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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
,
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...
| Published in: | Circulation Research |
|---|---|
| ISSN: | 0009-7330 1524-4571 |
| Published: |
Ovid Technologies (Wolters Kluwer Health)
2022
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa59209 |
| first_indexed |
2022-01-18T11:49:14Z |
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| last_indexed |
2024-11-14T12:15:05Z |
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<?xml version="1.0"?><rfc1807><datestamp>2024-02-01T15:40:19.2314494</datestamp><bib-version>v2</bib-version><id>59209</id><entry>2022-01-18</entry><title>Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia</title><swanseaauthors><author><sid>a2e211f7bd379c81e9c393637803a0a0</sid><ORCID>0000-0001-9852-1135</ORCID><firstname>Christopher</firstname><surname>George</surname><name>Christopher George</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-01-18</date><deptcode>MEDS</deptcode><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 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>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</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. Terentyev).</funders><projectreference/><lastEdited>2024-02-01T15:40:19.2314494</lastEdited><Created>2022-01-18T11:36:51.6178754</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Shanna</firstname><surname>Hamilton</surname><orcid>0000-0003-1016-4706</orcid><order>1</order></author><author><firstname>Radmila</firstname><surname>Terentyeva</surname><order>2</order></author><author><firstname>Vladimir</firstname><surname>Bogdanov</surname><order>3</order></author><author><firstname>Tae Yun</firstname><surname>Kim</surname><orcid>0000-0003-0605-9575</orcid><order>4</order></author><author><firstname>Fruzsina</firstname><surname>Perger</surname><order>5</order></author><author><firstname>Jiajie</firstname><surname>Yan</surname><order>6</order></author><author><firstname>Xun</firstname><surname>Ai</surname><orcid>0000-0003-0739-0286</orcid><order>7</order></author><author><firstname>Cynthia A.</firstname><surname>Carnes</surname><order>8</order></author><author><firstname>Andriy E.</firstname><surname>Belevych</surname><order>9</order></author><author><firstname>Christopher</firstname><surname>George</surname><orcid>0000-0001-9852-1135</orcid><order>10</order></author><author><firstname>Jonathan P.</firstname><surname>Davis</surname><order>11</order></author><author><firstname>Sandor</firstname><surname>Gyorke</surname><order>12</order></author><author><firstname>Bum-Rak</firstname><surname>Choi</surname><orcid>0000-0001-7319-3219</orcid><order>13</order></author><author><firstname>Dmitry</firstname><surname>Terentyev</surname><orcid>0000-0002-9530-7384</orcid><order>14</order></author></authors><documents><document><filename>59209__23761__d3f53bf864294e008bf6fb9cc8bccb75.pdf</filename><originalFilename>59209.pdf</originalFilename><uploaded>2022-04-01T15:21:55.4073907</uploaded><type>Output</type><contentLength>8552660</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2022 The Authors. 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2024-02-01T15:40:19.2314494 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 MEDS 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 Medical School COLLEGE CODE MEDS 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 |
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|
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine |
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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 |
2022-03-04T06:15:40Z |
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1857623834350321664 |
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11.096913 |