Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia
Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia
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DOI：
10.1016/j.atherosclerosis.2007.09.019
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发表时间：
2008-05-01
期刊：
影响因子：
5.3
通讯作者：
Thiery, Joachim
中科院分区：
文献类型：
--
作者：
Mueller, Marc A.;Beutner, Frank;Thiery, Joachim
依维莫司抑制增殖细胞中的哺乳动物雷帕霉素靶标（mTOR）。它被广泛用于移植患者，也被药物洗脱支架用于治疗心血管疾病。然而，关于mTOR抑制剂对血管壁的病理生理学作用的数据有限。我们的目的是阐明依维莫司对胆固醇诱导的动脉粥样硬化和LDL受体缺陷（LDLR-/-）小鼠循环细胞介质的影响。雄性高胆固醇血症LDLR-/-小鼠通过皮下植入渗透微型泵接受溶剂（A组; n = 28）或依维莫司，剂量为0.05 mg/kg（B组，n = 22）和1.5 mg/kg（C组，n = 29）/体重/天，研究期为12周。组B显示头臂动脉（BCA）处的动脉粥样硬化病变减少44%。在C组中，动脉粥样硬化病变在BCA中减少了85%，在主动脉根部减少了60%。这与两个治疗组中病变复杂性显著降低相关（p < 0.001），尽管血浆胆固醇增加了40%。依维莫司导致循环细胞介质（如白细胞介素-1 α、白细胞介素-5、GM-CSF和白细胞介素-12 p40）显著减少。依维莫司增加KC的血浆水平，但对研究的其他18种循环细胞介质没有影响。依维莫司强烈抑制LDL受体（-/-）小鼠的动脉粥样硬化发展，尽管有严重的高胆固醇血症。依维莫司应用对循环细胞介质的影响很小。动脉粥样硬化病变的显著减少与早期巨噬细胞富集病变向晚期动脉粥样硬化斑块的延迟转变有关。(c)2007爱思唯尔爱尔兰有限公司保留所有权利。
Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR-/-) mice. Male hypercholesterolemic LDLR-/- mice received either solvent (group A; n = 28) or everolimus at 0.05 mg/kg (group B, n = 22) and 1.5 mg/kg (group C, n = 29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p < 0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1 alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques. (c) 2007 Elsevier Ireland Ltd. All rights reserved.