Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background

Circulation. 2009 Mar 10;119(9):1253-62. doi: 10.1161/CIRCULATIONAHA.108.798983. Epub 2009 Feb 23.

Abstract

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 alpha-myosin heavy chain (alpha-MyHC), the applicability of the data to humans, whose cardiomyocytes contain predominantly beta-MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a beta-MyHC transgenic mouse heart in which >80% of the alpha-MyHC was replaced by beta-MyHC, which is the predominant myosin isoform in human cardiac muscle.

Methods and results: To determine the effects of cMyBP-C phosphorylation in a beta-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 beta-MyHC background (beta). These mice were then crossed into the cMyBP-C((t/t)) background to ensure the absence of endogenous cMyBP-C. cMyBP-C((t/t)/beta) and cMyBP-C(AllP)(-)(:(t/t)/beta) mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the beta-MyHC background. cMyBP-C(AllP+:(t/t)/beta) and cMyBP-C(WT:(t/t)/beta) hearts showed no morbidity and mortality, and cMyBP-C(AllP+:(t/t)/beta) hearts were significantly cardioprotected from ischemia/reperfusion injury.

Conclusions: cMyBP-C phosphorylation is necessary for basal myocardial function in the beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ca(2+) Mg(2+)-ATPase / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Coronary Circulation / physiology
  • Cross-Linking Reagents / metabolism
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Function Tests
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction / physiology
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / physiopathology
  • Myocytes, Cardiac / physiology
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Phosphorylation / physiology
  • Protein Structure, Tertiary
  • Ventricular Myosins / genetics*
  • Ventricular Myosins / metabolism*

Substances

  • Carrier Proteins
  • Cross-Linking Reagents
  • myosin-binding protein C
  • Ca(2+) Mg(2+)-ATPase
  • Ventricular Myosins
  • Myosin Heavy Chains