Donners Marjo M P C, Bot Ilze, De Windt Leon J, van Berkel Theo J C, Daemen Mat J A P, Biessen Erik A L, Heeneman Sylvia
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, the Netherlands.
Am J Transplant. 2005 Jun;5(6):1204-15. doi: 10.1111/j.1600-6143.2005.00821.x.
Since atherosclerosis is a chronic inflammatory disease, we tested the hypothesis that the immunosuppressive drug FK506 would attenuate the development of atherosclerosis using a mouse model of collar-induced atherosclerosis. ApoE-/- mice were treated for 4 weeks with the immunosuppressive drug FK506 (0.05 mg/kg/day), yielding sustained blood levels (approximately 0.2 ng/mL) without systemic side effects. Atherosclerotic plaque development of FK506-treated mice was significantly reduced (63%) while plaque cell density was increased (52%) compared to controls. Importantly, FK506 also blocked progression of pre-existing atherosclerotic plaques. Plaque area of pre-existing plaques was 35% reduced by FK506. Cell density (35%) and collagen content (51%) were significantly increased, whereas necrotic core content was decreased (42%), indicating a more stable plaque morphology. Similar results were found during spontaneous atherosclerotic plaque development in ApoE-/- mice (treatment 17-25 weeks of age). Flow-cytometric analysis showed no peripheral effects on blood cell count or T-cell activation after FK506-treatment. In vitro, FK506 decreased vascular smooth muscle cell (VSMC) apoptosis and inhibited nuclear factor of activated T cells (NFAT)-luciferase reporter activity at concentrations in the range of the in vivo concentration. Low-dose FK506 inhibits collar-induced atherosclerotic plaque development and progression and induces more stable plaque phenotypes in ApoE-/- mice without any peripheral side effects.
由于动脉粥样硬化是一种慢性炎症性疾病，我们使用颈圈诱导的动脉粥样硬化小鼠模型，检验了免疫抑制药物FK506会减弱动脉粥样硬化发展的这一假设。用免疫抑制药物FK506（0.05毫克/千克/天）对载脂蛋白E基因敲除（ApoE-/-）小鼠进行4周治疗，可产生持续的血药浓度（约0.2纳克/毫升）且无全身副作用。与对照组相比，经FK506治疗的小鼠动脉粥样硬化斑块发展显著减少（63%），而斑块细胞密度增加（52%）。重要的是，FK506还能阻止已存在的动脉粥样硬化斑块进展。FK506使已存在斑块的面积减少35%。细胞密度（35%）和胶原含量（51%）显著增加，而坏死核心含量减少（42%），表明斑块形态更稳定。在ApoE-/-小鼠自发性动脉粥样硬化斑块发展过程中（17 - 25周龄时治疗）也发现了类似结果。流式细胞术分析显示，FK506治疗后对血细胞计数或T细胞活化无外周影响。在体外，FK506在体内浓度范围内可降低血管平滑肌细胞（VSMC）凋亡并抑制活化T细胞核因子（NFAT）-荧光素酶报告基因活性。低剂量FK506可抑制颈圈诱导的动脉粥样硬化斑块发展和进展，并在ApoE-/-小鼠中诱导更稳定的斑块表型，且无任何外周副作用。
