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Published on: January 22, 2019
Macrophage-Derived Legumain Promotes Pulmonary Hypertension by Activating the MMP (Matrix Metalloproteinase)-2/TGF
Peiyuan Bai1, Luheng Lyu2, Tingting Yu3
1From the Department of Cardiology, Ruijin Hospital (P.B., N.W., A.L.), Shanghai Jiaotong University School of Medicine, China.
Abstract:
Objective- Macrophages participate in the pathogenesis of pulmonary arterial hypertension (PAH). Lgmn (Legumain), a newly discovered cysteine proteinase belonging to the C13 peptidase family, is primarily expressed in macrophages; however, its roles in PAH remain unknown. Approach and Results- Herein, Lgmn was upregulated in lung tissues of PAH mice subjected to hypoxia plus SU5416 and PAH rats challenged with monocrotaline. Global Lgmn ablation and macrophage-specific ablation alleviated PAH compared with wild-type mice, evident from a reduction in right ventricular systolic pressure, the ratio of the right ventricular wall to the left ventricular wall plus the septum, the pulmonary vascular media thickness, and pulmonary vascular muscularization. Increased expression of ECM (extracellular matrix) proteins was correlated with MMP (matrix metalloproteinase)-2 activation and TGF (transforming growth factor)-β1 signaling in the PAs. Although Lgmn did not affect inflammatory cell infiltration and PA smooth muscle cell proliferation, it drove increased the synthesis of ECM proteins via MMP-2 activation. MMP-2 hydrolyzed the TGF-β1 precursor to the active form. An Lgmn-specific inhibitor markedly ameliorated PAH. Clinically, serum Lgmn levels were closely associated with the severity of idiopathic PAH. Conclusions- Our results indicate that Lgmn inhibition could be an effective strategy for preventing or delaying PAH.
Insights
Legumain (Lgmn), an enzyme in macrophages, is elevated in pulmonary arterial hypertension (PAH). Inhibiting Lgmn reduced PAH severity in animal models, suggesting it as a potential therapeutic target for this condition.
Area of Science:
- Cardiovascular Research
- Pulmonary Medicine
- Biochemistry
Background:
- Macrophages play a key role in the pathogenesis of pulmonary arterial hypertension (PAH).
- Legumain (Lgmn), a cysteine proteinase predominantly expressed in macrophages, has an unknown role in PAH.
- Understanding Lgmn's function in PAH is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of Legumain (Lgmn) in the development and progression of pulmonary arterial hypertension (PAH).
- To determine if Lgmn inhibition can serve as a therapeutic strategy for PAH.
Main Methods:
- Assessed Lgmn expression in lung tissues of rodent models of PAH.
- Utilized global and macrophage-specific Lgmn knockout mice and an Lgmn-specific inhibitor to evaluate PAH.
- Measured pulmonary vascular remodeling, right ventricular pressures, extracellular matrix (ECM) protein expression, matrix metalloproteinase-2 (MMP-2) activation, and transforming growth factor-β1 (TGF-β1) signaling.
Main Results:
- Lgmn expression was significantly upregulated in PAH models.
- Lgmn deficiency or inhibition markedly alleviated PAH, reducing vascular remodeling and right ventricular pressure.
- Lgmn promoted ECM synthesis and TGF-β1 activation via MMP-2, independent of inflammatory cell infiltration or smooth muscle cell proliferation.
- Elevated serum Lgmn levels correlated with idiopathic PAH severity in patients.
Conclusions:
- Legumain (Lgmn) plays a critical role in the pathogenesis of pulmonary arterial hypertension (PAH) by promoting extracellular matrix deposition and TGF-β1 activation.
- Lgmn inhibition represents a promising therapeutic strategy for preventing or ameliorating PAH.
- Targeting Lgmn could offer a novel approach to treating patients with pulmonary arterial hypertension.
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