Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Hamilton, Shanna; Terentyeva, Radmila; Bogdanov, Vladimir; Kim, Tae Yun; Perger, Fruzsina; Yan, Jiajie; Ai, Xun; Carnes, Cynthia A.; Belevych, Andriy E.; George, Christopher; Davis, Jonathan P.; Gyorke, Sandor; Choi, Bum-Rak; Terentyev, Dmitry

doi:10.1161/circresaha.121.320531

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Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

Shanna Hamilton

, Radmila Terentyeva, Vladimir Bogdanov, Tae Yun Kim

, Fruzsina Perger, Jiajie Yan, Xun Ai

, Cynthia A. Carnes, Andriy E. Belevych, Christopher George

, Jonathan P. Davis, Sandor Gyorke, Bum-Rak Choi

, Dmitry Terentyev

Circulation Research, Volume: 130, Issue: 5, Pages: 711 - 724

Swansea University Author: Christopher George

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DOI (Published version): 10.1161/circresaha.121.320531

Abstract

Background:Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca2+ homeostasis, impairing luminal Ca2+ regulation of the sarcoplasmic reticulum (SR) Ca2+ release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redo...

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Published in:	Circulation Research
ISSN:	0009-7330 1524-4571
Published:	Ovid Technologies (Wolters Kluwer Health) 2022
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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 Ca2+ 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 Ca2+ transient amplitude and SR Ca2+ content, and reduced proarrhythmic spontaneous Ca2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca2+-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 Ca2+-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 Ca2+ release and Ca2+-dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.</abstract><type>Journal Article</type><journal>Circulation Research</journal><volume>130</volume><journalNumber>5</journalNumber><paginationStart>711</paginationStart><paginationEnd>724</paginationEnd><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0009-7330</issnPrint><issnElectronic>1524-4571</issnElectronic><keywords>cardiovascular disease; constriction; heart failure; homeostasis; oxidoreductase</keywords><publishedDay>4</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-03-04</publishedDate><doi>10.1161/circresaha.121.320531</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This work was supported by The Ohio State University President’s Postdoc-toral Scholars Award (S. Hamilton), National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) K99HL155492 (S. Hamilton), NIH NIAAA R01AA024769 and NIH NHLBI RO1HL146744 (X. Ai), British Heart Foundation RG/15/6/31436 (C.H. George), NIH NHLBI R01HL132213 (J.P. Davis), NIH NHLBI R01HL063043 (S. Gyorke), NIH NHLBI R01HL074045 (S. Gyorke and J.P. Davis), NIH NHLBI R01HL142588, and NIH NHLBI HL121796 (D. 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spelling	v2 59209 2022-01-18 Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia a2e211f7bd379c81e9c393637803a0a0 0000-0001-9852-1135 Christopher George Christopher George true false 2022-01-18 BMS Background:Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca2+ homeostasis, impairing luminal Ca2+ regulation of the sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ 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 Ca2+ transient amplitude and SR Ca2+ content, and reduced proarrhythmic spontaneous Ca2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca2+-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 Ca2+-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 Ca2+ release and Ca2+-dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR. Journal Article Circulation Research 130 5 711 724 Ovid Technologies (Wolters Kluwer Health) 0009-7330 1524-4571 cardiovascular disease; constriction; heart failure; homeostasis; oxidoreductase 4 3 2022 2022-03-04 10.1161/circresaha.121.320531 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee This work was supported by The Ohio State University President’s Postdoc-toral Scholars Award (S. Hamilton), National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) K99HL155492 (S. Hamilton), NIH NIAAA R01AA024769 and NIH NHLBI RO1HL146744 (X. Ai), British Heart Foundation RG/15/6/31436 (C.H. George), NIH NHLBI R01HL132213 (J.P. Davis), NIH NHLBI R01HL063043 (S. Gyorke), NIH NHLBI R01HL074045 (S. Gyorke and J.P. Davis), NIH NHLBI R01HL142588, and NIH NHLBI HL121796 (D. Terentyev). 2024-02-01T15:40:19.2314494 2022-01-18T11:36:51.6178754 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Shanna Hamilton 0000-0003-1016-4706 1 Radmila Terentyeva 2 Vladimir Bogdanov 3 Tae Yun Kim 0000-0003-0605-9575 4 Fruzsina Perger 5 Jiajie Yan 6 Xun Ai 0000-0003-0739-0286 7 Cynthia A. Carnes 8 Andriy E. Belevych 9 Christopher George 0000-0001-9852-1135 10 Jonathan P. Davis 11 Sandor Gyorke 12 Bum-Rak Choi 0000-0001-7319-3219 13 Dmitry Terentyev 0000-0002-9530-7384 14 59209__23761__d3f53bf864294e008bf6fb9cc8bccb75.pdf 59209.pdf 2022-04-01T15:21:55.4073907 Output 8552660 application/pdf Version of Record true © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License true eng https://creativecommons.org/licenses/by-nc-nd/4.0/
title	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
spellingShingle	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia Christopher George
title_short	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
title_full	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
title_fullStr	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
title_full_unstemmed	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
title_sort	Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
author_id_str_mv	a2e211f7bd379c81e9c393637803a0a0
author_id_fullname_str_mv	a2e211f7bd379c81e9c393637803a0a0_***_Christopher George
author	Christopher George
author2	Shanna Hamilton Radmila Terentyeva Vladimir Bogdanov Tae Yun Kim Fruzsina Perger Jiajie Yan Xun Ai Cynthia A. Carnes Andriy E. Belevych Christopher George Jonathan P. Davis Sandor Gyorke Bum-Rak Choi Dmitry Terentyev
format	Journal article
container_title	Circulation Research
container_volume	130
container_issue	5
container_start_page	711
publishDate	2022
institution	Swansea University
issn	0009-7330 1524-4571
doi_str_mv	10.1161/circresaha.121.320531
publisher	Ovid Technologies (Wolters Kluwer Health)
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str	1
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description	Background:Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca2+ homeostasis, impairing luminal Ca2+ regulation of the sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ 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 Ca2+ transient amplitude and SR Ca2+ content, and reduced proarrhythmic spontaneous Ca2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca2+-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 Ca2+-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 Ca2+ release and Ca2+-dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.
published_date	2022-03-04T15:40:19Z
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score	11.021648

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

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