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.
Highlights
Over the past two decades, there has been considerable progress in the treatment of chronic heart failure yet, even with the best of modern therapy, heart failure is still associated with 5-year mortality rate of 45%-60% [1]
Decreased contractile function, ventricular enlargement, cellular hypertrophy and action potential duration prolongation occur in the transverse aortic banding model of cardiomyopathy
Isolated ventricular cardiomyocytes from hearts of transverse aortic banding (TAB) mice had increased capacitance, representing cell size (291±16, n = 14 vs. 158±11 pF, n = 17, p < .01), and longer action potentials than controls (8.0±1.1 vs. 3.1±.2, 19.2±2.0 vs. 10.3±.6, and 32.0±2.4 vs. 20.5±1.1 msec for action potential duration at 50%, 75% and 90% repolarization, respectively, n = 25 cells from 3 TAB mice and 27 cells from 4 sham mice, p < .01 for each comparison, Fig 1C and 1D). These findings indicate that TAB effectively resulted in typical findings of decreased contractile function, ventricular enlargement, cellular hypertrophy and action potential changes associated with heart failure
Summary
Over the past two decades, there has been considerable progress in the treatment of chronic heart failure yet, even with the best of modern therapy, heart failure is still associated with 5-year mortality rate of 45%-60% [1]. The KATP channel is one of the most abundant cardiac membrane protein complexes and has the unique ability to adjust membrane excitability in response to changes in the energetic status of the cell [4, 5, 8,9,10,11,12,13,14]. KATP channels have been shown to be critical regulators of cardiac membrane excitability in response to heart rate acceleration [15]. A high surface expression of membrane KATP channels ensures a rapid reduction in APD in response to metabolic challenges thereby providing optimal myocardial energetics, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force [16, 17, 29,30,31,32]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
