Macrophage-Derived Legumain Promotes Pulmonary Hypertension by Activating the MMP (Matrix Metalloproteinase)-2/TGF (Transforming Growth Factor)-β1 Signaling
Macrophage-Derived Legumain Promotes Pulmonary Hypertension by Activating the MMP (Matrix Metalloproteinase)-2/TGF (Transforming Growth Factor)-β1 Signaling
复制标题
巨噬细胞来源的 Legumain 通过激活 MMP（基质金属蛋白酶）-2/TGF（转化生长因子）-β 1 信号传导促进肺动脉高压
DOI：
10.1161/atvbaha.118.312254
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发表时间：
2019-04-01
影响因子：
8.7
通讯作者：
Lyu, Ankang
中科院分区：
文献类型：
--
作者：
Bai, Peiyuan;Lyu, Luheng;Lyu, Ankang
目的-巨噬细胞参与肺动脉高压（PAH）的发病机制. Lgmn（Legumain）是一种新发现的半胱氨酸蛋白酶，属于C13肽酶家族，主要在巨噬细胞中表达;然而，其在PAH中的作用仍不清楚。方法和结果-在此，Lgmn在缺氧加SU 5416的PAH小鼠和用野百合碱攻击的PAH大鼠的肺组织中上调。与野生型小鼠相比，整体Lgmn消融和巨噬细胞特异性消融缓解了PAH，这从右心室收缩压、右心室壁与左心室壁加间隔的比率、肺血管中膜厚度和肺血管肌化的降低中可见一斑。ECM（细胞外基质）蛋白表达增加与PA中MMP（基质金属蛋白酶）-2活化和TGF（转化生长因子）-β 1信号传导相关。虽然Lgmn不影响炎性细胞浸润和PA平滑肌细胞增殖，但它通过MMP-2活化促进ECM蛋白的合成。MMP-2将TGF-β 1前体水解成活性形式。Lgmn特异性抑制剂显著改善PAH。临床上，血清Lgmn水平与特发性PAH的严重程度密切相关。结论-我们的结果表明Lgmn抑制可能是预防或延迟PAH的有效策略。
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)-beta 1 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-beta 1 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.