Exosomal CagA derived from Helicobacter pylori-infected gastric epithelial cells induces macrophage foam cell formation and promotes atherosclerosis
Exosomal CagA derived from Helicobacter pylori-infected gastric epithelial cells induces macrophage foam cell formation and promotes atherosclerosis
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幽门螺杆菌感染的胃上皮细胞来源的外泌体CagA诱导巨噬细胞泡沫细胞形成并促进动脉粥样硬化
DOI：
10.1016/j.yjmcc.2019.07.011
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发表时间：
2019
影响因子：
5
通讯作者：
Hu Bo
中科院分区：
文献类型：
--
作者：
Yang Shuai;Xia Yuan peng;Luo Xue ying;Chen Shao li;Li Bo wei;Ye Zi ming;Chen Sheng cai;Mao Ling;Jin Hui juan;Li Ya nan;Hu Bo
背景血清流行病学研究表明，CagA阳性幽门螺杆菌（H. pylori）、动脉粥样硬化及相关临床事件。然而，这种联系尚未得到很好的验证。本研究旨在探讨H. pylori PMSS 1（一种CagA阳性菌株，能将CagA转运到宿主细胞中）和外泌体CagA在动脉粥样硬化的进展中的作用。pylori加速甚至诱导动脉粥样硬化，H.幽门螺杆菌感染的C57/BL 6小鼠和ApoE−/−小鼠在不同的饮食条件下饲养。确定H.幽门螺杆菌感染的胃上皮细胞来源的外泌体（Hp-GES-EVs）和外泌体CagA在动脉粥样硬化中的作用，ApoE−/−小鼠静脉或腹腔注射生理盐水、GES-EVs、Hp-GES-EVs和重组CagA蛋白（rCagA）。pyloriPMSS 1感染不诱导但促进巨噬细胞衍生的泡沫细胞形成，并在两种动物模型中增加动脉粥样硬化斑块的生长和不稳定性。同时，循环中的Hp-GES-EV被主动脉斑块摄取，并分泌CagA。此外，含有CagA的EV和rCagA在体外和体内加剧巨噬细胞源性泡沫细胞的形成和病变的发展，重现了CagA阳性的H.幽门。CagA通过下调转录因子PPARγ和LXRα的表达，抑制胆固醇外排转运蛋白的转录，从而促进泡沫细胞的形成。幽门感染相关的动脉粥样硬化。提示预防和根除CagA阳性H.幽门螺杆菌感染可降低动脉粥样硬化及相关事件的发生率。
BackgroundSeroepidemiological studies have highlighted a positive relation between CagA-positive Helicobacter pylori (H. pylori), atherosclerosis and related clinic events. However, this link has not been well validated. The present study was designed to explore the role ofH. pyloriPMSS1 (a CagA-positive strain that can translocate CagA into host cells) and exosomal CagA in the progression of atherosclerosis.MethodsTo evaluate whetherH. pyloriaccelerates or even induces atherosclerosis,H. pylori-infected C57/BL6 mice and ApoE−/−mice were maintained under different dietary conditions. To identify the role ofH. pylori-infected gastric epithelial cells-derived exosomes (Hp-GES-EVs) and exosomal CagA in atherosclerosis, ApoE−/−mice were given intravenous or intraperitoneal injections of saline, GES-EVs,Hp-GES-EVs, and recombinant CagA protein (rCagA).FindingsCagA-positiveH. pyloriPMSS1 infection does not induce but promotes macrophage-derived foam cell formation and augments atherosclerotic plaque growth and instability in two animal models. Meanwhile, circulatingHp-GES-EVs are taken up in aortic plaque, and CagA is secreted inHp-GES-EVs. Furthermore, the CagA-containing EVs and rCagA exacerbates macrophage-derived foam cell formation and lesion developmentin vitroandin vivo, recapitulating the pro-atherogenic effects of CagA-positiveH. pylori. Mechanistically, CagA suppresses the transcription of cholesterol efflux transporters by downregulating the expression of transcriptional factors PPARγ and LXRα and thus enhances foam cell formation.InterpretationThese results may provide new insights into the role of exosomal CagA in the pathogenesis of CagA-positiveH. pyloriinfection-related atherosclerosis. It is suggested that preventing and eradicating CagA-positiveH. pyloriinfection could reduce the incidence of atherosclerosis and related events.