Rho-ROCK信号通路在肝纤维化形成过程中的作用
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摘要
肝纤维化是一种由多种因素导致的慢性疾病,严重威胁着人类的健康,目前尚无有效的治疗手段。Rho-ROCK信号通路是机体内一条重要的信号转导通路,可以影响细胞收缩、迁移、骨架重塑等生理功能以及平滑肌收缩,细胞凋亡等。该通路可以由多种炎性因子激发,通过激酶级联反应,影响细胞和机体的一系列生物学行为。同时,Rho-ROCK信号转导通路也与肝纤维化的发生密切相关,本文就这二者的关系作一综述,以期为肝纤维化的治疗提供新的思路与方法。
Hepatic fibrosis is a chronic disease caused by a variety of factors, which is a serious threat to human health. There is currently no effective means to treat it. Rho-ROCK signal pathway is an important signal transduction pathway that affects the physiological functions such as cell contraction, migration and remodeling of the skeleton as well as smooth muscle contraction and cell apoptosis. This pathway can be stimulated by a variety of inflammatory factors that affect a range of biological behaviors in cells and the body through kinase cascades. At the same time, Rho-ROCK signal transduction pathway is also closely related to the occurrence of hepatic fibrosis, this article reviews the relationship between the Rho-ROCK pathway and hepatic fibrosis,in order to provide new ideas and methods for the treatment of hepatic fibrosis.
Hepatic fibrosis is a chronic disease caused by a variety of factors, which is a serious threat to human health. There is currently no effective means to treat it. Rho-ROCK signal pathway is an important signal transduction pathway that affects the physiological functions such as cell contraction, migration and remodeling of the skeleton as well as smooth muscle contraction and cell apoptosis. This pathway can be stimulated by a variety of inflammatory factors that affect a range of biological behaviors in cells and the body through kinase cascades. At the same time, Rho-ROCK signal transduction pathway is also closely related to the occurrence of hepatic fibrosis, this article reviews the relationship between the Rho-ROCK pathway and hepatic fibrosis,in order to provide new ideas and methods for the treatment of hepatic fibrosis.
引文
[1]Lachenmeier DW, Monakhova YB, Rehm J. Influence of unrecorded alcohol consumption on liver cirrhosis mortality. World J Gastroenterol, 2014, 20(23):7217-7222
[2]Lin J, Wu JF, Zhang Q, et al. Virus-related liver cirrhosis:Molecular basis and therapeutic options. World J Gastroenterol, 2014, 20(21):6457-6469
[3]Okazaki I, Noro T, Tsutsui N, et al. Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis(NASH):involvement of matrix metalloproteinases(MMPs)and tissue inhibitors of metalloproteinase(TIMPs). Cancers(Basel), 2014, 6(3):1220-1255
[4]高强,李旭光,樊莉,等.肝纤维化发病机制的研究进展.现代生物医学进展, 2017, 17(14):2780-2785, 2677
[5]Asrani SK, Larson JJ, Yawn B, et al. Underestimation of liver-related mortality in the United States. Gastroenterology, 2013, 145(2):375-382 e371-372
[6]Tsou PS, Haak AJ, Khanna D, et al. Cellular mechanisms of tissue fibrosis. 8. current and future drug targets in fibrosis:focus on Rho GTPase-regulated gene transcription. Am J Physiol Cell Physiol. 2014, 307(1):C2-C13
[7]张迪,程敏,康馨丹,等. PI3K/Akt信号传导通路在乙醛刺激下大鼠肝星状细胞株HSC-T6增殖中的作用.山东医药, 2016, 56(45):6-8
[8]戴琦,罗勇兵,李梦乔,等.益气活血利水汤抑制慢性肝纤维化大鼠肝脏Wnt/β-catenin信号通路.基因组学与应用生物学, 2018(4):1697-1704
[9]Fabregat I, Caballero-Díaz D. Transforming growth factor-β-Induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol, 2018, 8:357
[10]李欣,朱英.肝纤维化发生相关信号传导通路研究进展.实用肝脏病杂志, 2015, 18(1):101-104
[11]Nagatoya K, Moriyama T, Kawada N, et al. Y-27632prevent stubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int, 2002, 61(5):1684-1695
[12]Shinokawa FL. Rho-kinase as a novel therapeutic target intreatment of cardiovascular diseases. J Cardiovasc Pharmacol, 2002, 39(3):319-327
[13]Murali A, Rajalingam K. Small Rho GTPases in the control of cell shape and mobility. Cell Mol Life Sci, 2014,71(9):1703-1721
[14]韩佳寅,易艳,梁爱华,等. Rho/ROCK信号通路研究进展.药学学报, 2016, 51(6):853-859
[15]Schwartz M. Rho signalling at a glance. J Cell Sci, 2004,117:5457-5458
[16]漆秀洁,李静,谭利平,等.Rho/Rock信号通路与肺纤维化相关性的研究进展.上海交通大学学报(医学版),2016, 36(10):1533-1536
[17]孙由静,张闻多,汪芳. Rho激酶:他汀类药物抗动脉粥样硬化的重要靶点.中国动脉硬化杂志, 2013, 21(1):84-88
[18]Amin E, Dubey BN, Zhang SC, et al. Rho-kinase:regulation,(dys)function, and inhibition. Biol Chem, 2013,394(11):1399-1410
[19]Knipe RS, Tager AM, Liao JK. The Rho kinases:critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev, 2015, 67(1):103-117
[20]易龙,张乾勇,糜漫天.Rho家族蛋白在肿瘤侵袭转移中作用.中国公共卫生, 2007,(4):492-494
[21]张小兰,李旭,肖冰,等.血管紧张素Ⅱ对大鼠肝星状细胞收缩及Rho-Rock通路的影响.南方医科大学学报,2008,(6):968-971
[22]Melton AC, Datta A, Yee HF.[Ca2+]i-independentcontractile forcegeneration by rat hepatic stellate cells in response to endothelin-1. Am J Physiol Gastrointest Liver Physiol, 2006, 290(1):G7-G13
[23]孙岚,辛文妤,于昕,等.非对称性二甲基精氨酸通过Rho/ROCK信号通路介导大鼠血管平滑肌细胞迁移.中国分子心脏病学杂志, 2012, 12(1):37-42
[24]王玉珍,姜慧卿,扈彩霞,等.法舒地尔通过Rho/ROCK信号通路抑制肝星状细胞黏附、迁移和增殖.中华肝脏病杂志, 2006,(11):821-823
[25]王波.细胞骨架重排及Rho信号传导途径在肝纤维化中的作用机制研究.武汉:华中科技大学, 2004
[26]高庆强,陈海,陈赟,等.法舒地尔对前列腺癌PC3细胞增殖与凋亡的影响.国际泌尿系统杂志, 2016,(5):694-698
[27]Tang Y, He Y, Zhang P, et al. LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis. Mol Cancer, 2018, 17(1):77
[28]Yu WY, Yu CH, Dai W, et al. Effect of Rho-ROCK signaling pathway on pulmonary fibrosis. J Chin Pharm Sci, 2016, 25(1):3-11
[29]Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest, 2013,123(3):1096-1108
[30]李君,孙建平,付晓波.Rho/Rock信号通路在原发性高血压肾纤维化中作用.青岛大学医学院学报, 2010,46(02):113-115, 118
[31]高海成.Rho/Rock通路在大鼠心肌纤维化发生机制中的作用及阿魏酸钠的干预研究.吉林:吉林大学, 2009
[32]Shimizu Y, Dobashi K, Iizuka K, et al.Contribution of small GTPase Rho andi ts target protei n Rock in a murine model of lung fibrosis. Am J Respir Crit Care Med,2001, 163(1):210-217
[33]宋鑫,张林医,苏梦琦,等. Rho相关卷曲螺旋形成蛋白激酶1在大鼠肝纤维化不同阶段表达及意义.中华实验外科杂志, 2017,(6):967-969
[34]Tada S, Iwamoto H, Nakamuta M, et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol, 2001,34(4):529-536
[35]英嵩崧,李旭,张振书.血管紧张素1-7对大鼠肝星状细胞Rho-Rock信号转导通路的影响.现代消化及介入诊疗, 2013, 18(3):145-147
[36]周晋航,陈先祥,吴黎明,等.腺苷蛋氨酸对过度激活的Rho-ROCK通路介导的糖尿病肝损伤的改善作用.医学综述, 2016, 22(20):4090-4093
[37]梁昌宇,覃山羽,姜海行,等.骨髓间充质干细胞对大鼠急性肝损伤修复的影响.世界华人消化杂志, 2009,17(12):1178-1184
[38]张锦生.肝星状细胞激活的内在机制.世界华人消化杂志, 2005,(7):831-834
[39]Gong W, Pecci A, Roth S, et al. Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. Hepatology, 1998, 28:492-502
[40]Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev, 1997, 11:2295-2322
[41]周雯,杨玲,胡胜军. Rho蛋白与肝星状细胞.世界华人消化杂志, 2009, 17(24):2469-2473
[42]Laleman W, Landeghem L, Wilmer A, et al. Portal hypertension:from pathophysiology to clinical practice. Liver Int, 2005, 25:1079-1090
[43]Reynaert H, Thompson MG, Thomas T, et al. Hepatic stellate cells:role in microcirculation and pathophysiology of portal hypertension. Gut, 2002, 50:571-581
[44]Rockey DC. Vascular mediators in the injured liver.Hepatology, 2003, 37:4-12
[45]Saab S, Tam SP, Tran BN, et al. Myosin mediates contractile force generation by hepatic stellate cells in response to endothelin-1. J Biomed Sci, 2002, 9:607-612
[46]Shi J, Wei L. Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp(Warsz), 2007, 55:61-75
[47]扈彩霞,陈新月,王玉珍,等.法舒地尔抑制大鼠肝纤维化组织ROCK-I、α-SMA、p-MBS Thr-697表达.传染病信息, 2011, 24(03):140-142, 170
[48]Xie Y, Song T, Huo M, et al. Fasudil alleviates hepatic fibrosis in type 1 diabetic rats:involvement of the inflammation and RhoA/ROCK pathway. Eur Rev Med Pharmacol Sci, 2018, 22(17):5665-5677
[49]吴晓玲,曾维政,蒋明德,等.红景天甙对肝纤维化大鼠肝组织ROCK表达的影响.世界华人消化杂志, 2009,17(08):765-769
[50]杨玲,但丹,朱锐,等.β-榄香烯抑制肝星状细胞表达ANGⅡ及RhoA/ROCK信号.中国中药杂志,2009,34(04):458-463
[2]Lin J, Wu JF, Zhang Q, et al. Virus-related liver cirrhosis:Molecular basis and therapeutic options. World J Gastroenterol, 2014, 20(21):6457-6469
[3]Okazaki I, Noro T, Tsutsui N, et al. Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis(NASH):involvement of matrix metalloproteinases(MMPs)and tissue inhibitors of metalloproteinase(TIMPs). Cancers(Basel), 2014, 6(3):1220-1255
[4]高强,李旭光,樊莉,等.肝纤维化发病机制的研究进展.现代生物医学进展, 2017, 17(14):2780-2785, 2677
[5]Asrani SK, Larson JJ, Yawn B, et al. Underestimation of liver-related mortality in the United States. Gastroenterology, 2013, 145(2):375-382 e371-372
[6]Tsou PS, Haak AJ, Khanna D, et al. Cellular mechanisms of tissue fibrosis. 8. current and future drug targets in fibrosis:focus on Rho GTPase-regulated gene transcription. Am J Physiol Cell Physiol. 2014, 307(1):C2-C13
[7]张迪,程敏,康馨丹,等. PI3K/Akt信号传导通路在乙醛刺激下大鼠肝星状细胞株HSC-T6增殖中的作用.山东医药, 2016, 56(45):6-8
[8]戴琦,罗勇兵,李梦乔,等.益气活血利水汤抑制慢性肝纤维化大鼠肝脏Wnt/β-catenin信号通路.基因组学与应用生物学, 2018(4):1697-1704
[9]Fabregat I, Caballero-Díaz D. Transforming growth factor-β-Induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol, 2018, 8:357
[10]李欣,朱英.肝纤维化发生相关信号传导通路研究进展.实用肝脏病杂志, 2015, 18(1):101-104
[11]Nagatoya K, Moriyama T, Kawada N, et al. Y-27632prevent stubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int, 2002, 61(5):1684-1695
[12]Shinokawa FL. Rho-kinase as a novel therapeutic target intreatment of cardiovascular diseases. J Cardiovasc Pharmacol, 2002, 39(3):319-327
[13]Murali A, Rajalingam K. Small Rho GTPases in the control of cell shape and mobility. Cell Mol Life Sci, 2014,71(9):1703-1721
[14]韩佳寅,易艳,梁爱华,等. Rho/ROCK信号通路研究进展.药学学报, 2016, 51(6):853-859
[15]Schwartz M. Rho signalling at a glance. J Cell Sci, 2004,117:5457-5458
[16]漆秀洁,李静,谭利平,等.Rho/Rock信号通路与肺纤维化相关性的研究进展.上海交通大学学报(医学版),2016, 36(10):1533-1536
[17]孙由静,张闻多,汪芳. Rho激酶:他汀类药物抗动脉粥样硬化的重要靶点.中国动脉硬化杂志, 2013, 21(1):84-88
[18]Amin E, Dubey BN, Zhang SC, et al. Rho-kinase:regulation,(dys)function, and inhibition. Biol Chem, 2013,394(11):1399-1410
[19]Knipe RS, Tager AM, Liao JK. The Rho kinases:critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev, 2015, 67(1):103-117
[20]易龙,张乾勇,糜漫天.Rho家族蛋白在肿瘤侵袭转移中作用.中国公共卫生, 2007,(4):492-494
[21]张小兰,李旭,肖冰,等.血管紧张素Ⅱ对大鼠肝星状细胞收缩及Rho-Rock通路的影响.南方医科大学学报,2008,(6):968-971
[22]Melton AC, Datta A, Yee HF.[Ca2+]i-independentcontractile forcegeneration by rat hepatic stellate cells in response to endothelin-1. Am J Physiol Gastrointest Liver Physiol, 2006, 290(1):G7-G13
[23]孙岚,辛文妤,于昕,等.非对称性二甲基精氨酸通过Rho/ROCK信号通路介导大鼠血管平滑肌细胞迁移.中国分子心脏病学杂志, 2012, 12(1):37-42
[24]王玉珍,姜慧卿,扈彩霞,等.法舒地尔通过Rho/ROCK信号通路抑制肝星状细胞黏附、迁移和增殖.中华肝脏病杂志, 2006,(11):821-823
[25]王波.细胞骨架重排及Rho信号传导途径在肝纤维化中的作用机制研究.武汉:华中科技大学, 2004
[26]高庆强,陈海,陈赟,等.法舒地尔对前列腺癌PC3细胞增殖与凋亡的影响.国际泌尿系统杂志, 2016,(5):694-698
[27]Tang Y, He Y, Zhang P, et al. LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis. Mol Cancer, 2018, 17(1):77
[28]Yu WY, Yu CH, Dai W, et al. Effect of Rho-ROCK signaling pathway on pulmonary fibrosis. J Chin Pharm Sci, 2016, 25(1):3-11
[29]Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest, 2013,123(3):1096-1108
[30]李君,孙建平,付晓波.Rho/Rock信号通路在原发性高血压肾纤维化中作用.青岛大学医学院学报, 2010,46(02):113-115, 118
[31]高海成.Rho/Rock通路在大鼠心肌纤维化发生机制中的作用及阿魏酸钠的干预研究.吉林:吉林大学, 2009
[32]Shimizu Y, Dobashi K, Iizuka K, et al.Contribution of small GTPase Rho andi ts target protei n Rock in a murine model of lung fibrosis. Am J Respir Crit Care Med,2001, 163(1):210-217
[33]宋鑫,张林医,苏梦琦,等. Rho相关卷曲螺旋形成蛋白激酶1在大鼠肝纤维化不同阶段表达及意义.中华实验外科杂志, 2017,(6):967-969
[34]Tada S, Iwamoto H, Nakamuta M, et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol, 2001,34(4):529-536
[35]英嵩崧,李旭,张振书.血管紧张素1-7对大鼠肝星状细胞Rho-Rock信号转导通路的影响.现代消化及介入诊疗, 2013, 18(3):145-147
[36]周晋航,陈先祥,吴黎明,等.腺苷蛋氨酸对过度激活的Rho-ROCK通路介导的糖尿病肝损伤的改善作用.医学综述, 2016, 22(20):4090-4093
[37]梁昌宇,覃山羽,姜海行,等.骨髓间充质干细胞对大鼠急性肝损伤修复的影响.世界华人消化杂志, 2009,17(12):1178-1184
[38]张锦生.肝星状细胞激活的内在机制.世界华人消化杂志, 2005,(7):831-834
[39]Gong W, Pecci A, Roth S, et al. Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. Hepatology, 1998, 28:492-502
[40]Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev, 1997, 11:2295-2322
[41]周雯,杨玲,胡胜军. Rho蛋白与肝星状细胞.世界华人消化杂志, 2009, 17(24):2469-2473
[42]Laleman W, Landeghem L, Wilmer A, et al. Portal hypertension:from pathophysiology to clinical practice. Liver Int, 2005, 25:1079-1090
[43]Reynaert H, Thompson MG, Thomas T, et al. Hepatic stellate cells:role in microcirculation and pathophysiology of portal hypertension. Gut, 2002, 50:571-581
[44]Rockey DC. Vascular mediators in the injured liver.Hepatology, 2003, 37:4-12
[45]Saab S, Tam SP, Tran BN, et al. Myosin mediates contractile force generation by hepatic stellate cells in response to endothelin-1. J Biomed Sci, 2002, 9:607-612
[46]Shi J, Wei L. Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp(Warsz), 2007, 55:61-75
[47]扈彩霞,陈新月,王玉珍,等.法舒地尔抑制大鼠肝纤维化组织ROCK-I、α-SMA、p-MBS Thr-697表达.传染病信息, 2011, 24(03):140-142, 170
[48]Xie Y, Song T, Huo M, et al. Fasudil alleviates hepatic fibrosis in type 1 diabetic rats:involvement of the inflammation and RhoA/ROCK pathway. Eur Rev Med Pharmacol Sci, 2018, 22(17):5665-5677
[49]吴晓玲,曾维政,蒋明德,等.红景天甙对肝纤维化大鼠肝组织ROCK表达的影响.世界华人消化杂志, 2009,17(08):765-769
[50]杨玲,但丹,朱锐,等.β-榄香烯抑制肝星状细胞表达ANGⅡ及RhoA/ROCK信号.中国中药杂志,2009,34(04):458-463
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