心肌纤维化的信号传导机制及中医药治疗探讨
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摘要
心肌纤维化是心力衰竭发展的重要机制,是心力衰竭病人预后不良的主要原因。心肌纤维化的形成过程涉及多种信号传导机制,可划分为促进心肌纤维化形成的信号传导机制[肾素-血管紧张素-醛固酮系统、转化生长因子β_1(TGF-β_1)/信号转导蛋白(Smads)、炎症反应、氧化应激反应]和抑制心肌纤维化形成的信号传导机制(gp130-JAKs-STAT3信号通路),通过对信号传导机制的进一步研究,可加深对心肌纤维化的理解,为临床治疗心肌纤维化提供新的靶标。中医药治疗心肌纤维化具有"标本同治"的优势,研究证实多种中药复方和单味药均不同程度的抑制心肌纤维化,但其对心肌纤维化信号传导机制的研究尚存在不足,值得进一步探讨。
Studies have confirmed that myocardial fibrosis is an important mechanism in the development of heart failure,it has important influence on the prognosis of heart failure.A variety of signal transduction mechanism was involved in the formation process of myocardial fibrosis.It can be divided into two kinds:the signal transduction mechanism promoting myocardial fibrosis formation(renin-angiotensin-aldosterone system,transforming growth factor(TGF)-β_1/Smads signaling pathway,inflammatory response,oxidative stress response)and the signal transduction mechanism inhibiting myocardial fibrosis formation(gp130-JAKs-STAT3 signaling pathway).Further research on the signal transduction mechanism of myocardial fibrosis can provide new targets for the clinical treatment of myocardial fibrosis.Traditional Chinese medicine can simultaneous treat the manifestation and root cause of myocardial fibrosis and has been proved an immense advantage.A variety of traditional Chinese medicine compound and single herbs has been proved to have inhibitory effects of myocardial fibrosis,but the signal transduction mechanism remains unclear.It is worth further discussing.
Studies have confirmed that myocardial fibrosis is an important mechanism in the development of heart failure,it has important influence on the prognosis of heart failure.A variety of signal transduction mechanism was involved in the formation process of myocardial fibrosis.It can be divided into two kinds:the signal transduction mechanism promoting myocardial fibrosis formation(renin-angiotensin-aldosterone system,transforming growth factor(TGF)-β_1/Smads signaling pathway,inflammatory response,oxidative stress response)and the signal transduction mechanism inhibiting myocardial fibrosis formation(gp130-JAKs-STAT3 signaling pathway).Further research on the signal transduction mechanism of myocardial fibrosis can provide new targets for the clinical treatment of myocardial fibrosis.Traditional Chinese medicine can simultaneous treat the manifestation and root cause of myocardial fibrosis and has been proved an immense advantage.A variety of traditional Chinese medicine compound and single herbs has been proved to have inhibitory effects of myocardial fibrosis,but the signal transduction mechanism remains unclear.It is worth further discussing.
引文
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[11]Liu XH,Gai YL,Liu F,et al.Trimetazidine inhibits pressure overloadinduced cardiac fibrosis through NADPH oxidase–ROS–CTGF pathway[J].Cardiovascular Research,2010,88(1):150-158.
[12]Lu XL,Zhao P,Zhang ZG.Myocardial fibrosis:a chronic inflammatory process[J].Journal of Clinical Rehabilitative Tissue Engineering Research,2007,11(51):10416-10420.
[13]杨贵芳,彭文,赵琴.心力衰竭免疫学机制及治疗的研究进展[J].中国循环杂志,2015,30(2):193-195.
[14]Van Linthout S,Miteva K,Tscho C.Crosstalk between fibroblasts and inflammatory cells[J].Cardiovascular Research,2014,102(1):258-269.
[15]Shi JJ,Wei L.Regulation of JAK/STAT signalling by SOCS in the myocardium[J].Cardiovascular Research,2012,96(1):345-347.
[16]Boengler K,Hilfiker-Kleiner D,Drexler H,et al.The myocardial JAK/STAT pathway:from protection to failure[J].Pharmacology&Therapeutics,2008,120(1):172-185.
[17]Jacoby JJ,Kalinowski A,Liu MG,et al.Cardiomyocyte-restricted knockout of STAT3results in higher sensitivity to inflammation,cardiac fibrosis,and heart failure with advanced age[J].Proc Natl Acad Sci,2003,100(22):12929-12934.
[18]Gonzalez A,Ravassa S,Loperena I,et al.Association of depressed cardiac gp130-mediated antiapoptotic pathways with stimulated cardiomyocyte apoptosis in hypertensive patients with heart failure[J].J Hypertens,2007,25(10):2148-2157.
[19]Peng Y,Zhou B,Wang YY,et al.Association between polymorphisms in the signal transducer and activator of transcription and dilated cardiomyopathy in the Chinese Han population[J].Mol Cell Biochem,2012,360(1):197-203.
[20]Hilfiker-Kleiner D,Hilfiker A,Fuchs M,et al.Signal transducer and activator of transcription 3is required for myocardial capillary growth,control of interstitial matrix deposition,and heart protection from ischemic injury[J].Circul Res,2004,95(1):187-195.
[21]Haghikia A,Ricke-Hoch M,Stapel B,et al.STAT3,a key regulator of cell-to-cell communication in the heart[J].Cardiovascular Research,2014,102(1):281-289.
[22]余雄伟,陈争跃,聂振禹,等.JAK/STAT信号通路与组织器官纤维化的相关性研究进展[J].新医学,2014,45(11):710-713.
[23]Fischer P,Hilfiker-Kleiner D.Survival pathways in hypertrophy and heart failure:the gp130-STAT3axis[J].Basic Res Cardiol,2007,102(1):393-411.
[24]吴美芳,吕仕超,张军平.心肌纤维化中医诊疗思路探析[J].时珍国医国药,2015,26(3):677-679.
[25]吴美芳,吕仕超,李萌,等.中医药干预心肌纤维化的效应与机制[J].中国中西医结合杂志,2014,34(7):887-891.
[26]曾宇,张三印.中医药对心肌纤维化的研究进展[J].云南中医中药杂志,2015,36(1):68-70.
[27]张海啸,史载祥,贾海忠,等.大蒜素通过部分阻抑TGF-β1介导的Smads信号改善压力超负荷大鼠心肌反应性纤维化[J].中国中西医结合杂志,2012,32(5):666-670.
[28]冯俊,李树生,屠恩远.丹参酮ⅡA通过下调CTGF抗血管紧张素Ⅱ诱导的心肌成纤维细胞Ⅰ型、Ⅲ型胶原合成[J].中国中医急症,2012,21(4):560-561;573.
[29]徐基杰,瞿惠燕,戎靖枫,等.鹿红颗粒对心力衰竭大鼠ACE2-Ang(1-7)轴的影响[J].上海中医药大学学报,2015,29(6):41-44.
[30]赵淑明,郭秋红,张志良,等.葶苈生脉方对慢性心衰大鼠血清肿瘤坏死因子-α、白细胞介素-6及心肌胶原的影响[J].时珍国医国药,2010,21(1):153-154.
[31]霍根红,李玉贤.参附强心胶囊对充血性心力衰竭大鼠心肌纤维化的影响[J].中医学报,2011,26(3):322-323.
[32]束长城,魏万林,张灵,等.芪参益气滴丸对肾性高血压大鼠心肌纤维化及CTGF表达的影响[J].军事医学,2012,36(9):678-682;686.
[2]宋秉春,张金国.心肌纤维化发病机制及治疗进展[J].济宁医学院学报,2015,38(1):65-67;70.
[3]MacLean J,Pasumarthi KBS.Signaling mechanisms regulating fibroblaet activation,phenocoversion and fibroblast in the heart[J].Indian Journal of Biochemistry&Biophysics,2014,51(1):476-482.
[4]Lajiness JD,Conway SJ.Origin,development,and differentiation of cardiac fibroblasts.[J].Journal of Molecular&Cellular Cardiology,2014,70(9):2.
[5]王禹川,丁燕生,刘梅林.不同因子致心肌纤维化分子学机制[J].医学综述,2012,18(17):2736-2740.
[6]Somanna NK,Yariswamy M,Garagliano JM,et al.Aldosteroneinduced cardiomyocyte growth,and fibroblast migration and proliferation are mediated by TRAF3IP2[J].Cellular Signalling,2015,27(10):1928.
[7]陈蓉,谢梅林.TGF-β/Smads信号通路在心肌纤维化发生和治疗中应用前景的研究进展[J].中国药理学通报,2012,28(9):1189-1192.
[8]Dzeshka MS,Lip GY,Snezhitskiy V,et al.Cardiac fibrosis in patients with atrial fibrillation:mechanisms and clinical implications[J].Journal of the American College of Cardiology,2015,66(8):943-959.
[9]Cavalera M,Wang J,Frangogiannis NG.Obesity,metabolic dysfunction,and cardiac fibrosis:pathophysiological pathways,molecular mechanisms,and therapeutic opportunities[J].Translational Research,2014,164(4):323-335.
[10]Zhao Q D,Viswanadhapalli S,Williams P,et al.NADPH oxidase4induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways[J].Circulation,2015,131(7):643-655.
[11]Liu XH,Gai YL,Liu F,et al.Trimetazidine inhibits pressure overloadinduced cardiac fibrosis through NADPH oxidase–ROS–CTGF pathway[J].Cardiovascular Research,2010,88(1):150-158.
[12]Lu XL,Zhao P,Zhang ZG.Myocardial fibrosis:a chronic inflammatory process[J].Journal of Clinical Rehabilitative Tissue Engineering Research,2007,11(51):10416-10420.
[13]杨贵芳,彭文,赵琴.心力衰竭免疫学机制及治疗的研究进展[J].中国循环杂志,2015,30(2):193-195.
[14]Van Linthout S,Miteva K,Tscho C.Crosstalk between fibroblasts and inflammatory cells[J].Cardiovascular Research,2014,102(1):258-269.
[15]Shi JJ,Wei L.Regulation of JAK/STAT signalling by SOCS in the myocardium[J].Cardiovascular Research,2012,96(1):345-347.
[16]Boengler K,Hilfiker-Kleiner D,Drexler H,et al.The myocardial JAK/STAT pathway:from protection to failure[J].Pharmacology&Therapeutics,2008,120(1):172-185.
[17]Jacoby JJ,Kalinowski A,Liu MG,et al.Cardiomyocyte-restricted knockout of STAT3results in higher sensitivity to inflammation,cardiac fibrosis,and heart failure with advanced age[J].Proc Natl Acad Sci,2003,100(22):12929-12934.
[18]Gonzalez A,Ravassa S,Loperena I,et al.Association of depressed cardiac gp130-mediated antiapoptotic pathways with stimulated cardiomyocyte apoptosis in hypertensive patients with heart failure[J].J Hypertens,2007,25(10):2148-2157.
[19]Peng Y,Zhou B,Wang YY,et al.Association between polymorphisms in the signal transducer and activator of transcription and dilated cardiomyopathy in the Chinese Han population[J].Mol Cell Biochem,2012,360(1):197-203.
[20]Hilfiker-Kleiner D,Hilfiker A,Fuchs M,et al.Signal transducer and activator of transcription 3is required for myocardial capillary growth,control of interstitial matrix deposition,and heart protection from ischemic injury[J].Circul Res,2004,95(1):187-195.
[21]Haghikia A,Ricke-Hoch M,Stapel B,et al.STAT3,a key regulator of cell-to-cell communication in the heart[J].Cardiovascular Research,2014,102(1):281-289.
[22]余雄伟,陈争跃,聂振禹,等.JAK/STAT信号通路与组织器官纤维化的相关性研究进展[J].新医学,2014,45(11):710-713.
[23]Fischer P,Hilfiker-Kleiner D.Survival pathways in hypertrophy and heart failure:the gp130-STAT3axis[J].Basic Res Cardiol,2007,102(1):393-411.
[24]吴美芳,吕仕超,张军平.心肌纤维化中医诊疗思路探析[J].时珍国医国药,2015,26(3):677-679.
[25]吴美芳,吕仕超,李萌,等.中医药干预心肌纤维化的效应与机制[J].中国中西医结合杂志,2014,34(7):887-891.
[26]曾宇,张三印.中医药对心肌纤维化的研究进展[J].云南中医中药杂志,2015,36(1):68-70.
[27]张海啸,史载祥,贾海忠,等.大蒜素通过部分阻抑TGF-β1介导的Smads信号改善压力超负荷大鼠心肌反应性纤维化[J].中国中西医结合杂志,2012,32(5):666-670.
[28]冯俊,李树生,屠恩远.丹参酮ⅡA通过下调CTGF抗血管紧张素Ⅱ诱导的心肌成纤维细胞Ⅰ型、Ⅲ型胶原合成[J].中国中医急症,2012,21(4):560-561;573.
[29]徐基杰,瞿惠燕,戎靖枫,等.鹿红颗粒对心力衰竭大鼠ACE2-Ang(1-7)轴的影响[J].上海中医药大学学报,2015,29(6):41-44.
[30]赵淑明,郭秋红,张志良,等.葶苈生脉方对慢性心衰大鼠血清肿瘤坏死因子-α、白细胞介素-6及心肌胶原的影响[J].时珍国医国药,2010,21(1):153-154.
[31]霍根红,李玉贤.参附强心胶囊对充血性心力衰竭大鼠心肌纤维化的影响[J].中医学报,2011,26(3):322-323.
[32]束长城,魏万林,张灵,等.芪参益气滴丸对肾性高血压大鼠心肌纤维化及CTGF表达的影响[J].军事医学,2012,36(9):678-682;686.