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Background <p>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.</p> Methods <p>Male C57BL6 mice with HACE1 knockout (KO) were subjected to 30&#xa0;min of ischemia via ligation of the left anterior descending artery, followed by 0, 2, 6, or 24&#xa0;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&#xa0;mg/kg) or vehicle was administered.</p> Results <p>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(<i>P</i> &lt; 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(<i>P</i> &lt; 0.05). On the other hand, HACE1 knockout further reduced superoxide dismutase (SOD) activity in the myocardium(<i>P</i> &lt; 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(<i>P</i> &lt; 0.05).</p> Conclusion <p>Collectively, our data show that myocardial I/RI is associated with&#xa0;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.</p>

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HACE1 protects against myocardial ischemia–reperfusion injury via inhibition of mitochondrial fission in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月3日

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  • Bang-Xia Liu,
  • Juan Zheng,
  • Zhan-Wei Tang,
  • Lei Gao,
  • Meng Wang,
  • Ying Sun,
  • Chen Chen,
  • Heng-Chen Yao

摘要

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.