassium (KATP) channel has been long associated with the ability to preserve myocardial function and viability under stress. High surface expression of membrane KATP channels ensures a rapid energy-sparing reduction in action potential duration (APD) in response to metabolic challenges, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, thus sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force. In healthy hearts, calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates the Kir6.2 KATP channel subunit initiating a cascade responsible for KATP channel endocytosis. Here, activation of CaMKII in a transaortic banding (TAB) model of heart failure is coupled with a 35-40% reduction in surface expression of KATP channels compared to hearts from sham-operated mice. Linkage between KATP channel expression and CaMKII is verified in isolated cardiomyocytes in which activation of CaMKII results in downregulation of KATP channel current. Accordingly, shortening of monophasic APD is slowed in response to hypoxia or heart rate acceleration in failing compared to non-failing hearts, a phenomenon previously shown to result in significant increases in oxygen consumption. Even in the absence of coronary artery disease, failing myocardium can be further injured by ischemia due to a mismatch between metabolic supply and demand. Ischemia-reperfusion injury, following ischemic preconditioning, is diminished in hearts with CaMKII inhibition compared to wild-type hearts and this advantage is largely eliminated when myocardial KATP channel expression is absent, supporting that the myocardial protective benefit of CaMKII inhibition in heart failure may be substantially mediated by KATP channels. Recognition of CaMKII-dependent downregulation of KATP channel expression as a mechanism for vulnerability to injury in failing hearts points to strategies targeting this interaction for potential preventives or treatments.

• Authors: Zhan Gao, Ana Sierra, Zhiyong Zhu, Siva Rama Krishna Koganti, Ekaterina Subbotina, Ankit Maheshwari, Mark E Anderson, Leonid V Zingman, Denice M Hodgson-Zingman
• Journal: PloS one (PLoS One) Vol. 11 Issue 3 Pg. e0151337 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26964104 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• KATP Channels
• Protein Kinase Inhibitors
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Action Potentials (drug effects)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
• Cell Membrane (drug effects, metabolism)
• Enzyme Activation (drug effects)
• Female
• Gene Expression Regulation (drug effects)
• Heart Failure (complications, metabolism, pathology, physiopathology)
• Heart Ventricles (drug effects, pathology)
• Hypertrophy
• KATP Channels (metabolism)
• Male
• Mice
• Myocardial Contraction (drug effects)
• Myocardial Reperfusion Injury (complications)
• Protein Kinase Inhibitors (pharmacology)
• Time Factors