Wang Zaicun, Wang Shumei, Wang Zunzhe, Yun Tiantian, Wang Chenchen, Wang Huating
Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China.
Department of General Practice, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, 250013, China.
Biochem Biophys Res Commun. 2017 Aug 19;490(2):194-201. doi: 10.1016/j.bbrc.2017.06.020. Epub 2017 Jun 8.
Atherosclerosis is a chronic inflammatory cardiovascular disease with high mortality worldwide. Tofacitinib (CP-690,550), an oral small-molecule Janus kinase inhibitor, has been shown to be effective in the treatment of rheumatoid arthritis, autoimmune encephalomyelitis and ulcerative colitis. However, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of Tofacitinib on atherogenic diet (ATD)-induced atherosclerosis using apolipoprotein E deficient (apoE-/-) mice. Atherosclerosis-prone apoE-/- mice were fed with ATD and treated with or without Tofacitinib through intragastrical administration (10 mg kg day) for 8 weeks. Our results showed that Tofacitinib did not change plasma lipids, while significantly reduced the levels of plasma pro-inflammatory cytokines IL-6 and TNF-α. It also significantly attenuated atherosclerotic plaque lesion in the aortic root and macrophages contained in plaque as shown with Mac2 immuno-staining. Peritoneal macrophages (PMC) were separated from apoE-/- mice fed with 8-week ATD, and then subjected to inflammation tests. Flow cytometry analysis of F4/80 and CD206 and mRNA levels of M1 and M2 macrophages markers showed that M1 macrophages decreased while M2 macrophages increased in Tofacitinib treated group. Expressions of other inflammatory genes also indicated an anti-inflammatory status in mice treated with Tofacitinib. Ox-LDL was used to induce foam cell formation from PMC in wild type mice, and the results displayed a reduced formation of foam cells and decreased inflammation in mice with Tofacitinib administration (1 μM). The mRNA and protein levels of ATP binding cassette subfamily A member 1 (ABCA1), a key gene involved in cholesterol efflux, remarkably increased, while it was absence of alterations in scavenger receptors expression. Therefore, we demonstrated that Tofacitinib could attenuate atherosclerosis and foam cells formation by inhibiting inflammation and upregulating ABCA1 expression.
动脉粥样硬化是一种慢性炎症性心血管疾病，在全球范围内死亡率很高。托法替布（CP - 690,550）是一种口服小分子Janus激酶抑制剂，已被证明在治疗类风湿性关节炎、自身免疫性脑脊髓炎和溃疡性结肠炎方面有效。然而，其对动脉粥样硬化的保护作用仍知之甚少。本研究的目的是使用载脂蛋白E缺陷（apoE - / -）小鼠评估托法替布对致动脉粥样化饮食（ATD）诱导的动脉粥样硬化的影响。将易患动脉粥样硬化的apoE - / -小鼠喂食ATD，并通过胃内给药（10 mg/kg/天）给予或不给予托法替布治疗8周。我们的结果表明，托法替布不会改变血脂，同时显著降低血浆促炎细胞因子IL - 6和TNF - α的水平。如Mac2免疫染色所示，它还显著减轻了主动脉根部的动脉粥样硬化斑块病变以及斑块中所含的巨噬细胞。从喂食8周ATD的apoE - / -小鼠中分离出腹腔巨噬细胞（PMC），然后进行炎症测试。F4/80和CD206的流式细胞术分析以及M1和M2巨噬细胞标志物的mRNA水平表明，托法替布治疗组中M1巨噬细胞减少而M2巨噬细胞增加。其他炎症基因的表达也表明托法替布治疗的小鼠处于抗炎状态。用氧化型低密度脂蛋白（Ox - LDL）诱导野生型小鼠的PMC形成泡沫细胞，结果显示给予托法替布（1 μM）的小鼠中泡沫细胞形成减少且炎症减轻。参与胆固醇流出的关键基因ATP结合盒亚家族A成员1（ABCA1）的mRNA和蛋白质水平显著增加，而清道夫受体表达没有变化。因此，我们证明托法替布可通过抑制炎症和上调ABCA1表达来减轻动脉粥样硬化和泡沫细胞形成。
