Effect of hepatocyte growth factor on mice with hypoxic pulmonary arterial hypertension: a preliminary study

TANG Hu-Ting; MU Wei-Hao; XIANG Yu-Jing; AN Yong

doi:10.7499/j.issn.1008-8830.2203127

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Chinese Journal of Contemporary Pediatrics ›› 2022, Vol. 24 ›› Issue (8) : 936-941. DOI: 10.7499/j.issn.1008-8830.2203127

EXPERIMENTAL RESEARCH

Effect of hepatocyte growth factor on mice with hypoxic pulmonary arterial hypertension: a preliminary study

TANG Hu-Ting, MU Wei-Hao, XIANG Yu-Jing, AN Yong

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Abstract

Objective To study the association between hepatocyte growth factor (HGF) and treatment response in mice with hypoxic pulmonary arterial hypertension (HPAH) and the possibility of HGF as a new targeted drug for HPAH. Methods After successful modeling, the HPAH model mice were randomly divided into two groups: HPAH group and HGF treatment group (tail vein injection of recombinant mouse HGF 1 mg/kg), with 10 mice in each group. Ten normal mice were used as the control group. After 5 weeks, echocardiography was used to measure tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio; the Griess method was used to measure the content of nitric oxide in serum; ELISA was used to measure the serum level of endothelin-1; transmission electron microscopy was used to observe changes in the ultrastructure of pulmonary artery. Results Compared with the HGF treatment and normal control groups, the HPAH group had significantly higher tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio (P<0.05). The transmission electron microscopy showed that the HPAH group had massive destruction of vascular endothelial cells and disordered arrangement of the elastic membrane of arteriolar intima with rupture and loss. The structure of vascular endothelial cells was almost complete and the structure of arterial intima elastic membrane was almost normal in the HGF treatment group. Compared with the normal control and HGF treatment groups, the HPAH group had significantly higher serum levels of nitric oxide and endothelin-1 (P<0.05). Conclusions Increasing serum HGF level can alleviate the impact of HPAH on the cardiovascular system of mice, possibly by repairing endothelial cell injury, improving vascular remodeling, and restoring the normal vasomotor function of pulmonary vessels.

Key words

Hypoxic pulmonary arterial hypertension / Hepatocyte growth factor / Vascular remodeling / Echocardiography / Mouse

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TANG Hu-Ting, MU Wei-Hao, XIANG Yu-Jing, AN Yong. Effect of hepatocyte growth factor on mice with hypoxic pulmonary arterial hypertension: a preliminary study[J]. Chinese Journal of Contemporary Pediatrics. 2022, 24(8): 936-941 https://doi.org/10.7499/j.issn.1008-8830.2203127

References

1 Saito T, Miyagawa K, Chen SY, et al. Upregulation of human endogenous retrovirus-K is linked to immunity and inflammation in pulmonary arterial hypertension[J]. Circulation, 2017, 136(20): 1920-1935. PMID: 28935667. PMCID: PMC5685911. DOI: 10.1161/CIRCULATIONAHA.117.027589.
2 Radik M, Kmecova Z, Veteskova J, et al. Hepatocyte growth factor plays a particular role in progression of overall cardiac damage in experimental pulmonary hypertension[J]. Int J Med Sci, 2019, 16(6): 854-863. PMID: 31337959. PMCID: PMC6643116. DOI: 10.7150/ijms.31690.
3 中华医学会心血管病学分会肺血管病学组, 中华心血管病杂志编辑委员会. 中国肺高血压诊断和治疗指南2018[J]. 中华心血管病杂志, 2018, 46(12): 933-964. PMID: 30572400. DOI: 10.3760/cma.j.issn.0253-3758.2018.12.006.
4 Naito A, Sakao S, Lang IM, et al. Endothelial cells from pulmonary endarterectomy specimens possess a high angiogenic potential and express high levels of hepatocyte growth factor[J]. BMC Pulm Med, 2018, 18(1): 197. PMID: 30594174. PMCID: PMC6310963. DOI: 10.1186/s12890-018-0769-3.
5 白辉科, 秦廷江, 杜明成, 等. HGF/c-Met轴介导EPCs治疗大鼠HPAH的初步实验研究[J]. 重庆医科大学学报, 2019, 44(11): 1506-1512. DOI: 10.13406/j.cnki.cyxb.001817.
6 Sharma RK, Oliveira AC, Yang T, et al. Gut pathology and its rescue by ACE2 (angiotensin-converting enzyme 2) in hypoxia-induced pulmonary hypertension[J]. Hypertension, 2020, 76(1): 206-216. PMID: 32418496. PMCID: PMC7505091. DOI: 10.1161/HYPERTENSIONAHA.120.14931.
7 袁天翊, 陈迪, 孙姝婵, 等. 低氧诱导小鼠肺动脉高压药物评价模型的建立[J]. 医药导报, 2021, 40(7): 857-863. DOI: 10.3870/j.issn.1004-0781.2021.07.002.
8 赵帅, 张博. 低氧性肺动脉高压的研究进展[J]. 广东医学, 2018, 39(S2): 268-270. DOI: 10.3969/j.issn.1001-9448.2018.z1.094.
9 陈雨思, 李江. 肺动脉高压靶向药物治疗现状和展望[J]. 中国临床新医学, 2020, 13(9): 852-858. DOI: 10.3969/j.issn.1674-3806.2020.09.02.
10 王瑞, 武云. 肺动脉高压靶向药物治疗的研究进展[J]. 医学综述, 2022, 28(9): 1776-1783.
11 Li T, Li S, Feng Y, et al. Combination of dichloroacetate and atorvastatin regulates excessive proliferation and oxidative stress in pulmonary arterial hypertension development via p38 signaling[J]. Oxid Med Cell Longev, 2020, 2020: 6973636. PMID: 32617141. PMCID: PMC7306075. DOI: 10.1155/2020/6973636.
12 Chu T, Huang M, Zhao Z, et al. Atorvastatin reduces accumulation of vascular smooth muscle cells to inhibit intimal hyperplasia via p38 MAPK pathway inhibition in a rat model of vein graft[J]. Arq Bras Cardiol, 2020, 115(4): 630-636. PMID: 33111860. PMCID: PMC8386959. DOI: 10.36660/abc.20190231.
13 Gorenoi V, Brehm MU, Koch A, et al. Growth factors for angiogenesis in peripheral arterial disease[J]. Cochrane Database Syst Rev, 2017, 6(6): CD011741. PMID: 28594443. PMCID: PMC6481523. DOI: 10.1002/14651858.CD011741.pub2.
14 秦廷江, 杜明成, 王朝辉, 等. HGF/c-Met促进大鼠骨髓内皮祖细胞迁移能力[J]. 基础医学与临床, 2016, 36(12): 1611-1617. DOI: 10.3969/j.issn.1001-6325.2016.12.001.
15 杜明成, 秦廷江, 夏世辉, 等. 过表达c-Met蛋白诱导内皮祖细胞分布于肺动脉高压大鼠肺组织[J]. 基础医学与临床, 2016, 36(5): 644-650. DOI: 10.16352/j.issn.1001-6325.2016.05.014.
16 Pang Y, Liang MT, Gong Y, et al. HGF reduces disease severity and inflammation by attenuating the NF-κB signaling in a rat model of pulmonary artery hypertension[J]. Inflammation, 2018, 41(3): 924-931. PMID: 29442198. DOI: 10.1007/s10753-018-0747-1.
17 Tahara Y, Ido A, Yamamoto S, et al. Hepatocyte growth factor facilitates colonic mucosal repair in experimental ulcerative colitis in rats[J]. J Pharmacol Exp Ther, 2003, 307(1): 146-151. PMID: 12954797. DOI: 10.1124/jpet.103.054106.
18 Desole C, Gallo S, Vitacolonna A, et al. HGF and MET: from brain development to neurological disorders[J]. Front Cell Dev Biol, 2021, 9: 683609. PMID: 34179015. PMCID: PMC8220160. DOI: 10.3389/fcell.2021.683609.
19 Oliveira AG, Araújo TG, Carvalho BM, et al. The role of hepatocyte growth factor (HGF) in insulin resistance and diabetes[J]. Front Endocrinol (Lausanne), 2018, 9: 503. PMID: 30214428. PMCID: PMC6125308. DOI: 10.3389/fendo.2018.00503.
20 Meng SS, Guo FM, Zhang XW, et al. mTOR/STAT-3 pathway mediates mesenchymal stem cell-secreted hepatocyte growth factor protective effects against lipopolysaccharide-induced vascular endothelial barrier dysfunction and apoptosis[J]. J Cell Biochem, 2019, 120(3): 3637-3650. PMID: 30242894. DOI: 10.1002/jcb.27642.
21 陶金, 夏培哲, 周瑜, 等. 人胎盘胎儿来源间充质干细胞通过旁分泌肝细胞生长因子减轻脂多糖诱导的人肺微血管内皮细胞损伤[J]. 细胞与分子免疫学杂志, 2019, 35(2): 109-114. PMID: 30975274. DOI: 10.13423/j.cnki.cjcmi.008769.
22 Yin Y, Guo J, Teng F, et al. Preparation of a novel one-armed anti-c-met antibody with antitumor activity against hepatocellular carcinoma[J]. Drug Des DevelTher, 2019, 13: 4173-4184. PMID: 31849449. PMCID: PMC6911325. DOI: 10.2147/DDDT.S224491.
23 Xu X, Zhi T, Chao H, et al. ERK1/2/mTOR/Stat3 pathway-mediated autophagy alleviates traumatic brain injury-induced acute lung injury[J]. BiochimBiophys Acta Mol Basis Dis, 2018, 1864(5 Pt A): 1663-1674. PMID: 29466698. DOI: 10.1016/j.bbadis.2018.02.011.
24 Pan J, Li K, Huang W, et al. MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling[J]. PLoS One, 2017, 12(10): e0186245. PMID: 29016699. PMCID: PMC5634643. DOI: 10.1371/journal.pone.0186245.
25 王睿, 潘进进, 王定友, 等. “蓝嘴唇”: 缺氧性肺动脉高压肺血管重构研究进展[J]. 中国科学(生命科学), 2021, 51(12): 1637-1645. DOI: 10.1360/SSV-2021-0432.
26 Kim YC, Lee J, An JN, et al. Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis[J]. Sci Rep, 2019, 9(1): 13495. PMID: 31530851. PMCID: PMC6749055. DOI: 10.1038/s41598-019-49756-z.
27 谢晴晴, 孙一帆. 肝细胞生长因子与肿瘤发生发展的关系进展[J]. 中国医药导报, 2021, 18(33): 45-48, 67.
28 姜炜, 尹析凡, 朱洁琳. 慢性心力衰竭患者血清肝细胞生长因子、可溶性ST2及D-二聚体水平与心功能及心血管事件的关系[J]. 心脑血管病防治, 2021, 21(5): 426-429. DOI: 10.3969/j.issn.1009-816x.2021.05.003.
29 Huang TX, Guan XY, Fu L. Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells[J]. Am J Cancer Res, 2019, 9(9): 1889-1904. PMID: 31598393. PMCID: PMC6780671.