Related Experiment Video
Updated: Oct 5, 2025
09:36
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
1.4K
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
Summary
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.
Related Concept Videos
01:28Mechanism of Cardiac Arrhythmias
1.1K
Arrhythmias are irregular heart rhythms occurring when the heart's electrical impulses become abnormal. These disturbances can lead to various symptoms, depending on their severity and the underlying cause. Some common factors contributing to arrhythmias include hypoxia, ischemia, electrolyte imbalances, excessive catecholamine exposure, drug toxicity, and muscle overstretching. Arrhythmias can be classified into two main types based on the rate and site of origin of abnormal heart rhythms.
1.1K
01:29Disturbances in Heart Rhythm
1.5K
Arrhythmia or dysrhythmia refers to an abnormal heart rhythm caused by a defect in the heart's conduction system. It can cause the heart to beat irregularly, too quickly, or too slowly, leading to symptoms like chest pain, shortness of breath, and fainting. Factors such as stress, caffeine, alcohol, nicotine, cocaine, certain drugs, congenital defects, diseases, and electrolyte abnormalities can trigger arrhythmias.
Arrhythmias are categorized by their speed, rhythm, and origin. A slow heart...
Arrhythmias are categorized by their speed, rhythm, and origin. A slow heart...
1.5K
01:31Regulation of the Unfolded Protein Response
2.6K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.6K
01:18Dysrhythmias IV: Characteristics of Bradyarrhythmias
141
Bradyarrhythmias are cardiac rhythm disorders characterized by a slower-than-normal heart rate, typically defined as fewer than 60 beats per minute. Some of which are discussed here:Sinus BradycardiaSinus bradycardia presents a heart rate lower than 60 beats per minute, with a regular rhythm originating from the SA node. The ECG typically shows normal P waves preceding each QRS complex, a normal PR interval (0.12 to 0.20 seconds), and a normal QRS duration (0.06 to 0.10 seconds).First-Degree AV...
141
01:34Directing Proteins to the Rough Endoplasmic Reticulum
11.0K
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
11.0K
01:23Rheumatic Heart Disease I: Introduction
74
Rheumatic heart disease or RHD is a chronic condition that results from rheumatic fever, causing permanent damage to the heart valves.Etiology and Risk FactorsIt primarily arises from rheumatic fever, an inflammatory disease that can develop after untreated or inadequately treated group A streptococcal (GAS) pharyngitis. Streptococcus spreads through direct contact with oral or respiratory secretions. While the bacteria are the causative agents, factors like malnutrition, overcrowding, poor...
74