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(Circulation. 2009;119:1253-1262.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Cardiac Myosin Binding Protein-C Phosphorylation in a β-Myosin Heavy Chain Background

Sakthivel Sadayappan, PhD; James Gulick, MS; Raisa Klevitsky, MD; John N. Lorenz, PhD; Michelle Sargent, BS; Jeffery D. Molkentin, PhD; Jeffrey Robbins, PhD

From the Department of Pediatrics, Cincinnati Children’s Hospital Medical Center (S.S., J.G., R.K., M.S., J.D.M., J.R.), and Department of Molecular and Cellular Physiology, University of Cincinnati (J.N.L.), Cincinnati, Ohio.

Correspondence to Jeffrey Robbins, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}cchmc.org

Received June 12, 2008; accepted December 19, 2008.

Background— Cardiac myosin binding protein-C (cMyBP-C) phosphorylation modulates cardiac contractility. When expressed in cMyBP-C–null (cMyBP-C^(t/t)) hearts, a cMyBP-C phosphomimetic (cMyBP-C^AllP+) rescued cardiac dysfunction and protected the hearts from ischemia/reperfusion injury. However, cMyBP-C function may be dependent on the myosin isoform type. Because these replacements were performed in the mouse heart, which contains predominantly -myosin heavy chain (-MyHC), the applicability of the data to humans, whose cardiomyocytes contain predominantly β-MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a β-MyHC transgenic mouse heart in which >80% of the -MyHC was replaced by β-MyHC, which is the predominant myosin isoform in human cardiac muscle.

Methods and Results— To determine the effects of cMyBP-C phosphorylation in a β-MyHC background, transgenic mice expressing normal cMyBP-C (cMyBP-C^WT), nonphosphorylatable cMyBP-C (cMyBP-C^AllP–), or cMyBP-C^AllP+ were bred into the β-MyHC background (β). These mice were then crossed into the cMyBP-C^(t/t) background to ensure the absence of endogenous cMyBP-C. cMyBP-C^(t/t)/β and cMyBP-C^{AllP–:(t/t)/β} mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the β-MyHC background. cMyBP-C^{AllP+:(t/t)/β} and cMyBP-C^WT:(t/t)/β hearts showed no morbidity and mortality, and cMyBP-C^{AllP+:(t/t)/β} hearts were significantly cardioprotected from ischemia/reperfusion injury.

Conclusions— cMyBP-C phosphorylation is necessary for basal myocardial function in the β-MyHC background and can preserve function after ischemia/reperfusion injury. Our studies justify exploration of cMyBP-C phosphorylation as a therapeutic target in the human heart.

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Clinical Summaries
Circulation 2009 119: 1177-1179. [Extract] [Full Text]