Interdepartmental Program in Vascular Biology and Therapeutics, Departments of Pathology and Surgery, Yale University School of Medicine, New Haven, Connecticut; Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Interdepartmental Program in Vascular Biology and Therapeutics, Departments of Pathology and Surgery, Yale University School of Medicine, New Haven, Connecticut.
J Am Coll Cardiol. 2014;63(1):21-9. doi: 10.1016/j.jacc.2013.08.694. Epub 2013 Aug 28.
The aim of this study was to determine the role of suppressor of cytokine signaling 1 (SOCS1) in graft arteriosclerosis (GA).
GA, the major cause of late cardiac allograft failure, is initiated by immune-mediated endothelial activation resulting in vascular inflammation and consequent neointima formation. SOCS1, a negative regulator of cytokine signaling, is highly expressed in endothelial cells (ECs) and may prevent endothelial inflammatory responses and phenotypic activation.
Clinical specimens of coronary arteries with GA, with atherosclerosis, or without disease were collected for histological analysis. SOCS1 knockout or vascular endothelial SOCS1 (VESOCS1) transgenic mice were used in an aorta transplant model of GA. Mouse aortic ECs were isolated for in vitro assays.
Dramatic but specific reduction of endothelial SOCS1 was observed in human GA and atherosclerosis specimens, which suggested the importance of SOCS1 in maintaining normal endothelial function. SOCS1 deletion in mice resulted in basal EC dysfunction. After transplantation, SOCS1-deficient aortic grafts augmented leukocyte recruitment and neointima formation, whereas endothelial overexpression of SOCS1 diminished arterial rejection. Induction of endothelial adhesion molecules in early stages of GA was suppressed by the VESOCS1 transgene, and this effect was confirmed in cultured aortic ECs. Moreover, VESOCS1 maintained better vascular function during GA progression. Mechanistically, endothelial SOCS1, by modulating both basal and cytokine-induced expression of the adhesion molecules platelet/endothelial cell adhesion molecule-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, restrained leukocyte adhesion and transendothelial migration during inflammatory cell infiltration.
SOCS1 prevents GA progression by preserving endothelial function and attenuating cytokine-induced adhesion molecule expression in vascular endothelium.
本研究旨在探讨细胞因子信号转导抑制因子 1（SOCS1）在移植后动脉粥样硬化（GA）中的作用。
GA 是心脏移植物晚期衰竭的主要原因，其发病机制是免疫介导的内皮细胞激活，导致血管炎症和随后的新生内膜形成。SOCS1 是细胞因子信号的负调节剂，在血管内皮细胞（ECs）中高度表达，可能防止内皮炎症反应和表型激活。
收集伴有 GA、动脉粥样硬化或无病变的冠状动脉临床标本进行组织学分析。SOCS1 基因敲除或血管内皮 SOCS1（VESOCS1）转基因小鼠用于 GA 的主动脉移植模型。分离小鼠主动脉 ECs 进行体外检测。
在人类 GA 和动脉粥样硬化标本中观察到内皮 SOCS1 的显著但特异性降低，这提示 SOCS1 在维持正常内皮功能中的重要性。小鼠 SOCS1 缺失导致基础 EC 功能障碍。移植后，SOCS1 缺陷的主动脉移植物增加白细胞募集和新生内膜形成，而内皮过表达 SOCS1 则减少动脉排斥反应。GA 早期诱导的内皮黏附分子的表达被 VESOCS1 转基因抑制，并且在培养的主动脉 ECs 中得到了证实。此外，VESOCS1 在 GA 进展过程中维持更好的血管功能。在机制上，内皮 SOCS1 通过调节黏附分子血小板/内皮细胞黏附分子-1、细胞间黏附分子-1 和血管细胞黏附分子-1 的基础表达和细胞因子诱导表达，抑制炎症细胞浸润过程中的白细胞黏附和跨内皮迁移。
SOCS1 通过维持内皮功能和减弱血管内皮细胞中细胞因子诱导的黏附分子表达来防止 GA 的进展。
