幽门螺杆菌感染胃上皮细胞诱导血管生成素样蛋白4表达的机制及其功能研究

陈婉燕; 岳耕羽; 徐小林; 庄园

doi:10.16016/j.2097-0927.202309118

您当前的位置：

首页 >

文章列表页 >

幽门螺杆菌感染胃上皮细胞诱导血管生成素样蛋白4表达的机制及其功能研究

基础医学 | 更新时间：2026-01-09

- 幽门螺杆菌感染胃上皮细胞诱导血管生成素样蛋白4表达的机制及其功能研究
- Regulatory and functional mechanism of angiopoietin-like protein-4 in gastric epithelial cells with Helicobacter pylori infection
- 陆军军医大学学报 2024年46卷第9期页码：997-1006
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)药学与检验医学系微生物与生化药学教研室
  2.563000 贵州遵义，遵义医科大学附属医院消化内科
- 作者简介：
  
  [ 庄园，E-mail: yuanzhuang1983@yahoo.com ZHUANG Yuan, E-mail: yuanzhuang1983@yahoo.com
- 基金信息：
  
  国家自然科学基金面上项目(82070578)
- DOI：10.16016/j.2097-0927.202309118
  中图分类号： R322.44;R378.99;R341
- 收稿：2023-09-21，
  
  修回：2023-12-27，
  
  纸质出版：2024-05-15
- 稿件说明：
移动端阅览
陈婉燕, 岳耕羽, 徐小林, 等. 幽门螺杆菌感染胃上皮细胞诱导血管生成素样蛋白4表达的机制及其功能研究[J]. 陆军军医大学学报, 2024,46(9):997-1006.

Wanyan CHEN, Gengyu YUE, Xiaolin XU, et al. Regulatory and functional mechanism of angiopoietin-like protein-4 in gastric epithelial cells with Helicobacter pylori infection[J]. Journal of Army Medical University, 2024, 46(9): 997-1006.
陈婉燕, 岳耕羽, 徐小林, 等. 幽门螺杆菌感染胃上皮细胞诱导血管生成素样蛋白4表达的机制及其功能研究[J]. 陆军军医大学学报, 2024,46(9):997-1006. DOI： 10.16016/j.2097-0927.202309118.

Wanyan CHEN, Gengyu YUE, Xiaolin XU, et al. Regulatory and functional mechanism of angiopoietin-like protein-4 in gastric epithelial cells with Helicobacter pylori infection[J]. Journal of Army Medical University, 2024, 46(9): 997-1006. DOI： 10.16016/j.2097-0927.202309118.

摘要

目的

探究血管生成素样蛋白4(angiopoietin-like 4

ANGPTL4)在幽门螺杆菌(

Helicobacter pylori

，

H.pylori

)感染的胃上皮细胞中的表达调控及其功能机制。

方法

收集2021年11月陆军军医大学第二附属医院消化内科胃镜室

H.pylori

阳性患者的胃镜标本以及

H.pylori

感染小鼠的胃组织，利用免疫荧光染色技术检测ANGPTL4在胃组织中的表达部位；用

H.pylori

感染胃上皮细胞和胃类器官，运用实时荧光定量PCR和Western blot等检测ANGPTL4的表达；探讨

H.pylori

感染诱导ANGPTL4表达的调控机制；利用ANGPTL4重组蛋白刺激胃上皮细胞，检测其对密封蛋白1 (claudin 1，CLDN1)表达的影响。

结果

H.pylori

感染能显著诱导胃上皮细胞ANGPTL4表达增加，且具有毒力因子CagA依赖性、细菌浓度依赖性和感染时间依赖性(

＜0.05)；相对于未感染组和CagA敲除(△

cagA

)

H.pylori

感染组，野生型(wild-type，WT)

H.pylori

感染组的人和小鼠胃类器官ANGPTL4表达显著上调(

＜0.05)；调控机制方面，阻断信号通路NF-κB可明显抑制胃上皮细胞ANGPTL4表达增加(

＜0.05)；功能机制方面，ANGPTL4重组蛋白通过激活通路ERK下调胃上皮细胞CLDN1表达(

＜0.05)。

结论

H.pylori

依赖毒力因子CagA通过激活NF-κB信号通路诱导胃上皮细胞表达ANGPTL4；AN

GPTL4激活通路ERK下调胃上皮细胞CLDN1表达，从而影响

H.pylori

感染相关胃部疾病的发展。

Abstract

Objective

To explore the regulatory and functional mechanism of angiopoietin-like 4 (ANGPTL4) expression in gastric epithelial cells infected with

Helicobacter pylori

(

H.pylori

Methods

H.pylori

-positive gastric specimens from Department of Gastroenterology of second Affiliated Hospital of Army Medical University in November 2021 and the gastric tissues of

H.pylori

-infected mice were collected

and the expression locations of ANGPTL4 in these gastric tissues were detected by immunofluorescence assay. After gastric epithelial cells and gastric organoids were infected with

H.pylori

the expression of ANGPTL4 was detected by real-time PCR and Western blotting. The regulatory mechanism of

H.pylori

-induced ANGPTL4 expression was investigated by cellular models above. Recombinant ANGPTL4 was used to stimulate gastric epithelial cells to investigate the effect of ANGPTL4 on the claudin 1 (CLDN1) expression.

Results

H.pylori

infection significantly increased the expression of ANGPTL4 in gastric epithelial cells in a CagA-dependent

bacterial concentration-dependent and infection time-dependent manner (

0.05). Compared to uninfected cells and CagA knockout (△cagA)

H.pylori

-induced ones

the ANGPTL4 expression was significantly increased in WT

H.pylori

-infected human and mouse gastric organoid (

0.05). Blocking NF-κB signaling pathway significantly inhibited the enhanced ANGPTL4 expression in

H.pylori

-infected gastric epithelial cells (

0.05). Recombinant ANGPTL4 activated ERK signaling pathway to down-regulate the CLDN1 expression in gastric epith

elial cells (

0.05).

Conclusion

H.pylori

activates NF-κB signaling pathway to up-regulate ANGPTL4 expression in gastric epithelial cells in a CagA-dependent manner

and ANGPTL4 activates ERK signaling pathway to down-regulate the CLDN1 expression in gastric epithelial cells

which may contributes to the development of gastric diseases induced by

H.pylori

infection.

关键词

Keywords

references

MARSHALL B J, WARREN J R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration[J]. Lancet, 1984, 1(8390): 1311-1315. DOI: 10.1016/s0140-6736(84)91816-6.

SALAMA N R, HARTUN G M L, MVLLER A. Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori [J ] . Nat Rev Microbiol, 2013, 11(6): 385-399. DOI: 10.1038/nrmicro3016.

DOOLEY C P, COHEN H, FITZGIBBONS P L, et al . Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons[J ] . N Engl J Med, 1989, 321(23): 1562-1566. DOI: 10.1056/NEJM198912073212302..

GOODWIN C S, ARMSTRONG J A, MARSHALL B J. Campylobacter pyloridis, gastritis, and peptic ulceration[J ] . J Clin Pathol, 1986, 39(4): 353-365. DOI: 10.1136/jcp.39.4.353.

PLUMMER M, FRANCESCHI S, VIGNAT J, et al . Global burden of gastric cancer attributable to Helicobacter pylori [J ] . Int J Cancer, 2015, 136(2): 487-490. DOI: 10.1002/ijc.28999..

BOYANOVA L, HADZHIYSKI P, GERGOVA R, et al . Evolution of Helicobacter pylori resistance to antibiotics: a topic of increasing concern[J ] . Antibiotics, 2023, 12(2): 332. DOI: 10.3390/antibiotics12020332..

AMIEVA M, JR PEEK R M. Pathobiology of Helicobacter pylori -induced gastric cancer[J ] . Gastroenterology, 2016, 150(1): 64-78. DOI: 10.1053/j.gastro.2015.09.004.

ANSARI S, YAMAOKA Y. Helicobacter pylori virulence factor cytotoxin-associated gene A (CagA)-mediated gastric pathogenicity[J ] . Int J Mol Sci, 2020, 21(19): 7430. DOI: 10.3390/ijms21197430.

SANTULLI G. Angiopoietin-like proteins: a comprehensive look[J]. Front Endocrinol, 2014, 5: 4. DOI: 10.3389/fendo.2014.00004.

YIN W, ROMEO S, CHANG S R, et al . Genetic variation in ANGPTL4 provides insights into protein processing and function[J ] . J Biol Chem, 2009, 284(19): 13213-13222. DOI: 10.1074/jbc.M900553200.

LEI X, SHI F J, BASU D, et al . Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity[J ] . J Biol Chem, 2011, 286(18): 15747-15756. DOI: 10.1074/jbc.M110.217638.

FOLSOM A R, PEACOCK J M, DEMERATH E, et al . Variation in ANGPTL4 and risk of coronary heart disease: the atherosclerosis risk in communities study[J ] . Metabolism, 2008, 57(11): 1591-1596. DOI: 10.101 6/j.metabol.2008.06.016.

PADUA D, ZHANG X H F, WANG Q Q, et al . TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4[J ] . Cell, 2008, 133(1): 66-77. DOI: 10.1016/j.cell.2008.01.046.

KOREK E, KRAUSS H. Novel adipokines: their potential role in the pathogenesis of obesity and metabolic disorders[J]. Postepy Hig Med Dosw, 2015, 69: 799-810.

SODHI A, MA T, MENON D, et al . Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema[J ] . J Clin Invest, 2019, 129(11): 4593-4608. DOI: 10.1172/JCI120879.

GOH Y Y, PAL M, CHONG H C, et al . Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing[J ] . J Biol Chem, 2010, 285(43): 32999-33009. DOI: 10.1074/jbc.M110.108175.

GUO L, LI S Y, JI F Y, et al . Role of Angptl4 in vascular permeability and inflammation[J ] . Inflamm Res, 2014, 63(1): 13-22. DOI: 10.1007/s00011-013-0678-0.

LV Y P, CHENG P, ZHANG J Y, et al . Helicobacter pylori -induced matrix metallopeptidase-10 promotes gastric bacterial colonization and gastritis[J ] . Sci Adv, 2019, 5(4): eaau6547. DOI: 10.1126/sciadv.aau6547..

TENG Y S, XIE R, XU J Y, et al . Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection[J ] . Cell Mol Immunol, 2023, 20(8): 924-940. DOI: 10.1038/s41423-023-01055-4..

TENG Y S, CANG B C, MAO F Y, et al . Expression of ETS1 in gastric epithelial cells positively regulate inflammatory response in Helicobacter pylori -associated gastritis[J ] . Cell Death Dis, 2020, 11(7): 498. DOI: 10.1038/s41419-020-2705-8..

IDOWU S, BERTRAND P P, WALDUCK A K. Gastric organoids: advancing the study of H. pylori pathogenesis and inflammation[J ] . Helicobacter, 2022, 27(3): e12891. DOI: 10.1111/hel.12891.

LANCASTER M A, KNOBLICH J A. Organogenesis in a dish: modeling development and disease using organoid technologies[J]. Science, 2014, 345(6194): 1247125. DOI: 10.1126/science.1247125.

TOHIDPOUR A. CagA-mediated pathogenesis of Helicobacter pylori [J ] . Microb Pathog, 2016, 93: 44-55. DOI: 10.1016/j.micpath.2016.01.005.

CHOI S, KIM N, PARK J H, et al . Effect of Helicobacter pylori infection and its eradication on the expression of tight junction proteins in the gastric epithelium in relation to gastric carcinogenesis[J ] . Helicobacter, 2022, 27(6): e12929. DOI: 10.1111/hel.12929..

GOMEZ PERDIGUERO E, LIABOTIS-FONTUGNE A, DURAND M, et al . ANGPTL4-αvβ3 interaction counteracts hypoxia-induced vascular permeability by modulating Src signalling downstream of vascular endothelial growth factor receptor 2[J ] . J Pathol, 2016, 240(4): 461-471. DOI: 10.1002/path.4805.

HUANG R L, TEO Z, CHONG H C, et al . ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters[J ] . Blood, 2011, 118(14): 3990-4002. DOI: 10.1182/blood-2011-01-328716.

ALGOOD H M, COVER T L. Helicobacter pylori persistence: an overview of interactions between H. pylori and host immune defenses[J ] . Clin Microbiol Rev, 2006, 19(4): 597-613. DOI: 10.1128/CMR.00006-06..

KERSTEN S, MANDARD S, TAN N S, et al . Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene[J ] . J Biol Chem, 2000, 275(37): 28488-28493. DOI: 10.1074/jbc.M004029200.

LIU D J, PELOSO G M, YU H J, et al . Exome-wide association study of plasma lipids in > 300000 individuals[J ] . Nat Genet, 2017, 49: 1758-1766. DOI: 10.1038/ng.3977.

GUSAROVA V, O'DUSHLAINE C, TESLOVICH T M, et al . Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes[J ] . Nat Commun, 2018, 9(1): 2252. DOI: 10.1038/s41467-018-04611-z.

ZUO Y, HEZ, CHEN Y, et al . Dual role of ANGPTL4 in inflammation[J ] . Inflammation Res, 2023, 72(6): 1303-1313. DOI: 10.1007/s00011-023-01753-9.

浏览量

165

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

川藏线官兵幽门螺杆菌感染的相关因素分析

幽门螺杆菌感染对胃黏膜上皮细胞REDD1表达的影响及调控机制

联动成像内镜辅助诊断幽门螺杆菌感染的临床价值

10 137例胃息肉的临床及病理特征分析

肾上腺髓质素在幽门螺杆菌感染中的表达调控及其功能的初步研究