HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice
Abstract Background HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1 (HACE1) has been found to be associated with mitochondrial protection. Mitochondrial damage is a critical contributor to myocardial ischemia–reperfusion injury (I/RI). However, little is known about the role...
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2025-02-01
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Online Access: | https://doi.org/10.1186/s12872-024-04445-2 |
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author | Bang-Xia Liu Juan Zheng Zhan-Wei Tang Lei Gao Meng Wang Ying Sun Chen Chen Heng-Chen Yao |
author_facet | Bang-Xia Liu Juan Zheng Zhan-Wei Tang Lei Gao Meng Wang Ying Sun Chen Chen Heng-Chen Yao |
author_sort | Bang-Xia Liu |
collection | DOAJ |
description | Abstract Background HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1 (HACE1) has been found to be associated with mitochondrial protection. Mitochondrial damage is a critical contributor to myocardial ischemia–reperfusion injury (I/RI). However, little is known about the role of HACE1 in the pathogenesis of myocardial I/RI. Methods Male C57BL6 mice with HACE1 knockout (KO) were subjected to 30 min of ischemia via ligation of the left anterior descending artery, followed by 0, 2, 6, or 24 h of reperfusion. The mice were evaluated for myocardial histopathological injury, serum troponin I (cTnI) levels, oxidative stress injury, apoptosis and cardiac function. Prior to ischemia, Mdivi-1(1.2 mg/kg) or vehicle was administered. Results The study revealed that increased expression of HACE1 was associated with myocardial ischemia/reperfusion injury (I/RI), and that knockout of HACE1 resulted in more severe myocardial damage and cardiac dysfunction during I/R(P < 0.05). The HACE1 knockout group exhibited higher levels of malondialdehyde (MDA), greater mitochondrial fission, and dissipation of mitochondrial membrane potential (MMP), leading to more apoptosis and severe cardiac dysfunction compared to the wild-type I/R group(P < 0.05). On the other hand, HACE1 knockout further reduced superoxide dismutase (SOD) activity in the myocardium(P < 0.05), further supporting the findings. However, the adverse effects were almost completely eliminated by pharmacological blockade of the dynamin-related protein 1 (Drp1) inhibitor, Mdivi-1, which inhibits mitochondrial fission during cardiac I/R(P < 0.05). Conclusion Collectively, our data show that myocardial I/RI is associated with HACE1 downregulation and Drp1 activation, causing cardiomyocytes to undergo cell death. Therefore, HACE1 could be a promising therapeutic target for the treatment of myocardial I/RI. |
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institution | Kabale University |
issn | 1471-2261 |
language | English |
publishDate | 2025-02-01 |
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series | BMC Cardiovascular Disorders |
spelling | doaj-art-c3387729405c4226b78073da3b3db7e72025-02-09T12:11:19ZengBMCBMC Cardiovascular Disorders1471-22612025-02-0125111210.1186/s12872-024-04445-2HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in miceBang-Xia Liu0Juan Zheng1Zhan-Wei Tang2Lei Gao3Meng Wang4Ying Sun5Chen Chen6Heng-Chen Yao7Liaocheng People’s Hospital, Shandong UniversityDepartment of Joint Laboratory for Translational Medicine Research, Liaocheng People’s Hospital, Shandong UniversityDepartment of Cardiology, Liaocheng People’s Hospital, Shandong UniversityDepartment of Nuclear Medicine, Liaocheng People’s Hospital, Shandong UniversityDepartment of Heart Failure and Cardiac Rehabilitation, Central Hospital affiliated to, Shandong First Medical UniversityDepartment of Cardiology, Liaocheng People’s Hospital, Shandong UniversityDepartment of Urology, Liaocheng People’s Hospital, Shandong UniversityDepartment of Cardiology, Liaocheng People’s Hospital, Shandong UniversityAbstract Background HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1 (HACE1) has been found to be associated with mitochondrial protection. Mitochondrial damage is a critical contributor to myocardial ischemia–reperfusion injury (I/RI). However, little is known about the role of HACE1 in the pathogenesis of myocardial I/RI. Methods Male C57BL6 mice with HACE1 knockout (KO) were subjected to 30 min of ischemia via ligation of the left anterior descending artery, followed by 0, 2, 6, or 24 h of reperfusion. The mice were evaluated for myocardial histopathological injury, serum troponin I (cTnI) levels, oxidative stress injury, apoptosis and cardiac function. Prior to ischemia, Mdivi-1(1.2 mg/kg) or vehicle was administered. Results The study revealed that increased expression of HACE1 was associated with myocardial ischemia/reperfusion injury (I/RI), and that knockout of HACE1 resulted in more severe myocardial damage and cardiac dysfunction during I/R(P < 0.05). The HACE1 knockout group exhibited higher levels of malondialdehyde (MDA), greater mitochondrial fission, and dissipation of mitochondrial membrane potential (MMP), leading to more apoptosis and severe cardiac dysfunction compared to the wild-type I/R group(P < 0.05). On the other hand, HACE1 knockout further reduced superoxide dismutase (SOD) activity in the myocardium(P < 0.05), further supporting the findings. However, the adverse effects were almost completely eliminated by pharmacological blockade of the dynamin-related protein 1 (Drp1) inhibitor, Mdivi-1, which inhibits mitochondrial fission during cardiac I/R(P < 0.05). Conclusion Collectively, our data show that myocardial I/RI is associated with HACE1 downregulation and Drp1 activation, causing cardiomyocytes to undergo cell death. Therefore, HACE1 could be a promising therapeutic target for the treatment of myocardial I/RI.https://doi.org/10.1186/s12872-024-04445-2HACE1Ischemia/reperfusionDrp1Mitochondrial fissionApoptosis |
spellingShingle | Bang-Xia Liu Juan Zheng Zhan-Wei Tang Lei Gao Meng Wang Ying Sun Chen Chen Heng-Chen Yao HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice BMC Cardiovascular Disorders HACE1 Ischemia/reperfusion Drp1 Mitochondrial fission Apoptosis |
title | HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice |
title_full | HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice |
title_fullStr | HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice |
title_full_unstemmed | HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice |
title_short | HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice |
title_sort | hace1 protects against myocardial ischemia reperfusion injury via inhibition of mitochondrial fission in mice |
topic | HACE1 Ischemia/reperfusion Drp1 Mitochondrial fission Apoptosis |
url | https://doi.org/10.1186/s12872-024-04445-2 |
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