Helicobacter pylori infection and endothelial dysfunction

幽门螺杆菌感染与内皮功能障碍

• 批准号: 10252889
• 负责人: ZHENGUO LIU
• 金额: $ 65.87万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252889
• 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; Cultured Cells; 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; Ultrasonography; 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

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，幽门螺杆菌患者患动脉粥样硬化的风险增加（H. 幽门螺杆菌感染。但是，幽门螺杆菌感染的动脉粥样硬化风险增加的机制是 目前未知。众所周知，内皮功能障碍在发展中起着至关重要的作用 动脉粥样硬化和相关心血管疾病。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。 消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。幽门螺杆菌感染患者的血清外泌体培养的人内皮细胞 体外迁移，增殖和管形成下降，表现出明显的功能障碍。外泌体 源自含有H.幽门螺杆菌的人类胃上皮细胞的条件培养基。 幽门螺杆菌毒因子细胞毒素相关基因A（CAGA）也显着降低了内皮功能 类似于血清外泌体。提出了本项目以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。具体目的是：1） 研究幽门螺杆菌感染对内皮功能的影响； 2）定义 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 幽门螺杆菌感染的患者被含有毒力因子CAGA的细菌感染小鼠 （C57BL/6小鼠，男性和女性）将被CAGA+ H.幽门螺体感染，以进行拟议的实验。到 确定CAGA蛋白对内皮功能的影响，CAGA-（负）幽门螺杆菌也将用于 重复体外和体内研究以进行比较。内皮功能将在小鼠中确定 用PBS和幽门螺杆菌作为对照，被CAGA+或CAGA-H.幽门螺杆菌感染。评估 外泌体在介导幽门螺杆菌感染对体内内皮功能的作用中的作用 将用GW4869处理以减少细胞外泌体的释放。如果假设是真的，那是 预计被CAGA+或 幽门螺杆菌（与幽门螺杆菌有关，如果Caga对幽门螺杆菌感染诱导的内皮很重要 功能障碍）。预计用GW4869抑制外泌体分泌有效恢复内皮 在幽门螺杆菌感染的小鼠中功能。拟议研究的数据将为您提供新的见解 幽门螺杆菌感染患者血管功能障碍发展的机制，并有助于 探索新的有效策略，以预防和治疗心血管疾病 与幽门螺杆菌感染有关的动脉粥样硬化。