Cell Communication and Signaling
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2023
·Vol. 21
·期 1
·1-17
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IF 8.4
Zhao Weiming,Wang Lan,Yang Juntang,Chen Xinyu,Guo Xiaoshu,Xu Kai,Wang Ningdan,Zhao Wenyu,Xia Cong,Lian Hui,Rosas Ivan,Yu Guoying
Background Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear. Methods To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively. Results In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model. Conclusion MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis.
Video abstract
研究领域:
呼吸病学
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细胞生物学
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分子生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER SCIENCE
·
2022
·
IF 6.518
Jie Liu,Huxia Wang,Miao Zhang,Yazhao Li,Ruiqi Wang,He Chen,Bo Wang,Xiaoqian Gao,Shaoran Song,Yaochun Wang,Yu Ren,Juan Li,Peijun Liu
Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti‐angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic‐related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient‐derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET‐1), an important regulator of angiogenesis and the hypoxia‐related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET‐1‐induced hypoxia‐inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Makhloufi Zoulikha,Jiahui Zou,Pei Yang,Jun Wu,Wei Wu,Kun Hao,Wei He
Endothelial dysfunction is thought to be one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly via an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF- κ B/ICAM-1/TNF- α /IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.
研究领域:
药理学
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纳米技术
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肺医学
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心血管研究
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
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