ENDOTHELIAL CELL DYSFUNCTION & APOPOTOSIS IN ACCELERATED GRAFT ARTERIOSCLEROSIS

内皮细胞功能障碍

• 批准号: 6273138
• 负责人: NICHOLAS A FLAVAHAN
• 金额: $ 24.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-30 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273138
• 关键词: CD antigens; apoptosis; arteriosclerosis; cell transplantation; cellular pathology; complement pathway; coronary artery; cytomegalovirus; cytotoxic T lymphocyte; electromyography; free radicals; guanine nucleotide binding protein; heart transplantation; immunocytochemistry; laboratory mouse; laboratory rat; nuclear factor kappa beta; oxidative stress; phosphatidylserines; receptor coupling; transfection; vascular endothelium

Accelerated graft arteriosclerOsis (AGA) represents a major obstacle to long term survival of heart transplant recipients. While it has become clear that AGA is a multifactorial problem, the specific mechanisms leading to AGA remain unknown. Because of their pivotal role in the maintenance of vessel homeostasis, endothelial cells (EcS) are likely to represent prime targets in the pathogenesis of AGA. Project 1 is designed to provide in-depth characterization of the process that affects ECs in AGA, from extracellular factors to intracellular molecular pathways that transduce messages to the genome of ECs. By integrating our studies on ECs with other projects of this program, we intend to provide information that will be key to the development of specific strategies to suppress AGA. In AGA, the functional damage to the endothelium is diffuse. Morphologically, areas of endothelial erosion can be found dispersed along the coronary vessels. Several mechanisms of BC ii-jury have been implicated in AGA: (i) oxidative injury resulting from ischemia/reperfusion at the time of surgery; (ii) immunological injuries involving complement activation, processing and presentation of antigens, activation and adhesion of T.lymphocytes, in particular cytolytic T- lymphocytes (CTL), sequestration of monocytes, production of antibodies against allo- or iso-antigens, and dysregulation of the immune system with Cyclosporine A; (iii) injury with CMV-infection/reactivation; and (iv) direct Cyclosporine A toxicity. These various mechanisms could contribute either independently or in concert, to the diffuse abnormalities of ECs in AGA. Particular emphasis will be placed on the following pathway, which will provide the basis for the specific aims of this project: (i) the initial injury results in uncoupling of Gi-2 from its membrane receptors; (ii) the uncoupling of Gi-2 then results in BC dysfunction and overexpression of Fas on the surface of ECs, through a pathway that requires NF-kappaB activation; (iii) overexpression of Fas, in turn, results in the "kiss of death" as CTL bind to the ECs through the interaction of Fas and Fas-ligand present on the CTL surface; (iv) increased BC apoptosis will further aggravate the dysfunctional aspect of the endothelium and promote fibrin production and deposition due to the abnormal presence of phosphatidylserine on the surface of ECs. As a result, the endothelium in these patients is not capable of carrying out its usual functions namely, vasodilation, anti-thrombotic effect, anti- proliferative effect for the cells of the vessel wall, control of the attachment of inflammatory cells, and homeostasis of extracellular protein production, leading to the development of AGA.

加速移植动脉硬化（AGA）代表了 心脏移植受者的长期生存。虽然它已经变成 清楚地表明，AGA是一个多因素问题，即特定机制 导致AGA仍然未知。由于它们在 维持血管稳态，内皮细胞（EC）可能 代表AGA发病机理中的主要靶标。项目1是设计的 为影响ECS的过程提供深入的表征 AGA，从细胞外因子到细胞内分子途径 将信息传递给ECS的基因组。通过整合我们对EC的研究 在该计划的其他项目中，我们打算提供信息 将是制定抑制AGA的特定策略的关键。在 AGA，对内皮的功能损害是分散的。 从形态上讲，可以发现内皮侵蚀的区域分散 冠状动脉。 BC II-JURY的几种机制已经 与AGA有关：（i）由 手术时的缺血/再灌注； （ii）免疫伤害 涉及抗原的补体激活，加工和表现， T.淋巴细胞的激活和粘附，特别是细胞溶解的T- 淋巴细胞（CTL），单核细胞的隔离，抗体的产生 针对同种或异抗原，以及免疫系统的失调 环孢素A； （iii）CMV感染/重新激活的损伤； （iv） 直接环孢菌素A毒性。这些各种机制可能有助于 无论是独立还是共同，以EC的弥漫性异常 Aga。特别重点将放在以下途径上 将为该项目的具体目的提供基础：（i） 最初的损伤导致GI-2与膜受体的解偶联； （ii）GI-2的解偶联，然后导致BC功能障碍和 通过EC表面的FAS过表达，通过一条途径 需要NF-kappab激活； （iii）FAS的过表达反过来 由于CTL通过 CTL表面上存在FAS和FAS配体的相互作用； （iv） BC凋亡增加将进一步加剧 内皮并促进纤维蛋白的产生和沉积 EC表面上磷脂酰丝氨酸的异常存在。 作为 结果，这些患者的内皮无法进行 它通常的功能，即血管舒张，抗栓性效应，抗 血管壁细胞的增殖作用，控制 炎症细胞的附着和细胞外蛋白的稳态 生产，导致AGA的发展。