Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

J Clin Invest. 2010 Dec;120(12):4375-87. doi: 10.1172/JCI37649. Epub 2010 Nov 22.

Abstract

Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor/calcium release channel (RyR2) is thought to play a role in heart failure (HF) progression. Inhibition of this leak is an emerging therapeutic strategy. To explore the role of chronic PKA phosphorylation of RyR2 in HF pathogenesis and treatment, we generated a knockin mouse with aspartic acid replacing serine 2808 (mice are referred to herein as RyR2-S2808D+/+ mice). This mutation mimics constitutive PKA hyperphosphorylation of RyR2, which causes depletion of the stabilizing subunit FKBP12.6 (also known as calstabin2), resulting in leaky RyR2. RyR2-S2808D+/+ mice developed age-dependent cardiomyopathy, elevated RyR2 oxidation and nitrosylation, reduced SR Ca2+ store content, and increased diastolic SR Ca2+ leak. After myocardial infarction, RyR2-S2808D+/+ mice exhibited increased mortality compared with WT littermates. Treatment with S107, a 1,4-benzothiazepine derivative that stabilizes RyR2-calstabin2 interactions, inhibited the RyR2-mediated diastolic SR Ca2+ leak and reduced HF progression in WT and RyR2-S2808D+/+ mice. In contrast, β-adrenergic receptor blockers improved cardiac function in WT but not in RyR2-S2808D+/+ mice.Thus, chronic PKA hyperphosphorylation of RyR2 results in a diastolic leak that causes cardiac dysfunction. Reversing PKA hyperphosphorylation of RyR2 is an important mechanism underlying the therapeutic action of β-blocker therapy in HF.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Amino Acid Substitution
  • Animals
  • Calcium Signaling / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Heart Failure / drug therapy
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutation, Missense
  • Myocardial Infarction / metabolism
  • Myocardium / metabolism
  • Phosphorylation
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Ryanodine Receptor Calcium Release Channel
  • Cyclic AMP-Dependent Protein Kinases