阿司匹林触发的脂氧素 A4 抑制载脂蛋白 E 小鼠动脉粥样硬化进展。
Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E mice.
机构信息
Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Karlinska Institutet, Stockholm, Sweden.
出版信息
Br J Pharmacol. 2017 Nov;174(22):4043-4054. doi: 10.1111/bph.13707. Epub 2017 Feb 14.
BACKGROUND AND PURPOSE
Atherosclerosis is characterized by a chronic non-resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE ) mice.
EXPERIMENTAL APPROACH
ApoE × Fpr2 and ApoE × Fpr2 mice were generated. Four-week-old mice fed a high-fat diet for 4 weeks and 16-week-old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen.
KEY RESULTS
ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE mice lacking the Fpr2 receptor.
CONCLUSION AND IMPLICATIONS
ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro-resolving agent has therapeutic potential for the treatment of atherosclerosis.
LINKED ARTICLES
This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
背景与目的
动脉粥样硬化的特征是动脉壁内发生慢性非解决性炎症。阿司匹林触发的脂氧素 A4（ATL）是一种有效的抗炎介质，参与炎症的解决。然而，以前尚未探索过通过 ATL 进行免疫靶向治疗动脉粥样硬化的治疗潜力。本研究旨在确定 ATL 及其受体 Fpr2 在载脂蛋白 E 缺陷（ApoE）小鼠动脉粥样硬化发展和进展中的作用。
实验方法
生成了 ApoE×Fpr2和 ApoE×Fpr2 小鼠。4 周龄的高脂饮食喂养 4 周的小鼠和 16 周龄的正常饮食喂养的小鼠接受含有载体或 ATL 的渗透泵治疗 4 周。测量主动脉根部和胸主动脉的动脉粥样硬化病变大小和细胞组成。测量血液中的脂质水平和白细胞计数，并从腹部主动脉和脾脏分离 mRNA。
主要结果
ATL 阻止了 ApoE 小鼠主动脉根部和胸主动脉的动脉粥样硬化进展。此外，ATL 减少了动脉粥样硬化病变中的巨噬细胞浸润和凋亡细胞。ATL 降低了脾脏和主动脉中几种细胞因子和趋化因子的 mRNA 水平，而循环白细胞水平不变。缺乏 Fpr2 受体的 ApoE 小鼠中，ATL 诱导的动脉粥样硬化保护作用消失。
结论和意义
ATL 通过 Fpr2 介导的局部和全身炎症减轻来阻止动脉粥样硬化进展。这些结果表明，这种抗炎和解决炎症的药物具有治疗动脉粥样硬化的治疗潜力。
相关文章
本文是针对“靶向炎症以降低心血管疾病风险”的专题部分的一部分。要查看此部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc 和 http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc。
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