Helicobacter pylori infection and endothelial dysfunction

摘要 最近的研究表明，幽门螺杆菌(H。 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(S)是 目前尚不清楚。众所周知，内皮功能障碍在血管内皮细胞瘤的发生发展中起着关键作用。 动脉粥样硬化和相关的心血管疾病。该项目的初步数据显示，H。 幽门螺杆菌感染显著损害患者和C57BL/6小鼠的内皮依赖性血管扩张。 根除患者和小鼠幽门螺杆菌感染显著改善内皮依赖性血管 放松一下。幽门螺杆菌感染患者血清外切体培养人内皮细胞 在体外表现出明显的功能障碍，迁移、增殖和管状形成减少。外切体 来源于人胃上皮细胞的条件培养液，该细胞与含有H. 幽门螺杆菌毒力因子细胞毒素相关基因A(CagA)也显著降低内皮功能 类似于血清外切体。本项目的提出是为了检验幽门螺杆菌感染 通过外切体介导的机制损害内皮功能。具体目标是：1) 研究幽门螺杆菌感染对内皮细胞功能的影响；以及2)确定幽门螺杆菌感染对内皮功能的影响 外切体在幽门螺杆菌感染对内皮细胞功能影响中的作用因为绝大多数人 幽门螺杆菌感染患者感染含有毒力因子CagA的细菌，小鼠 (C57BL/6雄性和雌性小鼠)将在拟议的实验中感染CagA+H.Pylori。至 确定CagA蛋白对内皮功能的影响，CagA阴性的幽门螺杆菌也将用于 重复体外和体内研究以进行比较。将在小鼠身上测定内皮功能 感染CagA+或CagA-Hp合并PBS，并以灭活Hp为对照。评估 外切体在介导幽门螺杆菌感染对内皮细胞功能影响中的作用 将用GW4869处理，以减少细胞外切体的释放。如果假设是真的，那么它就是真的。 预计感染CagA+或CagA+或CagA+的小鼠的内皮功能将显著下降 CagA-H.Pylori(如果CagA对Hp感染诱导的内皮细胞很重要，CagA+Hp更是如此 功能障碍)。GW4869抑制外切体分泌有望有效恢复内皮 幽门螺杆菌感染小鼠的功能。这项拟议研究的数据将提供对 幽门螺杆菌感染患者发生血管功能障碍的机制和帮助 特别是探索防治心血管疾病新的有效策略 与幽门螺杆菌感染相关的动脉粥样硬化。

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.