USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death
Myocardial ischemia–reperfusion (MI/R) injury is characterized by iron deposition and reactive oxygen species production, which can induce ferroptosis. Ferroptosis has also been proposed to promote cardiomyocyte death. The current study sought to define the mechanism governing cardiomyocyte death in...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-10-01
|
Series: | Frontiers in Physiology |
Subjects: | |
Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2020.551318/full |
_version_ | 1819045222283214848 |
---|---|
author | Shuxian Ma Linyan Sun Wenhao Wu Jiangli Wu Zhangnan Sun Jianjun Ren |
author_facet | Shuxian Ma Linyan Sun Wenhao Wu Jiangli Wu Zhangnan Sun Jianjun Ren |
author_sort | Shuxian Ma |
collection | DOAJ |
description | Myocardial ischemia–reperfusion (MI/R) injury is characterized by iron deposition and reactive oxygen species production, which can induce ferroptosis. Ferroptosis has also been proposed to promote cardiomyocyte death. The current study sought to define the mechanism governing cardiomyocyte death in MI/R injury. An animal model of MI/R was established by ligation and perfusion of the left anterior descending coronary artery, and a cellular model of IR was constructed in cardiomyocytes. ChIP assay was then conducted to determine the interaction among USP22, SIRT1, p53, and SLC7A11. Loss- and gain-of-function assays were also conducted to determine the in vivo and in vitro roles of USP22, SIRT1, and SLC7A11. The infarct size and pathological changes of myocardial tissue were observed using TCC and hematoxylin–eosin staining, and the levels of cardiac function– and myocardial injury–related factors of rats were determined. Cardiomyocyte viability and apoptosis were evaluated in vitro, followed by detection of ferroptosis-related indicators (glutathione (GSH), reactive oxygen species, lipid peroxidation, and iron accumulation). USP22, SIRT1, and SLC7A11 expressions were found to be down-regulated, whereas p53 was highly expressed during MI/R injury. USP22, SIRT1, or SLC7A11 overexpression reduced the infarct size and ameliorated pathological conditions, cardiac function, as evidenced by reduced maximum pressure, ejection fraction, maximum pressure rate, and myocardial injury characterized by lower creatine phosphokinase and lactate dehydrogenase levels in vivo. Moreover, USP22, SIRT1, or SLC7A11 elevation contributed to enhanced cardiomyocyte viability and attenuated ferroptosis-induced cell death in vitro, accompanied by increased GSH levels, as well as decreased reactive oxygen species production, lipid peroxidation, and iron accumulation. Together, these results demonstrate that USP22 overexpression could inhibit ferroptosis-induced cardiomyocyte death to protect against MI/R injury via the SIRT1/p53/SLC7A11 association. |
first_indexed | 2024-12-21T10:25:08Z |
format | Article |
id | doaj.art-a96bc0f836914e5caeec5e0337b02fc2 |
institution | Directory Open Access Journal |
issn | 1664-042X |
language | English |
last_indexed | 2024-12-21T10:25:08Z |
publishDate | 2020-10-01 |
publisher | Frontiers Media S.A. |
record_format | Article |
series | Frontiers in Physiology |
spelling | doaj.art-a96bc0f836914e5caeec5e0337b02fc22022-12-21T19:07:20ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-10-011110.3389/fphys.2020.551318551318USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte DeathShuxian Ma0Linyan Sun1Wenhao Wu2Jiangli Wu3Zhangnan Sun4Jianjun Ren5Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, ChinaDepartment of Anesthesiology, Qingyun People’s Hospital, Qingyun, ChinaDepartment of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, ChinaDepartment of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, ChinaDepartment of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, ChinaDepartment of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, ChinaMyocardial ischemia–reperfusion (MI/R) injury is characterized by iron deposition and reactive oxygen species production, which can induce ferroptosis. Ferroptosis has also been proposed to promote cardiomyocyte death. The current study sought to define the mechanism governing cardiomyocyte death in MI/R injury. An animal model of MI/R was established by ligation and perfusion of the left anterior descending coronary artery, and a cellular model of IR was constructed in cardiomyocytes. ChIP assay was then conducted to determine the interaction among USP22, SIRT1, p53, and SLC7A11. Loss- and gain-of-function assays were also conducted to determine the in vivo and in vitro roles of USP22, SIRT1, and SLC7A11. The infarct size and pathological changes of myocardial tissue were observed using TCC and hematoxylin–eosin staining, and the levels of cardiac function– and myocardial injury–related factors of rats were determined. Cardiomyocyte viability and apoptosis were evaluated in vitro, followed by detection of ferroptosis-related indicators (glutathione (GSH), reactive oxygen species, lipid peroxidation, and iron accumulation). USP22, SIRT1, and SLC7A11 expressions were found to be down-regulated, whereas p53 was highly expressed during MI/R injury. USP22, SIRT1, or SLC7A11 overexpression reduced the infarct size and ameliorated pathological conditions, cardiac function, as evidenced by reduced maximum pressure, ejection fraction, maximum pressure rate, and myocardial injury characterized by lower creatine phosphokinase and lactate dehydrogenase levels in vivo. Moreover, USP22, SIRT1, or SLC7A11 elevation contributed to enhanced cardiomyocyte viability and attenuated ferroptosis-induced cell death in vitro, accompanied by increased GSH levels, as well as decreased reactive oxygen species production, lipid peroxidation, and iron accumulation. Together, these results demonstrate that USP22 overexpression could inhibit ferroptosis-induced cardiomyocyte death to protect against MI/R injury via the SIRT1/p53/SLC7A11 association.https://www.frontiersin.org/articles/10.3389/fphys.2020.551318/fullubiquitin specific peptidase 22myocardial ischemia–reperfusion injurysirtuin-1p53solute carrier family 7 member 11ferroptosis |
spellingShingle | Shuxian Ma Linyan Sun Wenhao Wu Jiangli Wu Zhangnan Sun Jianjun Ren USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death Frontiers in Physiology ubiquitin specific peptidase 22 myocardial ischemia–reperfusion injury sirtuin-1 p53 solute carrier family 7 member 11 ferroptosis |
title | USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death |
title_full | USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death |
title_fullStr | USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death |
title_full_unstemmed | USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death |
title_short | USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death |
title_sort | usp22 protects against myocardial ischemia reperfusion injury via the sirt1 p53 slc7a11 dependent inhibition of ferroptosis induced cardiomyocyte death |
topic | ubiquitin specific peptidase 22 myocardial ischemia–reperfusion injury sirtuin-1 p53 solute carrier family 7 member 11 ferroptosis |
url | https://www.frontiersin.org/articles/10.3389/fphys.2020.551318/full |
work_keys_str_mv | AT shuxianma usp22protectsagainstmyocardialischemiareperfusioninjuryviathesirt1p53slc7a11dependentinhibitionofferroptosisinducedcardiomyocytedeath AT linyansun usp22protectsagainstmyocardialischemiareperfusioninjuryviathesirt1p53slc7a11dependentinhibitionofferroptosisinducedcardiomyocytedeath AT wenhaowu usp22protectsagainstmyocardialischemiareperfusioninjuryviathesirt1p53slc7a11dependentinhibitionofferroptosisinducedcardiomyocytedeath AT jiangliwu usp22protectsagainstmyocardialischemiareperfusioninjuryviathesirt1p53slc7a11dependentinhibitionofferroptosisinducedcardiomyocytedeath AT zhangnansun usp22protectsagainstmyocardialischemiareperfusioninjuryviathesirt1p53slc7a11dependentinhibitionofferroptosisinducedcardiomyocytedeath AT jianjunren usp22protectsagainstmyocardialischemiareperfusioninjuryviathesirt1p53slc7a11dependentinhibitionofferroptosisinducedcardiomyocytedeath |