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Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Shanna Hamilton1,2, Radmila Terentyeva1,2, Vladimir Bogdanov1,2

  • 1Department of Physiology and Cell Biology (S.H., R.T., V.B., F.P., J.Y., X.A., A.E.B., J.P.D., S.G., D.T.), The Ohio State University.

Circulation Research
|January 28, 2022
PubMed

Insights

Oxidative stress in cardiac disease increases RyR2 channel activity. Inhibiting Ero1α stabilizes the RyR2-ERp44 complex, reducing arrhythmias in hypertrophic hearts.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Oxidative Stress Research

Background:

  • Oxidative stress in cardiac disease disrupts calcium (Ca2+) homeostasis, affecting sarcoplasmic reticulum (SR) Ca2+ regulation by the RyR2 channel.
  • The precise mechanisms of redox-mediated RyR2 dysfunction in heart disease are not fully understood.
  • This study investigates the role of SR-resident oxidoreductases in modulating RyR2 function under oxidative stress.

Purpose of the Study:

  • To elucidate the role of endoplasmic reticulum oxidoreductase 1 alpha (Ero1α) in redox-mediated RyR2 channel dysfunction in cardiac hypertrophy.
  • To identify the molecular interactions between Ero1α, RyR2, and associated proteins in regulating SR Ca2+ handling.
  • To evaluate the therapeutic potential of targeting the Ero1α-ERp44-RyR2 axis for treating cardiac arrhythmias.

Main Methods:

  • Utilized a rat model of cardiac hypertrophy induced by thoracic aortic banding (TAB).
  • Employed ex vivo whole-heart optical mapping and Ca2+ and reactive oxygen species imaging in isolated ventricular myocytes (VMs).
  • Investigated the effects of pharmacological (EN460) and genetic inhibition/overexpression of Ero1α, alongside site-directed mutagenesis and molecular dynamics simulations.

Main Results:

  • Increased intra-SR oxidation and Ero1α expression were observed in TAB VMs, correlating with impaired Ca2+ handling.
  • Ero1α inhibition normalized SR redox state, improved Ca2+ transient amplitude and SR Ca2+ content, and reduced spontaneous Ca2+ waves.
  • Ero1α mediated RyR2 channel hyperactivation via dissociation of intraluminal protein ERp44, involving a redox-sensitive interaction at RyR2 cysteine 4806.

Conclusions:

  • A novel intraluminal interaction axis involving RyR2, ERp44, and Ero1α was identified in cardiac hypertrophy.
  • Inhibition of Ero1α stabilizes the RyR2-ERp44 complex, mitigating spontaneous Ca2+ release and Ca2+-dependent tachyarrhythmias.
  • Targeting Ero1α represents a promising therapeutic strategy for hypertrophic hearts, improving SR Ca2+ regulation without inducing hypo-oxidative stress.
Abstract

Keywords:
cardiovascular diseasesconstrictionheart failurehomeostasisoxidoreductases

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