The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

Hamilton, Shanna; Veress, Roland; Belevych, Andriy E.; Terentyev, Dmitry

doi:10.1007/s00424-020-02505-y

Cited by 14 publications

(11 citation statements)

References 83 publications

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“…Abnormally high RyR2 channel activity has a central role in contractile deficiency and arrhythmogenesis underlying sudden cardiac death 3 , 4 , 49 and posttranslational modifications of the channel including PKA/CaMKII-mediated phosphorylation or oxidation are involved, as well as their interplay (ie, ROS-CaMKII-RyR2) at the cytosolic face of RyR2. 5 , 50 Here, we show a novel regulatory axis for RyR2 ROS modulation involving the luminal ROS sensor Ero1α and the luminal RyR2-binding protein ERp44.…”

Section: Discussionmentioning

confidence: 99%

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Hamilton

Terentyeva

Bogdanov

et al. 2022

Circulation Research

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Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca 2+ homeostasis, impairing luminal Ca 2+ regulation of the sarcoplasmic reticulum (SR) Ca 2+ release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process. Methods: A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca 2+ and reactive oxygen species imaging in isolated ventricular myocytes (VMs). Results: The SR-targeted reactive oxygen species biosensor ERroGFP showed increased intra-SR oxidation in TAB VMs that was associated with increased expression of oxidoreductase Ero1α. Pharmacological (EN460) or genetic Ero1α inhibition normalized SR redox state, increased Ca 2+ transient amplitude and SR Ca 2+ content, and reduced proarrhythmic spontaneous Ca 2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca 2+ -dependent ventricular tachyarrhythmias in TAB hearts challenged with isoproterenol. Experiments in TAB VMs and human embryonic kidney 293 cells expressing human RyR2 revealed that an Ero1α-mediated increase in SR Ca 2+ -channel activity involves dissociation of intraluminal protein ERp44 from the RyR2 complex. Site-directed mutagenesis and molecular dynamics simulations demonstrated a novel redox-sensitive association of ERp44 with RyR2 mediated by intraluminal cysteine 4806. ERp44-RyR2 association in TAB VMs was restored by Ero1α inhibition, but not by reducing agent dithiothreitol, as hypo-oxidation precludes formation of covalent bond between RyR2 and ERp44. Conclusions: A novel axis of intraluminal interaction between RyR2, ERp44, and Ero1α has been identified. Ero1α inhibition exhibits promising therapeutic potential by stabilizing RyR2-ERp44 complex, thereby reducing spontaneous Ca 2+ release and Ca 2+ -dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.

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Section: Discussionmentioning

confidence: 99%

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Hamilton

Terentyeva

Bogdanov

et al. 2022

Circulation Research

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“…First, abnormalities of sCa may cause calcium disturbance in the cytoplasm of cardiomyocytes and interfere with myocardial contraction function 20. Second, altered calcium homeostasis may lead to change of platform depolarisation and cardiac action potential, causing increased arrhythmic risk 21. Third, calcium metabolism disorders may accelerate the formation of atherosclerotic plaques and progression of coronary artery calcification 22.…”

Section: Discussionmentioning

confidence: 99%

“…20 Second, altered calcium homeostasis may lead to change of platform depolarisation and cardiac action potential, causing increased arrhythmic risk. 21 Third, calcium metabolism disorders may accelerate the formation of atherosclerotic plaques and progression of coronary artery calcification. 22 In addition, the association of sCa with all-cause mortality risk in our study does not demonstrate causation.…”

Section: Open Accessmentioning

confidence: 99%

Altered serum calcium homeostasis independently predicts mortality in patients with acute coronary syndrome: a retrospective observational cohort study

Zhu

Zhao

et al. 2021

BMJ Open

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ObjectivesSerum calcium levels (sCa) were reported to be associated with risk of cardiovascular diseases. The aim of this study was to analyse the association between sCa and long-term mortality in patients with acute coronary syndrome (ACS).DesignA retrospective observational cohort study.SettingSingle-centre study with participants recruited from the local area.ParticipantsA total of consecutive 13 772 patients with ACS were included in this analysis. Patients were divided based on their sCa profile (≤2.1 mmol/L, 2.1–2.2 mmol/L, 2.2–2.3 mmol/L, 2.3–2.4 mmol/L, 2.4–2.5 mmol/L,>2.5 mmol/L) and followed up for a median of 2.96 years (IQR 1.01–4.07).Primary outcomeLong-term all-cause mortality.ResultsDuring a median follow-up period of 2.96 years, patients with sCa ≤2.1 mmol/L had the highest cumulative incidences of all-cause mortality (16.7%), whereas those with sCa 2.4–2.5 mmol/L had the lowest cumulative incidences of all-cause mortality (3.5%). After adjusting for potentially confounding variables, the Cox analysis revealed that compared with the reference group (sCa 2.4–2.5 mmol/L), all the other groups had higher mortality except for the sCa 2.3–2.4 mmol/L group (HR, 1.32, 95% CI 0.93 to 1.87). Restricted cubic splines showed that the relationship between sCa and all-cause mortality seemed to be U shaped. The optimal sCa cut-off point, 2.35 mmol/L, was determined based on the shape of restricted cubic splines.ConclusionsAltered serum calcium homeostasis at admission independently predicts all-cause mortality in patients with ACS. In addition, a U-shaped relationship between sCa and all-cause mortality exists, and maintaining sCa at approximately 2.35 mmol/L may minimise the risk of mortality.

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“…The increased incidence of malignant arrhythmias can contribute to heart failure, diabetic cardiomyopathy, senile cardiac insufficiency, and hereditary diseases [ 271 ]. Abnormalities in intracellular Ca 2+ homeostasis and mitochondrial dysfunction are considered to be key factors in the pathophysiology of these diseases [ 272 ]. Garcia Rivas et al showed that a perfusion of the MCU inhibitor RU360 could eliminate the incidence of arrhythmias caused by ischemia/reperfusion injury in an open-chest rat model [ 273 ].…”

Section: Targeting Mitochondria: Mitochondrial Ca 2+ ...mentioning

confidence: 99%

Mitochondrial Ca2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

Zhang

Wang

et al. 2022

IJMS

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Mitochondria are the sites of oxidative metabolism in eukaryotes where the metabolites of sugars, fats, and amino acids are oxidized to harvest energy. Notably, mitochondria store Ca2+ and work in synergy with organelles such as the endoplasmic reticulum and extracellular matrix to control the dynamic balance of Ca2+ concentration in cells. Mitochondria are the vital organelles in heart tissue. Mitochondrial Ca2+ homeostasis is particularly important for maintaining the physiological and pathological mechanisms of the heart. Mitochondrial Ca2+ homeostasis plays a key role in the regulation of cardiac energy metabolism, mechanisms of death, oxygen free radical production, and autophagy. The imbalance of mitochondrial Ca2+ balance is closely associated with cardiac remodeling. The mitochondrial Ca2+ uniporter (mtCU) protein complex is responsible for the uptake and release of mitochondrial Ca2+ and regulation of Ca2+ homeostasis in mitochondria and consequently, in cells. This review summarizes the mechanisms of mitochondrial Ca2+ homeostasis in physiological and pathological cardiac remodeling and the regulatory effects of the mitochondrial calcium regulatory complex on cardiac energy metabolism, cell death, and autophagy, and also provides the theoretical basis for mitochondrial Ca2+ as a novel target for the treatment of cardiovascular diseases.

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The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

Cited by 14 publications

References 83 publications

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Altered serum calcium homeostasis independently predicts mortality in patients with acute coronary syndrome: a retrospective observational cohort study

Mitochondrial Ca2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

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