Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA
Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA
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DOI：
10.1016/j.cardiores.2003.11.032
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发表时间：
2004-03-01
影响因子：
10.8
通讯作者：
Ball, SG
中科院分区：
文献类型：
--
作者：
Porter, KE;Turner, NA;Ball, SG
目的：不良心房和心室心肌重塑的特征在于纤维化、肌细胞死亡或肥大和成纤维细胞增殖。HMG-CoA还原酶抑制剂（他汀类药物）是广泛使用的降胆固醇药物，似乎对心肌重塑也有有益的影响。虽然他汀类药物已知可减少心肌细胞肥大，但其对心脏成纤维细胞增殖的影响尚不清楚。本研究旨在探讨辛伐他汀对人心房肌成纤维细胞增殖的影响。方法：从人右心耳活检组织中培养心肌成纤维细胞。通过细胞计数定量增殖，并通过细胞周期蛋白A的免疫印迹测定细胞周期进程。用免疫印迹和免疫细胞化学方法研究RhoA的表达、活化和细胞内定位。结果如下：辛伐他汀（0.1 - 1.0 μ mol/l）在细胞周期蛋白A表达上游的一个点以浓度依赖性方式抑制血清诱导的肌成纤维细胞增殖。这些作用被甲羟戊酸或香叶基香叶基焦磷酸（GGPP）逆转，但角鲨烯或法呢基焦磷酸（FPP）不能逆转，表明其机制涉及抑制Rho家族GTP酶，且不依赖于胆固醇合成。通过抑制Rho香叶基香叶基化或Rho激酶活化来模拟辛伐他汀的作用。此外，我们证明辛伐他汀通过阻止RhoA与细胞膜的结合以及与细胞增殖所需的下游效应物的相互作用来抑制RhoA功能。结论：辛伐他汀通过抑制RhoA牛儿基牛儿基化的机制，独立于胆固醇合成，降低培养的人心房肌成纤维细胞的增殖。因此，他汀类药物可能在预防与心肌成纤维细胞增殖相关的不良心肌重塑中发挥重要作用。(C)2003年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Adverse atrial and ventricular myocardial remodeling is characterized by fibrosis, myocyte death or hypertrophy and fibroblast proliferation. HMG-CoA reductase inhibitors (statins) are widely prescribed cholesterol-lowering drugs that also appear to have beneficial effects on myocardial remodeling. Although statins are known to reduce myocyte hypertrophy, their effect on cardiac fibroblast proliferation is unknown. The purpose of this study was to investigate the effects of simvastatin on human atrial myofibroblast proliferation. Methods: Cardiac myofibroblasts were cultured from biopsies of human right atrial appendage. Proliferation was quantified by cell counting and cell cycle progression determined by immunoblotting for Cyclin A. The expression, activation and intracellular localization of RhoA were investigated using immunoblotting and immunocytochemistry. Results: Simvastatin (0.1 - 1.0 mumol/l) inhibited serum-induced myofibroblast proliferation in a concentration-dependent manner at a point upstream of Cyclin A expression. These effects were reversed by mevalonate or geranylgeranyl pyrophosphate (GGPP), but not squalene or farnesyl pyrophosphate (FPP), indicating a mechanism involving inhibition of Rho-family GTPases and independent of cholesterol synthesis. The effects of simvastatin were mimicked by inhibiting Rho geranylgeranylation or Rho-kinase activation. Furthermore, we demonstrated that simvastatin inhibited RhoA function by preventing its association with the plasma membrane and hence, its interaction with downstream effectors required for cell proliferation. Conclusions: Simvastatin reduced proliferation of cultured human atrial myofibroblasts independently of cholesterol synthesis via a mechanism involving inhibition of RhoA geranylgeranylation. Statins may therefore have an important role in preventing adverse myocardial remodeling associated with cardiac myofibroblast proliferation. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.