Absence of the MFG-E8 gene prevents hypoxia-induced pulmonary hypertension in mice

被引:9
作者
Wang, Jun [1 ,2 ]
Wu, Jixing [1 ]
Zhu, Xianying [1 ]
Chen, Jinkun [3 ]
Zhao, Jianping [1 ]
Xu, Yongjian [1 ]
Xie, Jungang [1 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp,Dept Resp & Crit Care Med, Key Lab Pulm Dis,Hlth Minist,Natl Clin Res Ctr Re, Wuhan 430030, Hubei, Peoples R China
[2] Capital Med Univ, Beijing Chaoyang Hosp, Dept Rheumatol & Immunol, Beijing, Peoples R China
[3] St Johns Ravenscourt Sch, Winnipeg, MB, Canada
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
hypoxia; MFG-E8; pulmonary artery smooth muscle cells; pulmonary hypertension; pulmonary vascular remodeling; SMOOTH-MUSCLE-CELLS; ARTERIAL-HYPERTENSION; APOPTOTIC CELLS; MILK; PROLIFERATION; PROTEIN; GROWTH; EXPRESSION; PRESSURE; FACTOR-8;
D O I
10.1002/jcp.29885
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Pulmonary hypertension (PH) is a chronic vascular disease characterized by elevated pulmonary arterial resistance and vascular remodeling, and chronic hypoxia plays an important role in PH. Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein that regulates cell proliferation and apoptosis, but its role in hypoxia-induced PH is unknown. The current study aimed to determine the function and fundamental mechanisms of MFG-E8 in hypoxia-induced PH. Herein, we exposed mice to hypoxia for 5 weeks, and MFG-E8 was found to be elevated in mouse lung tissues, arteries, and plasma. Compared with wild-type littermates, mice lacking MFG-E8 showed a significant increase in the ratio of pulmonary artery acceleration time to ejection time (PAT/PET), while they showed decreases in right ventricular systolic pressure, the Fulton's Index, percent medial wall thickness (%WT), and vascular muscularization in pulmonary arteries. In addition, MFG-E8 protein levels were also increased in the serum of patients with chronic PH. Similarly, we observed a higher expression of MFG-E8 in human pulmonary artery smooth muscle cells (PASMCs) in the presence of hypoxic stimulation than MFG-E8 in cells in normoxic conditions. Furthermore, MFG-E8 silencing resulted in partial inhibition of proliferation, migration and cell cycle progression in human PASMCs, and the possible mechanisms might involve the interaction between MFG-E8 and the p-Akt/cyclin D1 pathway. Collectively, our study suggests that the absence of MFG-E8 can attenuate the development of hypoxia-induced PH and vascular remodeling. MFG-E8 can be a potential therapeutic target or a biomarker for PH.
引用
收藏
页码:587 / 600
页数:14
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