Regulatory T cells prevent plaque disruption in apolipoprotein E-knockout mice
Regulatory T cells prevent plaque disruption in apolipoprotein E-knockout mice
复制标题
调节性 T 细胞可防止载脂蛋白 E 敲除小鼠中的斑块破坏
DOI：
10.1016/j.ijcard.2013.03.026
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发表时间：
2013-10-03
影响因子：
3.5
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
--
作者：
Meng, Xiao;Li, Wenjun;Zhang, Yun
背景：CD4(+)CD25（+）调节性T细胞（Tregs）在动脉粥样硬化发生中引起了相当大的兴趣。我们假设Tregs治疗可能通过抑制炎症细胞因子分泌和基质金属蛋白酶（MMPs）表达以及增强动脉粥样硬化病变中P4H α 1的表达来剂量依赖性地稳定动脉粥样硬化斑块。方法与结果：建立载脂蛋白e敲除小鼠（ApoE-/-）颈动脉易损斑块模型。小鼠分为对照组、磷酸缓冲盐水（PBS）组、小剂量Tregs组、中剂量Tregs组、大剂量Tregs组和PC组。组织病理学分析显示，对照组、PBS组、小剂量Tregs组、中剂量Tregs组、大剂量Tregs组和PC组的斑块破裂率分别为50%、50%、43.8%、12.5%、12.5%和43.8%。Tregs处理导致颈动脉斑块中巨噬细胞和脂质相对含量显著降低，SMCs和胶原相对含量显著增加，斑块易损指数降低近50%。此外，Tregs处理在体内和体外均降低了促炎细胞因子、MMP-2和MMP-9的表达，但增加了P4Ha1的表达。Tregs的这些治疗作用大多是由转化生长因子和白细胞介素-10介导的。结论：在ApoE-/-小鼠中，过继转移Tregs剂量依赖性地改变了斑块组成，使斑块表型稳定，并降低了斑块破裂的发生率。其主要机制包括炎症因子、MMP-2和MMP-9的表达降低，颈动脉斑块中P4Ha1的表达增强。Tregs可能提供一种治疗易损斑块的新方法。2013爱思唯尔爱尔兰有限公司版权所有。
Background: CD4(+)CD25(+) regulatory T cells (Tregs) have received considerable interest in atherogenesis. We hypothesized that Tregs treatment may dose-dependently stabilize atherosclerotic plaques by inhibiting inflammatory cytokine secretion and matrix metalloproteinases (MMPs) expression and enhancing P4H alpha 1 expression in atherosclerotic lesions.Methods and results: We established a vulnerable carotid plaque model in apolipoprotein E-knockout mice (ApoE-/-). Mice were divided into control, phosphate buffered saline (PBS), small-dose Tregs, moderatedose Tregs, large-dose Tregs and PC groups. Histopathological analysis showed that the plaque disruption rate was 50%, 50%, 43.8%, 12.5%, 12.5% and 43.8% in the control, PBS, small-dose Tregs, moderate-dose Tregs, large-dose Tregs and PC groups. Tregs treatment resulted in a significant decrease in the relative contents of macrophages and lipids and a substantial increase in those of SMCs and collagen in the carotid plaque, leading to an almost 50% reduction of plaque vulnerability index. Furthermore, Tregs treatment decreased the expression of proinflammatory cytokines, MMP-2 and MMP-9 but increased the expression of P4Ha1 both in vivo and in vitro. Most of these therapeutic effects of Tregs were found to be mediated by transforming growth factor and interleukin-10.Conclusion: Adoptive transfer of Tregs dose-dependently changed plaque composition to a stable plaque phenotype and lowered the incidence of plaque disruption in ApoE-/- mice. The major mechanisms involved reduced expression of inflammatory cytokines and MMP-2 and MMP-9, and enhanced expression of P4Ha1 in the carotid plaque. Tregs may provide a novel approach to the treatment of vulnerable plaques. (C) 2013 Elsevier Ireland Ltd. All rights reserved.