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辛伐他汀通过Rho信号传导机制消除转化生长因子-β对结缔组织生长因子的表达及诱导作用。

Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism.

作者信息

Watts Keira L, Spiteri Monica A

机构信息

Lung Research, Institute of Science and Technology in Medicine, University Hospital of North Staffordshire/Keele University, Stoke on Trent, United Kingdom.

出版信息

Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1323-32. doi: 10.1152/ajplung.00447.2003. Epub 2004 Aug 6.

Abstract

Connective tissue growth factor (CTGF), a potent profibrotic mediator, acts downstream and in concert with transforming growth factor (TGF)-beta to drive fibrogenesis. Significant upregulation of CTGF has been reported in fibrogenic diseases, including idiopathic pulmonary fibrosis (IPF), and is partly responsible for associated excessive fibroblast proliferation and extracellular matrix deposition, but no effective therapy exists for averting such fibrogeneic events. Simvastatin has reported putative antifibrotic actions in renal fibroblasts; this study explores such actions on human IPF-derived and normal lung fibroblasts and examines associated driving mechanisms. Simvastatin reduces basal CTGF gene and protein expression in all fibroblast lines, overriding TGF-beta induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on CTGF/TGF-beta interaction were evaluated using transient reporter transfection of a CTGF promoter construct. Inhibition of CTGF promoter activity by simvastatin was most marked at 10 muM concentration, reducing activity by 76.2 and 51.8% over TGF-beta-stimulated cultures in IPF and normal fibroblasts, respectively. We also show that geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate, induces CTGF promoter activity following simvastatin inhibition by 55.3 and 31.1% over GGPP-negative cultures in IMR90 and IPF-derived fibroblasts, respectively, implicating small GTPase Rho involvement rather than Ras in these effects. Indeed, the specific Rho inhibitor C3 exotoxin significantly (P < 0.05) suppressed TGF-beta-induced CTGF promoter activity in transfected lung fibroblasts, a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs, thus demonstrating that simvastatin through a Rho signaling mechanism in lung fibroblasts can modulate CTGF expression and interaction with TGF-beta.

摘要

结缔组织生长因子(CTGF)是一种强效的促纤维化介质,在转化生长因子(TGF)-β的下游起作用,并与之协同驱动纤维化形成。在包括特发性肺纤维化(IPF)在内的纤维化疾病中,CTGF有显著上调,这部分导致了相关的成纤维细胞过度增殖和细胞外基质沉积,但目前尚无有效的治疗方法来避免此类纤维化事件。辛伐他汀在肾成纤维细胞中具有推测的抗纤维化作用;本研究探讨其对人IPF来源的和正常肺成纤维细胞的作用,并研究相关的驱动机制。辛伐他汀降低了所有成纤维细胞系中基础CTGF基因和蛋白的表达,通过抑制胆固醇合成途径来抑制TGF-β诱导。使用CTGF启动子构建体的瞬时报告基因转染评估了驱动辛伐他汀对CTGF/TGF-β相互作用影响的信号通路。辛伐他汀对CTGF启动子活性的抑制在10μM浓度时最为显著,在IPF和正常成纤维细胞中,分别比TGF-β刺激的培养物降低了76.2%和51.8%的活性。我们还表明,在IMR90和IPF来源的成纤维细胞中,香叶基香叶基焦磷酸(GGPP)而非法尼基焦磷酸在辛伐他汀抑制后分别比GGPP阴性培养物诱导CTGF启动子活性高55.3%和31.1%,这表明这些作用涉及小GTPase Rho而非Ras。事实上,特异性Rho抑制剂C3外毒素显著(P < 0.05)抑制了转染的肺成纤维细胞中TGF-β诱导的CTGF启动子活性,这一发现得到了显性负性和组成型活性RhoA构建体转染的进一步支持,从而证明辛伐他汀通过肺成纤维细胞中的Rho信号机制可以调节CTGF表达及其与TGF-β的相互作用。

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