Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis
Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis
复制标题
DOI：
10.1016/j.ijcha.2020.100529
复制
发表时间：
2020-06-01
影响因子：
2.9
通讯作者：
Daida, Hiroyuki
中科院分区：
文献类型：
--
作者：
Sato-Okabayashi, Yayoi;Isoda, Kikuo;Daida, Hiroyuki
背景：动脉粥样硬化是一种慢性炎症性疾病，在西方国家导致心脏病和中风的大多数病例。细胞毒性药物环磷酰胺(CPA)可以调节免疫功能，因此已被用于治疗自身免疫性疾病。有报道称CPA治疗可延长重度动脉粥样硬化患者的生存期，但其潜在机制尚不清楚。方法和结果：我们在一种小鼠动脉粥样硬化模型上观察了CPA的作用。持续口服低剂量CPA(20 mg/kg/天)可预防高脂饮食喂养的载脂蛋白E缺陷(apoE(-/-))小鼠的动脉粥样硬化。12周后，CPA治疗延缓了小鼠动脉粥样硬化的进展(9.92%比3.32%，P<；0.05，n=7)，并减少了斑块中巨噬细胞的含量(1.228比0.2975 mm(2)，P<；0.001)。流式细胞术(FACS)显示，外周血和脾细胞中B细胞和炎性T细胞(Th1细胞)数量减少，炎性单核细胞减少。而骨髓细胞在两组间无明显差异。主动脉组织中炎症细胞因子(IL-6)表达显著降低(P<；0.05)，抗炎细胞因子(精氨酸酶-1)表达有升高趋势，但两组间差异无统计学意义。大剂量CPA具有心脏毒性，但本研究所用剂量未显示出明显的心脏毒性。结论：口服CPA可通过对淋巴和炎症细胞的免疫调节作用，抑制apoE(-/-)小鼠动脉粥样硬化的发生和发展。(C)2020作者。爱思唯尔出版公司(Elsevier B.V.)
Background: Atherosclerosis is a chronic inflammatory disease responsible for most cases of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions, and it has therefore been used to treat patients with autoimmune diseases. Extension of survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood.Methods and results: We have investigated the effects of CPA in a murine model of atherosclerosis. Continuous oral administration of low-dose CPA (20 mg/kg/day) prevented atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice fed with a high fat diet. After 12 weeks, CPA treatment delayed progression of atherosclerosis in the mice (9.92% vs 3.32%, P < 0.05, n = 7) and reduced the macrophage content of plaques (1.228 vs 0.2975 mm(2), P < 0.001). Flow cytometry (FACS) showed that, in peripheral blood and spleen cells, the numbers of B cells and inflammatory T cells (Th1 cells) decreased, and inflammatory monocytes also decreased. However, there were no differences in the bone marrow cells between the two groups. The mRNA levels in the aorta showed significantly decreased inflammatory cytokine (interleukin6) (P < 0.05), and tended to increase anti-inflammatory cytokine (argininase-1), but no significant differences between the two groups. High dose CPA has cardiotoxicity, but the dose used in this study did not show significant cardiotoxicity.Conclusions: The results demonstrate that oral treatment with CPA inhibits initiation and progression of atherosclerosis in the apoE(-/-) mouse model through immunomodulatory effects on lymphoid and inflammatory cells. (C) 2020 The Authors. Published by Elsevier B.V.