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

Abstract

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.

Construction and analysis of the abnormal lncRNA–miRNA–mRNA network in hypoxic pulmonary hypertension

“…Some early changes in HPH are difficult to detect with traditional research tools and expertise. Much effort has been afforded to finding new therapeutic targets and biomarkers for HPH (18)(19)(20)(21). Most studies, however, have focused only on mRNAs (18,20,21).…”

“…Much effort has been afforded to finding new therapeutic targets and biomarkers for HPH (18)(19)(20)(21). Most studies, however, have focused only on mRNAs (18,20,21). In recent years, lncRNAs have attracted increasing attention due to their important roles in many diseases, but the functions and mechanisms of many lncRNAs in HPH are not yet clear.…”

Decrease in Tripartite Motif Containing 24 suppresses hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/mammalian target of rapamycin complex 1 pathway

“…Simultaneously, AKT reactivation by SC-79 significantly attenuated the decrease in the number of Ki-67 positive PASMCs induced by silencing TRIM24 ( Figure 6(a )). We also determined the expression of cyclin D1, a cell cycle regulator downstream of AKT in PASMCs [ 19 ]. We found that silencing TRIM24 inhibited the expression of cyclin D1 in hypoxia-challenged PASMCs, which was reversed by SC-79 (Supplementary Figure S2).…”

MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells

“…C57BL/6 wild-type (WT, MFG‐E8 +/+ ) mice (6–8 weeks) were purchased from Hunan Slyke Jingda Laboratory Animal Co., Ltd. MFG-E8 knockout (KO, MFG‐E8 −/− ) mice (C57BL/6 background) were generous gifts from Professor Jungang Xie, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. The gene knockout procedure was conducted as previously described [ 20 , 21 ]. Tail clipping and genomic DNA analysis were performed to determine the genotypes of the offspring.…”