Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury

Abstract The circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the ex...

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Main Authors: Zhen Qiu, Hao Ming, Shaoqing Lei, Bin Zhou, Bo Zhao, Yanli Yu, Rui Xue, Zhongyuan Xia
Format: Article
Language:English
Published: Nature Publishing Group 2021-01-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-020-03295-y
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spelling doaj-f213f68a64b14a96aedaee94959162882021-01-10T12:07:37ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111510.1038/s41419-020-03295-yRoles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injuryZhen Qiu0Hao Ming1Shaoqing Lei2Bin Zhou3Bo Zhao4Yanli Yu5Rui Xue6Zhongyuan Xia7Department of Anesthesiology, Renmin Hospital of Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital, Hubei University of MedicineDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityAbstract The circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the expression pattern of the circadian nuclear receptor Rev-erbα to maintain the stability of circadian genes such as BMAL1. However, the mechanism by which the HDAC3-orchestrated Rev-erbα/BMAL1 pathway increases MI/RI in diabetes and its relationship with mitophagy have yet to be elucidated. Here, we observed that the clock genes Rev-erbα, BMAL1, and C/EBPβ oscillations were altered in the hearts of rats with streptozotocin (STZ)-induced diabetes, with upregulated HDAC3 expression. Oscillations of Rev-erbα and BMAL1 were rapidly attenuated in diabetic MI/R hearts versus non-diabetic I/RI hearts, in accordance with impaired and rhythm-disordered circadian-dependent mitophagy that increased injury. Genetic knockdown of HDAC3 significantly attenuated diabetic MI/RI by mediating the Rev-erbα/BMAL1 circadian pathway to recover mitophagy. Primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA were exposed to hypoxia/reoxygenation (H/R) in vitro. The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high-glucose conditions compared with low-glucose conditions, with decreased BMAL1 expression and mitophagy levels. After H/R stimulation, high glucose aggravated H/R injury, with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 and mitophagy levels. HDAC3 and Rev-erbα siRNA can alleviate high glucose-induced and H/R-induced injury by upregulating BMAL1 to increase mitophagy. Collectively, these findings suggest that disruption of HDAC3-mediated circadian gene expression oscillations induces mitophagy dysfunction, aggravating diabetic MI/RI. Cardiac-specific HDAC3 knockdown could alleviate diabetic MI/RI by regulating the Rev-erbα/BMAL1 pathway to restore the activation of mitophagy.https://doi.org/10.1038/s41419-020-03295-y
collection DOAJ
language English
format Article
sources DOAJ
author Zhen Qiu
Hao Ming
Shaoqing Lei
Bin Zhou
Bo Zhao
Yanli Yu
Rui Xue
Zhongyuan Xia
spellingShingle Zhen Qiu
Hao Ming
Shaoqing Lei
Bin Zhou
Bo Zhao
Yanli Yu
Rui Xue
Zhongyuan Xia
Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
Cell Death and Disease
author_facet Zhen Qiu
Hao Ming
Shaoqing Lei
Bin Zhou
Bo Zhao
Yanli Yu
Rui Xue
Zhongyuan Xia
author_sort Zhen Qiu
title Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
title_short Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
title_full Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
title_fullStr Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
title_full_unstemmed Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
title_sort roles of hdac3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury
publisher Nature Publishing Group
series Cell Death and Disease
issn 2041-4889
publishDate 2021-01-01
description Abstract The circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the expression pattern of the circadian nuclear receptor Rev-erbα to maintain the stability of circadian genes such as BMAL1. However, the mechanism by which the HDAC3-orchestrated Rev-erbα/BMAL1 pathway increases MI/RI in diabetes and its relationship with mitophagy have yet to be elucidated. Here, we observed that the clock genes Rev-erbα, BMAL1, and C/EBPβ oscillations were altered in the hearts of rats with streptozotocin (STZ)-induced diabetes, with upregulated HDAC3 expression. Oscillations of Rev-erbα and BMAL1 were rapidly attenuated in diabetic MI/R hearts versus non-diabetic I/RI hearts, in accordance with impaired and rhythm-disordered circadian-dependent mitophagy that increased injury. Genetic knockdown of HDAC3 significantly attenuated diabetic MI/RI by mediating the Rev-erbα/BMAL1 circadian pathway to recover mitophagy. Primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA were exposed to hypoxia/reoxygenation (H/R) in vitro. The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high-glucose conditions compared with low-glucose conditions, with decreased BMAL1 expression and mitophagy levels. After H/R stimulation, high glucose aggravated H/R injury, with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 and mitophagy levels. HDAC3 and Rev-erbα siRNA can alleviate high glucose-induced and H/R-induced injury by upregulating BMAL1 to increase mitophagy. Collectively, these findings suggest that disruption of HDAC3-mediated circadian gene expression oscillations induces mitophagy dysfunction, aggravating diabetic MI/RI. Cardiac-specific HDAC3 knockdown could alleviate diabetic MI/RI by regulating the Rev-erbα/BMAL1 pathway to restore the activation of mitophagy.
url https://doi.org/10.1038/s41419-020-03295-y
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