Lovastatin-Mediated Changes in Human Tendon Cells.
Lovastatin-Mediated Changes in Human Tendon Cells.
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DOI：
10.1002/jcp.25010
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发表时间：
2015-10
影响因子：
5.6
通讯作者：
Hulley PA
中科院分区：
文献类型：
--
作者：
Kuzma-Kuzniarska M;Cornell HR;Moneke MC;Carr AJ;Hulley PA
他汀类药物是世界上最广泛的处方药之一。许多研究表明，它们通过降低胆固醇和抗动脉粥样硬化特性在预防心血管疾病方面具有有益作用。虽然一些他汀类药物患者可能会出现肌肉相关症状，但他汀类药物治疗的严重副作用很少，主要是由于肝脏中广泛的首过代谢。骨骼肌似乎是副作用的主要部位;然而，最近在肌腱中描述了一些他汀类药物相关的不良反应。这些副作用背后的机制仍然未知。这是第一项探索他汀类药物在人原代肌腱细胞中的肌腱特异性作用的研究。将细胞与不同浓度的洛伐他汀一起培养长达1周。在治疗剂量下培养的肌腱细胞中未观察到细胞活力或形态学的变化。短期暴露于治疗范围外的洛伐他汀浓度对肌腱细胞活力没有影响;但是，细胞迁移减少。辛伐他汀和阿托伐他汀，另外两种药物家族成员，也降低了细胞的迁移特性。长时间暴露于高浓度洛伐他汀诱导细胞骨架变化，导致细胞变圆和基质蛋白mRNA水平降低，但BMP-2表达增加。间隙连接通讯受损，但由于细胞形状的变化和分离，而不是直接的间隙连接抑制。这些影响伴随着Rap1a小GTdR的异戊二烯化的抑制。总的来说，我们发现他汀类药物以剂量依赖性方式减少人肌腱细胞的迁移，改变其表达谱并损害功能网络，但不抑制间隙连接功能。J.细胞。230：2543 - 2551，2015。版权所有© 2015作者.细胞生理学杂志由Wiley Periodicals，Inc.出版。
Statins are among the most widely prescribed drugs worldwide. Numerous studies have shown their beneficial effects in prevention of cardiovascular disease through cholesterol‐lowering and anti‐atherosclerotic properties. Although some statin patients may experience muscle‐related symptoms, severe side effects of statin therapy are rare, primarily due to extensive first‐pass metabolism in the liver. Skeletal muscles appear to be the main site of side effects; however, recently some statin‐related adverse effects have been described in tendon. The mechanism behind these side effects remains unknown. This is the first study that explores tendon‐specific effects of statins in human primary tenocytes. The cells were cultured with different concentrations of lovastatin for up to 1 week. No changes in cell viability or morphology were observed in tenocytes incubated with therapeutic doses. Short‐term exposure to lovastatin concentrations outside the therapeutic range had no effect on tenocyte viability; however, cell migration was reduced. Simvastatin and atorvastatin, two other drug family members, also reduced the migratory properties of the cells. Prolonged exposure to high concentrations of lovastatin induced changes in cytoskeleton leading to cell rounding and decreased levels of mRNA for matrix proteins, but increased BMP‐2 expression. Gap junctional communication was impaired but due to cell shape change and separation rather than direct gap junction inhibition. These effects were accompanied by inhibition of prenylation of Rap1a small GTPase. Collectively, we showed that statins in a dose‐dependent manner decrease migration of human tendon cells, alter their expression profile and impair the functional network, but do not inhibit gap junction function. J. Cell. Physiol. 230: 2543–2551, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.