Helicobacter pylori infection and endothelial dysfunction

幽门螺杆菌感染与内皮功能障碍

• 批准号: 10458021
• 负责人: ZHENGUO LIU
• 金额: $ 65.13万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458021
• 关键词: Acetylcholine; Acute; Adult; Age; Animals; Aorta; Asia; Atherosclerosis; Autoimmune Diseases; Bacteria; Blood Vessels; Body Fluids; Body mass index; Breath Tests; C57BL/6 Mouse; Cardiovascular Diseases; Cardiovascular Physiology; Carotid Arteries; Carotid Atherosclerotic Disease; Cell Communication; Cells; Cessation of life; China; Collaborations; Coronary Arteriosclerosis; Coronary artery; Cytotoxin; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Dilatation - action; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Exhibits; Female; Functional disorder; Gastrointestinal Diseases; General Population; Genes; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; Hematological Disease; Human; Hyperlipidemia; Hypertension; Impairment; In Vitro; Incidence; Infection; Injury; Ischemic Stroke; Lead; Lipids; Mediating; Membrane Lipids; MicroRNAs; Morbidity - disease rate; Multivesicular Body; Mus; Myocardial Infarction; Nitroglycerin; Obesity; Odds Ratio; Pathogenesis; Patients; Play; Population Heterogeneity; Prevention; Proteins; Relaxation; Research Personnel; Risk Factors; Role; Serum; Smoking; Stomach; Stroke; Structure; Testing; Tube; Urea; Vascular Diseases; Vascular Endothelium-Dependent Relaxation; Vasodilation; Virulence Factors; Virulent; atherosclerosis risk; brachial artery; cardiovascular risk factor; chronic liver disease; design; endothelial dysfunction; exosome; experimental study; extracellular vesicles; gender difference; healthy volunteer; improved; in vivo; infection rate; insight; male; microorganism; migration; mortality; nervous system disorder; novel; particle; prevent; sex; skin disorder; ultrasound

Abstract Recent studies have suggested an increased risk for atherosclerosis in patients with Helicobacter pylori (H. pylori) infection. However, the mechanism(s) for increased risk for atherosclerosis with H. pylori infection is currently unknown. It is well known that endothelial dysfunction plays a critical role in the development of atherosclerosis and related cardiovascular diseases. The preliminary data for the project have shown that H. pylori infection significantly impairs endothelium-dependent vasodilation in both patients and C57BL/6 mice. Eradication of H. pylori infection in patients and mice significantly improves endothelium-dependent vascular relaxation. Human endothelial cells cultured with serum exosomes from patients with H. pylori infection exhibited significant dysfunction with decreased migration, proliferation, and tube formation in vitro. Exosomes derived from conditioned media of human gastric epithelial cells cultured with H. pylori bacteria containing H. pylori virulent factor cytotoxin-associated gene A (CagA) also significantly decreased endothelial functions similar to serum exosomes. The present project is proposed to test the hypothesis that H. pylori infection impairs endothelial function through exosome-mediated mechanism. The specific aims are: 1) to investigate the effect of H. pylori infection on endothelial function; and 2) to define the role of exosomes in mediating the effect of H. pylori infection on endothelial function. Since the vast majority of patients with H. pylori infection are infected with the bacteria containing the virulence factor CagA, the mice (C57BL/6 mice, both male and female) will be infected with CagA+ H. pylori for the proposed experiments. To determine the effect of CagA protein on endothelial function, CagA- (negative) H. pylori will also be used to repeat the in vitro and in vivo studies for comparison. Endothelial function will be determined in the mice infected with either CagA+ or CagA- H. pylori with PBS as well as inactivated H. pylori as controls. To evaluate the role of exosomes in mediating the effect of H. pylori infection on endothelial function in vivo, the animals will be treated with GW4869 to decrease the release of exosomes from cells. If the hypothesis is true, it is expected that endothelial function will be significantly decreased in the mice infected with either CagA+ or CagA- H. pylori (more so with CagA+ H. pylori if CagA is important to H. pylori infection-induced endothelial dysfunction). Inhibition of exosomes secretion with GW4869 is anticipated to effectively restore endothelial function in mice with H. pylori infection. The data from the proposed study will provide novel insights into the mechanisms for the development of vascular dysfunction in the patients with H. pylori infection, and help explore new and effective strategies to preventing and treating cardiovascular diseases especially atherosclerosis associated with H. pylori infection.

抽象的 最近的研究表明幽门螺杆菌（H. pylori）患者发生动脉粥样硬化的风险增加。 幽门螺杆菌）感染。然而，幽门螺杆菌感染导致动脉粥样硬化风险增加的机制是 目前未知。众所周知，内皮功能障碍在疾病的发生发展中起着至关重要的作用。 动脉粥样硬化和相关的心血管疾病。该项目的初步数据表明，H. 幽门螺杆菌感染显着损害患者和 C57BL/6 小鼠的内皮依赖性血管舒张。 根除患者和小鼠的幽门螺杆菌感染可显着改善内皮依赖性血管 松弛。用幽门螺杆菌感染患者血清外泌体培养人内皮细胞 在体外表现出显着的功能障碍，迁移、增殖和管形成减少。外泌体 源自与含有幽门螺杆菌的幽门螺杆菌一起培养的人胃上皮细胞的条件培养基。 幽门螺杆菌毒力因子细胞毒素相关基因 A (CagA) 也显着降低内皮功能 与血清外泌体类似。本项目旨在检验幽门螺杆菌感染的假设 通过外泌体介导的机制损害内皮功能。具体目标是：1） 探讨幽门螺杆菌感染对内皮功能的影响； 2) 定义角色 外泌体介导幽门螺杆菌感染对内皮功能的影响。由于绝大多数 幽门螺杆菌感染患者被含有毒力因子CagA的细菌感染后，小鼠 （C57BL/6 小鼠，雄性和雌性）将感染 CagA+ 幽门螺杆菌以进行拟议的实验。到 确定 CagA 蛋白对内皮功能的影响，CagA-（阴性）幽门螺杆菌也将用于 重复体外和体内研究进行比较。将测定小鼠的内皮功能 用 PBS 感染 CagA+ 或 CagA- 幽门螺杆菌以及灭活的幽门螺杆菌作为对照。评估 外泌体在介导幽门螺杆菌感染对体内内皮功能的影响中的作用，动物 将用 GW4869 处理以减少细胞中外泌体的释放。如果假设为真，则 预计感染 CagA+ 或 CagA+ 的小鼠的内皮功能将显着下降 CagA-幽门螺杆菌（如果 CagA 对幽门螺杆菌感染诱导的内皮细胞很重要，则 CagA+ 幽门螺杆菌更是如此） 功能障碍）。 GW4869 抑制外泌体分泌有望有效恢复内皮细胞 幽门螺杆菌感染小鼠的功能。拟议研究的数据将为我们提供新的见解 幽门螺杆菌感染患者血管功能障碍的发生机制，并有助于 探索预防和治疗心血管疾病的新的有效策略 与幽门螺杆菌感染相关的动脉粥样硬化。

项目成果

Helicobacter pylori infection selectively attenuates endothelial function in male mice via exosomes-mediated ROS production.

幽门螺杆菌感染通过外泌体介导的 ROS 产生选择性减弱雄性小鼠的内皮功能。

• 发表时间: 2023
• 作者: Zhang, Linfang;Xia, Xiujuan;Wu, Hao;Liu, Xuanyou;Zhu, Qiang;Wang, Meifang;Hao, Hong;Cui, Yuqi;Li, De;Chen, Shi;Martinez;Hill, Michael A;Xu, Canxia;Liu, Zhenguo
• 通讯作者: Liu, Zhenguo

N-Acetylcysteine and Atherosclerosis: Promises and Challenges.

N-乙酰半胱氨酸和动脉粥样硬化：前景和挑战。

• 发表时间: 2023-12-04
• 作者: Cui, Yuqi;Zhu, Qiang;Hao, Hong;Flaker, Gregory C;Liu, Zhenguo
• 通讯作者: Liu, Zhenguo

CagA+ Helicobacter pylori, Not CagA- Helicobacter pylori, Infection Impairs Endothelial Function Through Exosomes-Mediated ROS Formation.

CagA 幽门螺杆菌，而非 CagA- 幽门螺杆菌，感染通过外泌体介导的 ROS 形成损害内皮功能。

• 发表时间: 2022
• 作者: Xia, Xiujuan;Zhang, Linfang;Wu, Hao;Chen, Feng;Liu, Xuanyou;Xu, Huifang;Cui, Yuqi;Zhu, Qiang;Wang, Meifang;Hao, Hong;Li, De;Fay, William P;Martinez;Hill, Michael A;Xu, Canxia;Liu, Zhenguo
• 通讯作者: Liu, Zhenguo