Macrophage-derived Legumain Promotes Pulmonary Hypertension

Background: Pulmonary arterial hypertension(PAH)is a rare and lethal cardiopulmonary disease that is defined as a resting mean pulmonary artery pressure(m PAP)of 25 mm Hg or above.Exuberant pulmonary vascular remodeling,a common pathological feature of all categories of PAH,causes progressive elevation of pulmonary vascular resistance(PVR)and pulmonary arterial pressure(PAP),eventually leading to right heart failure and death.Proliferation of vascular smooth muscle cells,accumulation of extracellular matrix(ECM)proteins,and perivascular infiltration of inflammatory cells are the principal events implicated in the remodeling process.Vasodilators are primarily used to treat PAH.Vasodilators improve the symptoms of PAH;however,they do not completely address the underlying drivers of disease pathogenesis and progression.Therefore,a better understanding of disease mechanisms is urgently required to find novel targeted therapies for PAH.Legumin(Lgmn)is highly expressed in lung tissue and is mainly localized to macrophages.The deposition of extracellular matrix in the pulmonary vessels is closely related to the activation of transforming growth factor ?1(TGF-?1).Lgmn is capable of activating matrix metalloproteinase-2(MMP-2).Based on this,we conclude that macrophage-derived Legumain promotes the development of pulmonary hypertension through the MMP-2/TGF-?1 signaling pathway.Objective:(1)to explore the relationship between Lgmn and pulmonary hypertension;(2)to explore the relationship between Lgmn and macrophages in lung tissue;(3)to further explore the specific mechanism of action of Lgmn-mediated ECM deposition in pulmonary hypertension.Methods and results: Lgmn was upregulated in lung tissues of PAH mice subjected to hypoxia plus SU5416(Hy Su)and PAH rats challenged with monocrotaline.Global Lgmn ablation and macrophage-specific ablation alleviated PAH compared to wild-type(WT)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 extracellular matrix(ECM)proteins was correlated with matrix metalloproteinase-2(MMP-2)activation and transforming growth factor(TGF)-?1 signaling in the pulmonary arteries(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.A Lgmn-specific inhibitor markedly ameliorated PAH.Clinically,serum Lgmn levels were closely associated with the severity of idiopathic PAH.Conclusions: Macrophage-derived Lgmn can aggravate the progression of pulmonary hypertension by promoting pulmonary vascular remodeling,and can be used as a molecular marker to assess the severity of pulmonary hypertension.Therefore,clinical inhibition of Lgmn function may be an effective strategy to prevent or delay pulmonary hypertension.