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Updated: Sep 26, 2025
LAD-Ligation: A Murine Model of Myocardial Infarction
Published on: October 14, 2009
Cardiac Resident Macrophage-Derived Legumain Improves Cardiac Repair by Promoting Clearance and Degradation of
Daile Jia1,2,3, Siqin Chen1,2,3,4, Peiyuan Bai1,2,3
1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (D.J., P.B., J.L., A.S., J.G.).
Insights
Legumain (Lgmn) is crucial for cardiac resident macrophages to clear dead heart cells after myocardial infarction. Lgmn deficiency impairs efferocytosis, worsening heart function and inflammation resolution.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Biology
Background:
- Cardiac resident macrophages, originating from embryonic hematopoiesis, maintain themselves within the heart.
- Following myocardial infarction, these macrophages are vital for clearing apoptotic cardiomyocytes through efferocytosis, a process essential for resolving inflammation and promoting tissue repair.
- The molecular mechanisms governing this efferocytosis process remain largely undefined.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the sustained clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction.
- To identify key molecular players involved in efferocytosis in the context of cardiac injury.
Main Methods:
- Utilized various transgenic mouse models (Lgmn-/-, LgmnF/F; LysMcre, LgmnF/F; Cx3cr1CreER, LgmnF/F; LyveCre) and adenoviral gene transfer for Lgmn overexpression to assess Lgmn's role in myocardial infarction.
- Analyzed immune cell infiltration and inflammation using flow cytometry and quantitative real-time polymerase chain reaction (qPCR).
- Quantified legumain (Lgmn) expression in cardiac tissues from patients with ischemic cardiomyopathy and healthy controls via immunohistochemistry and qPCR.
Main Results:
- Identified Lgmn as a gene specifically expressed by cardiac resident macrophages.
- Lgmn deficiency led to exacerbated cardiac dysfunction, accumulation of apoptotic cardiomyocytes, and reduced efferocytosis, alongside impaired intracellular calcium mobilization and defective phagosome formation.
- Lgmn deficiency promoted pro-inflammatory responses, characterized by increased infiltration of specific macrophage and monocyte subsets and altered expression of key inflammatory mediators.
Conclusions:
- Directly linked efferocytosis mediated by Lgmn to cardiac wound healing processes.
- Established Lgmn as a critical molecular link connecting the resolution of acute inflammation to the maintenance of organ function post-myocardial infarction.
Background:
Cardiac resident macrophages are self-maintaining and originate from embryonic hematopoiesis. After myocardial infarction, cardiac resident macrophages are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes (efferocytosis). This process is required for inflammation resolution and tissue repair; however, the underlying molecular mechanisms remain unknown. Therefore, we aimed to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction.
Methods:
Multiple transgenic mice such as Lgmn-/-, LgmnF/F; LysMCre, LgmnF/F; Cx3cr1CreER, LgmnF/F; LyveCre, and cardiac macrophage Lgmn overexpression by adenovirus gene transfer were used to determine the functional significance of Lgmn in myocardial infarction. Immune cell filtration and inflammation were examined by flow cytometry and quantitative real-time polymerase chain reaction. Moreover, legumain (Lgmn) expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction in the cardiac tissues of patients with ischemic cardiomyopathy and healthy control subjects.
Results:
We identified Lgmn as a gene specifically expressed by cardiac resident macrophages. Lgmn deficiency resulted in a considerable exacerbation in cardiac function, accompanied by the accumulation of apoptotic cardiomyocytes and a reduced index of in vivo efferocytosis in the border area. It also led to decreased cytosolic calcium attributable to defective intracellular calcium mobilization. Furthermore, the formation of LC3-II-dependent phagosome around secondary-encountered apoptotic cardiomyocytes was disabled. In addition, Lgmn deficiency increased infiltration of MHC-IIhigh CCR2+ macrophages and the enhanced recruitment of MHC-IIlow CCR2+ monocytes with downregulation of the anti-inflammatory mediators, interleukin-10, and transforming growth factor-β and upregulationof the proinflammatory mediators interleukin-1β, tumor necrosis factor-α, interleukin-6, and interferon-γ.
Conclusions:
Our results directly link efferocytosis to wound healing in the heart and identify Lgmn as a significant link between acute inflammation resolution and organ function.
