Smad3/siRNA阻断TGF-β1/Smad3信号转导通路的防治肝纤维化作用研究
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摘要
TGF-β1是一个多效性生长因子，在调节细胞外基质(ECM)的生成和器官、组织纤维化的发生、发展过程中发挥重要作用。肝星状细胞(HSCs)是肝内产生ECM的主要细胞，它的激活与活化状态的维持是肝纤维化的发生和发展过程中的重要事件之一，而HSCs的活化和生成ECM是由TGF-β1／Smad3信号通路调控的。大量研究表明，在不同位点、用不同的阻断剂如抗体、竞争性Ⅱ型TGF-β受体、Ⅰ型TGF-β受体(TβR-Ⅰ)的小分子抑制剂、寡义核苷酸或小干扰RNA(siRNA)等阻断TGF-β1／Smad3通路后，体内外均能抑制ECM的过渡生成，并能减轻器官纤维化的程度，但以Smad3蛋白为靶点拮抗TGF-β1／Smad3通路的研究尚无报道。
我们首先建立了TGF-β1／Smad3信号通路的虫荧光素酶的报告基因系统，通过TβR-Ⅰ的小分子抑制剂—SB-431542的抑制实验已确认此模型的有效性，并筛选了稳定表达的MvLu1细胞株。通过柚皮素抑制TGF-β1／Smad3的报告基因系统实验，我们首先证明柚皮素是TGF-β1／Smad3通路的拮抗剂；体外实验表明，柚皮素不仅可以抑制TGF-β1诱导的HSCs生成ECM，而且可以明显抑制Smad3的mRNA转录过程。首次证明柚皮素是通过直接或间接抑制Smad3的转录过程而阻断TGF-β1／Smad3信号通路的，其抗纤维化作用也至少部分是通过此作用机制来完成的。由于Smad3位于信号通路的下游、更接近靶基因，同时体内外实验表明Smad3基因敲除可以防治肝、肺等器官纤维化的发生，所以我们设计了siRNA来沉默Smad3基因。通过报告基因与RT-PCR实验，第一次证明Smad3的siRNA可剂量依赖型抑制其基因的表达，并可阻断TGF-β1／Smad3信号通路；同时可在mRNA和蛋白水平抑制TGF-β1诱导的HSCs生成ECM；DMN诱导的大鼠肝纤维化实验表明，siRNA／Smad3能明显增加实验鼠的存活率，增加其体重及肝的重量，能有效降低血清内TGF-β1和ECM组份水平，能明显改善肝功能，能显著降低肝内ECM组份的含量。表明siRNA／Smad3具有防治肝纤维化的作用，可向发展抗纤维化药物的发现进行更深入的研究。
The multiple biological actions of TGF-81 contribute to the regulation of the production, degradation, and accumulation of ECM proteins in a direct or indirect manner, and that it may play a pivotal role in the fibroproliferative changes in many vital organs and tissue. Activation of hepatic stellate cells (HSCs), leading to accumulation of extracellular matrix (ECM), is the central event of fibrogenesis. liver fibrosis occurs as a consequence of the transdifferentiation of HSCs into myofibroblasts and is orcharded by TGF-β/Smad3 signaling pathway. There are a number of reports of cellular or animal models of fibrosis where loss of TGF-β1/Smad3 cascade regulation results in a diminished fibrotic response where agents that block TGF-βfunction inhibit the production of ECM and reduce the fibrotic response in the liver and other tissues. Several strategies now exist for preventing or halting fibrogenesis, ranging from biological agents including antibodies, antisense oligonucleotides, soluble type II TGF-βreceptor and siRNA to small molecular compounds. However, it has not reported that an agent blocks TGF-β/Smad3 signaling cascade through targeting Smad3 protein.The luciferase reporter based on TGF-β/Smad3 signaling was developed, whose expression was inhibited by SB-431542, a small molecular inhibitor of type I TGF-βreceptor. A stable MvlLu strain cloned the reporter system was worked.Naringenin, a Chinese herbs extract, was firstly proven to be an antagonist of TGF-β/Smad3 signaling, which obviously inhibited the expression of the luciferase reporter. The compound could interdict not only the formation of ECM, but the transcription of Smad3 in HSCs induced by TGF-B1 in vitro. We firstly provided obvious evidences that naringenin can intervene TGF-β1/Smad3 signaling pathway by directly or indirectly down-regulated Smad3 protein expression to exert anti-fibrogenic effects, at least partly.But the most compellent example of events is that loss of Smad3, a downstream mediator of TGF-β1 signaling, might be resistant to fibrogenesis in vivo and in vitro. Based on these and other advances in understanding the fundamentals of the injury response and TGF-β1/Smad3 signal pathway, a strategy which blocks TGF-B signaling via silencing Smad3 gene with small interference RNA (siRNA) was developed. A siRNA/Smad3 could intervene the TGF-β1/Smad3 signaling, which was shown by the luciferase reporter system, and knockdown Smad3 gene in a dose-dependent manner from RT-PCR results. The siRNA could inhibit the expression of ECM at levels of mRNA and protein in HSCs induced by TGF-β1. The siRNA/Smad3 could survive, increase body weigh and liver weigh, decrease the serum levels of TGF-β1 and the components of serum ECM, improve the liver biological functions, and reduce the liver contents of ECM components in experimental liver fibrotic rats induced by DMN. These results implied that siRNA targeting Smad3 has exciting anti-fibrogenesis actions and future studies will be required to determine the approach is most beneficial.
我们首先建立了TGF-β1／Smad3信号通路的虫荧光素酶的报告基因系统，通过TβR-Ⅰ的小分子抑制剂—SB-431542的抑制实验已确认此模型的有效性，并筛选了稳定表达的MvLu1细胞株。通过柚皮素抑制TGF-β1／Smad3的报告基因系统实验，我们首先证明柚皮素是TGF-β1／Smad3通路的拮抗剂；体外实验表明，柚皮素不仅可以抑制TGF-β1诱导的HSCs生成ECM，而且可以明显抑制Smad3的mRNA转录过程。首次证明柚皮素是通过直接或间接抑制Smad3的转录过程而阻断TGF-β1／Smad3信号通路的，其抗纤维化作用也至少部分是通过此作用机制来完成的。由于Smad3位于信号通路的下游、更接近靶基因，同时体内外实验表明Smad3基因敲除可以防治肝、肺等器官纤维化的发生，所以我们设计了siRNA来沉默Smad3基因。通过报告基因与RT-PCR实验，第一次证明Smad3的siRNA可剂量依赖型抑制其基因的表达，并可阻断TGF-β1／Smad3信号通路；同时可在mRNA和蛋白水平抑制TGF-β1诱导的HSCs生成ECM；DMN诱导的大鼠肝纤维化实验表明，siRNA／Smad3能明显增加实验鼠的存活率，增加其体重及肝的重量，能有效降低血清内TGF-β1和ECM组份水平，能明显改善肝功能，能显著降低肝内ECM组份的含量。表明siRNA／Smad3具有防治肝纤维化的作用，可向发展抗纤维化药物的发现进行更深入的研究。
The multiple biological actions of TGF-81 contribute to the regulation of the production, degradation, and accumulation of ECM proteins in a direct or indirect manner, and that it may play a pivotal role in the fibroproliferative changes in many vital organs and tissue. Activation of hepatic stellate cells (HSCs), leading to accumulation of extracellular matrix (ECM), is the central event of fibrogenesis. liver fibrosis occurs as a consequence of the transdifferentiation of HSCs into myofibroblasts and is orcharded by TGF-β/Smad3 signaling pathway. There are a number of reports of cellular or animal models of fibrosis where loss of TGF-β1/Smad3 cascade regulation results in a diminished fibrotic response where agents that block TGF-βfunction inhibit the production of ECM and reduce the fibrotic response in the liver and other tissues. Several strategies now exist for preventing or halting fibrogenesis, ranging from biological agents including antibodies, antisense oligonucleotides, soluble type II TGF-βreceptor and siRNA to small molecular compounds. However, it has not reported that an agent blocks TGF-β/Smad3 signaling cascade through targeting Smad3 protein.The luciferase reporter based on TGF-β/Smad3 signaling was developed, whose expression was inhibited by SB-431542, a small molecular inhibitor of type I TGF-βreceptor. A stable MvlLu strain cloned the reporter system was worked.Naringenin, a Chinese herbs extract, was firstly proven to be an antagonist of TGF-β/Smad3 signaling, which obviously inhibited the expression of the luciferase reporter. The compound could interdict not only the formation of ECM, but the transcription of Smad3 in HSCs induced by TGF-B1 in vitro. We firstly provided obvious evidences that naringenin can intervene TGF-β1/Smad3 signaling pathway by directly or indirectly down-regulated Smad3 protein expression to exert anti-fibrogenic effects, at least partly.But the most compellent example of events is that loss of Smad3, a downstream mediator of TGF-β1 signaling, might be resistant to fibrogenesis in vivo and in vitro. Based on these and other advances in understanding the fundamentals of the injury response and TGF-β1/Smad3 signal pathway, a strategy which blocks TGF-B signaling via silencing Smad3 gene with small interference RNA (siRNA) was developed. A siRNA/Smad3 could intervene the TGF-β1/Smad3 signaling, which was shown by the luciferase reporter system, and knockdown Smad3 gene in a dose-dependent manner from RT-PCR results. The siRNA could inhibit the expression of ECM at levels of mRNA and protein in HSCs induced by TGF-β1. The siRNA/Smad3 could survive, increase body weigh and liver weigh, decrease the serum levels of TGF-β1 and the components of serum ECM, improve the liver biological functions, and reduce the liver contents of ECM components in experimental liver fibrotic rats induced by DMN. These results implied that siRNA targeting Smad3 has exciting anti-fibrogenesis actions and future studies will be required to determine the approach is most beneficial.
引文
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