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Updated: May 21, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
MARCHF6 regulates ferroptosis in myocardial ischemia-reperfusion injury via the ADAMTS4/SDC-1 pathway
Qi Lou1, Rui Bai2, Yongwu Liu3
1Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China; Institute of Cardiovascular Diseases, Jiangsu University, Zhenjiang, Jiangsu, China.
Insights
Myocardial ischemia-reperfusion injury (MIRI) is worsened by ferroptosis. Overexpressing MARCHF6 protects the heart by inhibiting ferroptosis via the MARCHF6/ADAMTS4/SDC-1 pathway, improving cardiac function.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Death Pathways
Background:
- Myocardial ischemia-reperfusion injury (MIRI) significantly impacts patient prognosis following acute myocardial infarction.
- Ferroptosis, a regulated cell death pathway, is implicated in MIRI pathogenesis.
- The specific role and regulatory mechanism of MARCHF6, an E3 ubiquitin ligase, in MIRI and ferroptosis were previously unclear.
Purpose of the Study:
- To investigate the role of MARCHF6 in myocardial ischemia-reperfusion injury (MIRI).
- To elucidate the mechanism by which MARCHF6 regulates ferroptosis in the context of MIRI.
- To determine the therapeutic potential of MARCHF6 in mitigating MIRI.
Main Methods:
- Established a mouse model of MIRI using AAV9-mediated MARCHF6 overexpression and coronary artery ligation.
- Assessed cardiac function, infarct size, and histological damage in MIRI mice.
- Analyzed serum myocardial injury markers (CK-MB, cTnI, LDH) and ferroptosis-related indicators.
- Utilized an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model of cardiomyocyte microvascular endothelial cells (CMECs).
- Investigated the MARCHF6/ADAMTS4/SDC-1 signaling axis.
Main Results:
- MARCHF6 overexpression significantly improved cardiac function and reduced myocardial injury in MIRI mice, decreasing infarct area by ~14%.
- Histological damage and cell death were markedly reduced in MARCHF6-overexpressing MIRI hearts.
- MARCHF6 overexpression suppressed ferroptosis markers, including lipid peroxidation, and modulated key ferroptosis regulators (ACSL4, 4-HNE, SLC7A11, GPX4).
- Mechanistically, MARCHF6 promoted ADAMTS4 degradation, upregulating SDC-1, thereby inhibiting ferroptosis in endothelial cells.
Conclusions:
- MARCHF6 overexpression confers significant cardioprotection against MIRI by inhibiting ferroptosis.
- The novel MARCHF6/ADAMTS4/SDC-1 pathway represents a promising therapeutic target for MIRI.
- Targeting MARCHF6 may offer a new strategy to improve outcomes for patients with acute myocardial infarction complicated by MIRI.
Abstract:
Myocardial ischemia-reperfusion injury is a key factor affecting prognosis after acute myocardial infarction. MARCHF6, as an E3 ubiquitin ligase, is closely implicated in the ferroptosis process. The role of MARCHF6 in MIRI and its mechanism for regulating myocardial cell ferroptosis remained unclear. A mouse model of MIRI overexpressing MARCHF6 was established by tail vein injection of MARCHF6-overexpressing AAV9 virus, followed by left anterior descending coronary artery ligation surgery in mice. High expression of MARCHF6 significantly improved cardiac function and reduced myocardial injury in MIRI mice. Compared with the MIRI mice, the MARCHF6 overexpression mice exhibited a reduction of approximately 14% in myocardial infarction area. Histological damage in the cardiac ischemic penumbra region was markedly alleviated, and the number of cell deaths was significantly decreased. Concurrently, MARCHF6 overexpression substantially reduced serum levels of myocardial injury markers CK-MB, cTnI, and LDH. Mitochondrial morphological alterations and expression of ferroptosis-related indicators in the ischemic penumbra of the heart indicated that MARCHF6 overexpression alleviated ferroptosis in MIRI hearts. In an OGD/R-induced cardiomyocyte microvascular endothelial cell (CMEC) model, MARCHF6 overexpression alleviated lipid peroxidation and inhibited ferroptosis. MARCHF6 overexpression suppressed the upregulation of ACSL4 and 4-HNE while blocking the downregulation of SLC7A11 and GPX4 in vivo and vitro. Mechanistically, MARCHF6 promoted the ubiquitin-mediated degradation of ADAMTS4, thereby upregulating its downstream target SDC-1. This sequence of events inhibits lipid peroxidation, mitigates mitochondrial damage, and ultimately blocks the ferroptosis process in endothelial cells. These findings unveil a novel regulatory pathway involving MARCHF6/ADAMTS4/SDC-1 against MIRI by inhibiting ferroptosis.