Porter Karen E, Turner Neil A, O'Regan David J, Balmforth Anthony J, Ball Stephen G
Institute for Cardiovascular Research, Worsley Building, University of Leeds, Leeds LS2 9JT, UK.
Cardiovasc Res. 2004 Mar 1;61(4):745-55. doi: 10.1016/j.cardiores.2003.11.032.
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.
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.
Simvastatin (0.1-1.0 micromol/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.
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.
心房和心室不良心肌重塑的特征是纤维化、心肌细胞死亡或肥大以及成纤维细胞增殖。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作用。虽然已知他汀类药物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。本研究的目的是探讨辛伐他汀对人心房肌成纤维细胞增殖的影响。
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，并通过免疫印迹法检测细胞周期蛋白A来确定细胞周期进程。使用免疫印迹法和免疫细胞化学法研究RhoA的表达、激活和细胞内定位。
辛伐他汀（0.1-1.0微摩尔/升）在细胞周期蛋白A表达的上游点以浓度依赖的方式抑制血清诱导的肌成纤维细胞增殖。这些作用可被甲羟戊酸或香叶基香叶基焦磷酸（GGPP）逆转，但不能被鲨烯或法尼基焦磷酸（FPP）逆转，表明其机制涉及抑制Rho家族GTP酶且独立于胆固醇合成。抑制Rho香叶基香叶基化或Rho激酶激活可模拟辛伐他汀的作用。此外，我们证明辛伐他汀通过阻止RhoA与质膜结合从而抑制其与细胞增殖所需下游效应器的相互作用来抑制RhoA功能。
辛伐他汀通过抑制RhoA香叶基香叶基化的机制独立于胆固醇合成减少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脏肌成纤维细胞增殖相关的不良心肌重塑中起重要作用。
