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

Sakthivel Sadayappan1, James Gulick, Raisa Klevitsky

  • 1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Ohio, USA.

Circulation
|February 25, 2009
PubMed
Abstract

Insights

Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is essential for normal heart function in a beta-myosin heavy chain (beta-MyHC) environment. This phosphorylation also protects the heart from ischemia/reperfusion injury, suggesting therapeutic potential.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cardiac Muscle Physiology

Background:

  • Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is a key regulator of cardiac contractility.
  • Previous studies in alpha-myosin heavy chain (alpha-MyHC) hearts showed cMyBP-C phosphomimetics rescued cardiac dysfunction.
  • The relevance to human hearts, which predominantly express beta-myosin heavy chain (beta-MyHC), remained unclear.

Purpose of the Study:

  • To investigate the role of cMyBP-C phosphorylation in a beta-MyHC background.
  • To determine if cMyBP-C phosphorylation is essential for cardiac function in beta-MyHC hearts.
  • To assess the cardioprotective effects of cMyBP-C phosphorylation against ischemia/reperfusion injury in a beta-MyHC context.

Main Methods:

  • Generated transgenic mice expressing different forms of cMyBP-C (WT, nonphosphorylatable, phosphomimetic) in a beta-MyHC background.
  • Crossed these mice into a cMyBP-C-null background to eliminate endogenous cMyBP-C.
  • Assessed cardiac function, survival, and response to ischemia/reperfusion injury.

Main Results:

  • Mice lacking functional cMyBP-C phosphorylation in the beta-MyHC background (cMyBP-C(AllP)(-):(t/t)/beta) exhibited premature death due to heart failure.
  • Hearts expressing phosphomimetic or wild-type cMyBP-C in the beta-MyHC background showed no significant morbidity or mortality.
  • Phosphomimetic cMyBP-C significantly protected these hearts from ischemia/reperfusion injury.

Conclusions:

  • cMyBP-C phosphorylation is critical for maintaining basal myocardial function in the beta-MyHC environment.
  • cMyBP-C phosphorylation confers significant protection against ischemia/reperfusion injury in the human-relevant beta-MyHC background.
  • Targeting cMyBP-C phosphorylation represents a promising therapeutic strategy for human heart conditions.

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