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.