Cytotoxin-associated gene A (CagA) promotes aortic endothelial inflammation and accelerates atherosclerosis through the NLRP3/caspase-1/IL-1β axis
Cytotoxin-associated gene A (CagA) promotes aortic endothelial inflammation and accelerates atherosclerosis through the NLRP3/caspase-1/IL-1β axis
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细胞毒素相关基因 A (CagA) 通过 NLRP3/caspase-1/IL-1β 轴促进主动脉内皮炎症并加速动脉粥样硬化
DOI：
10.1096/fj.202100695rr
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发表时间：
2021-11-01
期刊：
影响因子：
4.8
通讯作者：
Xia, Yuan-Peng
中科院分区：
文献类型：
--
作者：
Li, Bo-Wei;Liu, Yu;Xia, Yuan-Peng
动脉粥样硬化是一种慢性炎性疾病。慢性感染和动脉粥样硬化之间的病理生理相似性引发了这些疾病之间的兴趣。血清流行病学研究表明，表达癌蛋白和主要毒力因子细胞毒素相关基因A （CagA）的幽门螺杆菌菌株与动脉粥样硬化及相关临床事件呈正相关。然而，人们对其潜在机制知之甚少。在本研究中，通过酶联免疫吸附试验（ELISA）评估幽门螺杆菌感染和表达CagA菌株感染的血清阳性率，发现患者中CagA菌株的患病率与动脉粥样硬化的发生呈正相关，而不是幽门螺杆菌。相应地，我们发现在动脉粥样硬化早期，CagA增强了ApoE（-/-）小鼠斑块的生长，促进了小鼠主动脉内皮细胞（MAECs）粘附分子和炎症细胞因子的表达。在机制上，si-NLRP3和si-IL-1 β都减轻了CagA对haec炎症活化的促进作用。在体内，MCC950对NLRP3的抑制作用显著减弱了CagA对ApoE（-/-）小鼠斑块生长的促进作用。我们还提出NLRP3作为caga阳性幽门螺杆菌感染相关动脉粥样硬化的潜在治疗靶点，并强调炎症在动脉粥样硬化病理中的重要性。
Atherosclerosis is a chronic inflammatory disease. Pathophysiological similarities between chronic infections and atherosclerosis triggered interests between these conditions. The seroepidemiological study showed that Helicobacter pylori strains that express cytotoxin-associated gene A (CagA), an oncoprotein and a major virulence factor, was positively correlated with atherosclerosis and related clinical events. Nevertheless, the underlying mechanism is poorly understood. In this study, the seroprevalence of infection by H. pylori and by strains express CagA assessed by enzyme-linked immunosorbent assay (ELISA) showed that the prevalence of CagA strains rather than H. pylori in patients was positively correlated with atherogenesis. Correspondingly, we found that CagA augmented the growth of plaque of ApoE(-/-) mice in the early stage of atherosclerosis and promoted the expression of adhesion molecules and inflammatory cytokines in mouse aortic endothelial cells (MAECs). Mechanistically, both si-NLRP3 and si-IL-1 beta mitigated the promoting effect of CagA on the inflammatory activation of HAECs. In vivo, the inhibition of NLRP3 by MCC950 significantly attenuated the promoting effect of CagA on plaque growth of ApoE(-/-) mice. We also propose NLRP3 as a potential therapeutic target for CagA-positive H. pylori infection-related atherosclerosis and emphasize the importance of inflammation in atherosclerosis pathology.