他汀类药物,为何是一把双刃剑?
2015/08/16
一项新研究发现,他汀类药物会破坏干细胞的功能。他汀类药物有助于减缓动脉粥样硬化,但对机体的其他进程有阻碍作用。基于这些负面影响,研究人员建议在考虑使用他汀类药物时要衡量其风险。


他汀类药物减缓动脉粥硬化的功效提高了其在药物治疗中的地位,一些研究者提倡将其广泛用于心血管疾病的治疗中。然而,他汀类药物可产生副作用,包括使记忆力衰退、产生肌肉问题以及增加患糖尿病的风险。近日,发表于《 American Journal of Physiology -- Cell Physiology 》杂志上的研究解释了为何在有些情况下他汀类药物比其他药物更加有益,同时也揭示了他汀类药物对干细胞的负面影响,研究人员建议在考虑使用他汀类药物时要衡量其风险。

动脉粥样硬化与巨噬细胞

当血管内有斑块时会引发动脉粥样硬化,该疾病可到导致心脏病、中风和死亡。他汀类药物通过阻断肝脏中的胆固醇从而降低疾病风险。巨噬细胞在动脉粥样硬化斑块的形成和破裂中发挥重要的作用。巨噬细胞摄取沉积在血管壁中的脂肪并将更多的巨噬细胞、其他细胞以及与炎症有关的蛋白吸引到损伤部位。逐渐增强的炎症在血管壁形成了斑块,并使动脉逐渐变窄。同时巨噬细胞会释放一些酶来削弱纤维帽,使斑块在血流中裂开,斑块的破裂导致血栓引发心脏病或者中风。

巨噬细胞来自骨髓干细胞。在之前的研究中,杜兰大学医学院研究人员观察到,巨噬细胞可以由骨髓间充质干细胞(MSCs)分化而成,MSCs遍布人体的整个机体。骨髓干细胞主要是分化为血细胞,MSCs可形成所有类型的细胞,包括骨、软骨、肌细胞和巨噬细胞。

他汀类药物阻止干细胞分化

在本研究中,研究人员发现,长期使用他汀类药物会阻止MSCs分化成为巨噬细胞,从而减少炎症,稳定动脉斑块。然而,他汀类药物也阻止MSCs分化成为骨骼和软骨细胞,他汀类药物增加了MSCs的衰老和死亡速度,同时还降低MSCs的DNA修复能力。研究人员表示,对巨噬细胞分化的影响体现了他汀类药物的益处,然而对干细胞其他生物学特性的影响为其临床效应的不良反应提供了一种的解释。

研究人员称,他汀类药物的使用风险与其对干细胞的负面影响有关。他汀类药物疗法使动脉粥样硬化患者获益,但基于对干细胞的负面影响,他汀类药物可能不适合用于非动脉粥硬化患者心血疾病的预防。

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  • The Impact of Statins on Biological Characteristics of Stem Cells Provides a Novel Explanation for Their Pleotropic Beneficial and Adverse Clinical Effects.

    Statins reduce atherosclerotic events and cardiovascular mortality. Their side effects include memory loss, myopathy, cataract formation, and increased risk of diabetes. As cardiovascular mortality relates to plaque instability, which depends on the integrity of the fibrous cap, we hypothesize that the inhibition of the potential of Mesenchymal Stem Cells (MSCs) to differentiate into macrophages would help to explain the long known, but less understood "Non Lipid Associated" or pleiotropic benefit of statins on cardiovascular mortality. In the present investigation, MSCs were treated with atorvastatin or pravastatin at clinically relevant concentrations and their proliferation, differentiation potential, and gene expression profile were assessed. Both types of statins reduce the overall growth rate of MSCs. Especially, statins reduce the potential of MSCs to differentiate into macrophages while they exhibit no direct effect on macrophage function. These findings suggest that the limited capacity of MSCs to differentiate into macrophages could possibly result in decreased macrophage density within the arterial plaque, reduced inflammation, and subsequently enhance plaque stability. This would explain the Non Lipid Associated reduction in cardiovascular events. On a negative side, statins impair the osteogenic and chondrogenic differentiation potential of MSCs, increase cell senescence and apoptosis as indicated by up-regulation of p16, p53, Caspase 3, 8, and 9. Statins also impaired the expression of DNA repair genes including XRCC4, XRCC6, and Apex1. While the effect on macrophage differentiation explain the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects.

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