心肌纤维化致病机制的研究进展
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摘要
心脏结构重构包括心室扩张、心肌细胞肥厚、细胞凋亡、心肌纤维化等病理过程。心肌纤维化是心肌重构的主要表现之一,是多种疾病过程的共同病理结果,心肌纤维化越重,心功能越差。心肌纤维化是一个全球性的健康问题,它可以出现在各种形式的心脏疾病当中。尽管所患的疾病不同,但是其病理过程和转归却惊人的一致,即心脏组织中心肌成纤维细胞(cardiac fibroblasts,CFBs)的病理性增多、心肌细胞外基质(extracellular matrix,ECM)的异常沉积,从而导致心肌纤维化,心脏顺应性降低,心脏功能减退,最后出现充血性心力衰竭。据文献报道,刺激CFBs病理性增多的机制主要有心肌细胞承受的压力/容量负荷外在性因素作用和细胞因子的内在性因素作用。而导致ECM异常沉积主要受转化生长因子-β1(TGF-β1)、肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system,RAAS)、脂肪因子、糜酶等因素调节。本文对心肌纤维化中CFB的来源与增加的分子机制和ECM沉积影响因素的研究作一综述。
引文
[1]陈伟伟,高润霖,刘力生,等.中国心血管病报告2013概要[J].中国循环杂志,2014(7):487-491.
[2]PINTO A R,ILINYKH A,IVEY M J,et al.Revisiting cardiac cellular composition[J].Circ Res,2016,118(3):400-409.
[3]ALI S R,RANJBARVAZIRI S,TALKHABI M,et al.Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation[J].Circ Res,2014,115(7):625-635.
[4]CALDERONE A,BEL-HADJ S,DRAPEAU J,et al.Scar myofibroblasts of the infarcted rat heart express natriuretic peptides[J].J Cell Physiol,2006,207(1):165-173.
[5]TOMASEK J J,GABBIANI G,HINZ B,et al.Myofibroblasts and mechano-regulation of connective tissue remodelling[J].Nat Rev Mol Cell Biol,2002,3(5):349-363.
[6]VAN WAMEL A J,RUWHOF C,VAN der VALK-KOK-SHOOM L E,et al.The role of angiotensinⅡ,endothelin-1and transforming growth factor-beta as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy[J].Mol Cell Biochem,2001,218(1-2):113-124.
[7]CHRISTIA P,BUJAK M,GONZALEZ-QUESADA C,et al.Systematic characterization of myocardial inflammation,repair,and remodeling in a mouse model of reperfused myocardial infarction[J].J Histochem Cytochem,2013,61(8):555-570.
[8]SCHNEE J M,HSUEH W A.AngiotensinⅡ,adhesion,and cardiac fibrosis[J].Cardiovasc Res,2000,46(2):264-268.
[9]ZHANG R,ZHANG Y Y,HUANG X R,et al.C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease[J].Hypertension,2010,55(4):953-960.
[10]SARRAZY V,KOEHLER A,CHOW M L,et al.Integrins alphavbeta5 and alphavbeta3 promote latent TGF-beta1 activation by human cardiac fibroblast contraction[J].Cardiovasc Res,2014,102(3):407-417.
[11]WIPFF P J,RIFKIN D B,MEISTER J J,et al.Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix[J].J Cell Biol,2007,179(6):1311-1323.
[12]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(9):1189-1192.
[13]DAVIS J,BURR A R,DAVIS G F,et al.A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo[J].Dev Cell,2012,23(4):705-715.
[14]LEASK A.Potential therapeutic targets for cardiac fibrosis:TGFbeta,angiotensin,endothelin,CCN2,and PDGF,partners in fibroblast activation[J].Circ Res,2010,106(11):1675-1680.
[15]CHRISTIA P,BUJAK M,GONZALEZ-QUESADA C,et al.Systematic characterization of myocardial inflammation,repair,and remodeling in a mouse model of reperfused myocardial infarction[J].J Histochem Cytochem,2013,61(8):555-570.
[16]王禹川.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.
[17]YANG F,CHUNG A C,HUANG X R,et al.AngiotensinⅡinduces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and-independent Smad pathways:the role of Smad3[J].Hypertension,2009,54(4):877-884.
[18]ZHANG R,ZHANG Y Y,HUANG X R,et al.C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease[J].Hypertension,2010,55(4):953-960.
[19]MANO Y,ANZAI T,KANEKO H,et al.Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy[J].Circ J,2011,75(7):1717-1727.
[20]CHEN X Q,LIU X,WANG Q X,et al.Pioglitazone inhibits angiotensinⅡ-induced atrial fibroblasts proliferation via NF-kappa B/TGF-beta1/TRIF/TRAF6 pathway[J].Exp Cell Res,2015,330(1):43-55.
[21]ZOU Y,AKAZAWA H,QIN Y,et al.Mechanical stress activates angiotensinⅡtype 1 receptor without the involvement of angiotensinⅡ[J].Nat Cell Biol,2004,6(6):499-506.
[22]YAMAMOTO T,NAKAGAWA T,SUZUKI H,et al.Urinary angiotensinogen as a marker of intrarenal angiotensinⅡactivity associated with deterioration of renal function in patients with chronic kidney disease[J].J Am Soc Nephrol,2007,18(5):1558-1565.
[23]蔡辉,张蓓蓓.心脏成纤维细胞在心肌纤维化中的作用[J].微循环学杂志,2014(4):80-82.
[24]HUNTGEBURTH M,TIEMANN K,SHAHVERDYAN R,et al.Transforming growth factor beta(1)oppositely regulates the hypertrophic and contractile response to beta-adrenergic stimulation in the heart[J].PLo S One,2011,6(11):e26628.
[25]MARTIN J,KELLY D J,MIFSUD S A,et al.Tranilast attenuates cardiac matrix deposition in experimental diabetes:role of transforming growth factor-beta[J].Cardiovasc Res,2005,65(3):694-701.
[26]OKUNO M,AKITA K,MORIWAKI H,et al.Prevention of rat hepatic fibrosis by the protease inhibitor,camostat mesilate,via reduced generation of active TGF-beta[J].Gastroenterology,2001,120(7):1784-1800.
[27]INMAN G J,NICOLAS F J,CALLAHAN J F,et al.SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase(ALK)receptors ALK4,ALK5,and ALK7[J].Mol Pharmacol,2002,62(1):65-74.
[28]ZHAI Y,GAO X,WU Q,et al.Fluvastatin decreases cardiac fibrosis possibly through regulation of TGF-beta(1)/Smad 7 expression in the spontaneously hypertensive rats[J].Eur J Pharmacol,2008,587(1-3):196-203.
[29]CHEN P,XIE Y,SHEN E,et al.Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-beta1 signaling in coxsackievirus B3-induced cardiomyopathy[J].Eur J Pharmacol,2011,658(2-3):168-174.
[30]CHEN R,XUE J,XIE M L.Reduction of isoprenaline-induced myocardial TGF-beta1 expression and fibrosis in ostholetreated mice[J].Toxicol Appl Pharmacol,2011,256(2):168-173.
[31]SHEN X C,YANG Y P,XIAO T T,et al.Protective effect of oxymatrine on myocardial fibrosis induced by acute myocardial infarction in rats involved in TGF-beta(1)-Smads signal pathway[J].J Asian Nat Prod Res,2011,13(3):215-224.
[32]ZOU Y,AKAZAWA H,QIN Y,et al.Mechanical stress activates angiotensinⅡtype 1 receptor without the involvement of angiotensin II[J].Nat Cell Biol,2004,6(6):499-506.
[33]ZOU Y,AKAZAWA H,QIN Y,et al.Mechanical stress activates angiotensinⅡtype 1 receptor without the involvement of angiotensinⅡ[J].Nat Cell Biol,2004,6(6):499-506.
[34]MA F,LI Y,JIA L,et al.Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF beta/Smad activation and cardiac fibrosis induced by angiotensinⅡ[J].PLo SOne,2012,7(5):e35144.
[35]MARCINIEC K,PAWELCZAK B,LATOCHA M,et al.Synthesis,anti-breast cancer activity,and molecular docking study of a new group of acetylenic quinolinesulfonamide derivatives[J].Molecules,2017,22(2).pii:E300.
[36]王先梅,杨丽霞,宋武战,等.心脏糜酶活性改变在心肌肥厚患者心肌纤维化中的意义[J].中国病理生理杂志,2007(12):2327-2331.
[2]PINTO A R,ILINYKH A,IVEY M J,et al.Revisiting cardiac cellular composition[J].Circ Res,2016,118(3):400-409.
[3]ALI S R,RANJBARVAZIRI S,TALKHABI M,et al.Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation[J].Circ Res,2014,115(7):625-635.
[4]CALDERONE A,BEL-HADJ S,DRAPEAU J,et al.Scar myofibroblasts of the infarcted rat heart express natriuretic peptides[J].J Cell Physiol,2006,207(1):165-173.
[5]TOMASEK J J,GABBIANI G,HINZ B,et al.Myofibroblasts and mechano-regulation of connective tissue remodelling[J].Nat Rev Mol Cell Biol,2002,3(5):349-363.
[6]VAN WAMEL A J,RUWHOF C,VAN der VALK-KOK-SHOOM L E,et al.The role of angiotensinⅡ,endothelin-1and transforming growth factor-beta as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy[J].Mol Cell Biochem,2001,218(1-2):113-124.
[7]CHRISTIA P,BUJAK M,GONZALEZ-QUESADA C,et al.Systematic characterization of myocardial inflammation,repair,and remodeling in a mouse model of reperfused myocardial infarction[J].J Histochem Cytochem,2013,61(8):555-570.
[8]SCHNEE J M,HSUEH W A.AngiotensinⅡ,adhesion,and cardiac fibrosis[J].Cardiovasc Res,2000,46(2):264-268.
[9]ZHANG R,ZHANG Y Y,HUANG X R,et al.C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease[J].Hypertension,2010,55(4):953-960.
[10]SARRAZY V,KOEHLER A,CHOW M L,et al.Integrins alphavbeta5 and alphavbeta3 promote latent TGF-beta1 activation by human cardiac fibroblast contraction[J].Cardiovasc Res,2014,102(3):407-417.
[11]WIPFF P J,RIFKIN D B,MEISTER J J,et al.Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix[J].J Cell Biol,2007,179(6):1311-1323.
[12]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(9):1189-1192.
[13]DAVIS J,BURR A R,DAVIS G F,et al.A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo[J].Dev Cell,2012,23(4):705-715.
[14]LEASK A.Potential therapeutic targets for cardiac fibrosis:TGFbeta,angiotensin,endothelin,CCN2,and PDGF,partners in fibroblast activation[J].Circ Res,2010,106(11):1675-1680.
[15]CHRISTIA P,BUJAK M,GONZALEZ-QUESADA C,et al.Systematic characterization of myocardial inflammation,repair,and remodeling in a mouse model of reperfused myocardial infarction[J].J Histochem Cytochem,2013,61(8):555-570.
[16]王禹川.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.
[17]YANG F,CHUNG A C,HUANG X R,et al.AngiotensinⅡinduces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and-independent Smad pathways:the role of Smad3[J].Hypertension,2009,54(4):877-884.
[18]ZHANG R,ZHANG Y Y,HUANG X R,et al.C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease[J].Hypertension,2010,55(4):953-960.
[19]MANO Y,ANZAI T,KANEKO H,et al.Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy[J].Circ J,2011,75(7):1717-1727.
[20]CHEN X Q,LIU X,WANG Q X,et al.Pioglitazone inhibits angiotensinⅡ-induced atrial fibroblasts proliferation via NF-kappa B/TGF-beta1/TRIF/TRAF6 pathway[J].Exp Cell Res,2015,330(1):43-55.
[21]ZOU Y,AKAZAWA H,QIN Y,et al.Mechanical stress activates angiotensinⅡtype 1 receptor without the involvement of angiotensinⅡ[J].Nat Cell Biol,2004,6(6):499-506.
[22]YAMAMOTO T,NAKAGAWA T,SUZUKI H,et al.Urinary angiotensinogen as a marker of intrarenal angiotensinⅡactivity associated with deterioration of renal function in patients with chronic kidney disease[J].J Am Soc Nephrol,2007,18(5):1558-1565.
[23]蔡辉,张蓓蓓.心脏成纤维细胞在心肌纤维化中的作用[J].微循环学杂志,2014(4):80-82.
[24]HUNTGEBURTH M,TIEMANN K,SHAHVERDYAN R,et al.Transforming growth factor beta(1)oppositely regulates the hypertrophic and contractile response to beta-adrenergic stimulation in the heart[J].PLo S One,2011,6(11):e26628.
[25]MARTIN J,KELLY D J,MIFSUD S A,et al.Tranilast attenuates cardiac matrix deposition in experimental diabetes:role of transforming growth factor-beta[J].Cardiovasc Res,2005,65(3):694-701.
[26]OKUNO M,AKITA K,MORIWAKI H,et al.Prevention of rat hepatic fibrosis by the protease inhibitor,camostat mesilate,via reduced generation of active TGF-beta[J].Gastroenterology,2001,120(7):1784-1800.
[27]INMAN G J,NICOLAS F J,CALLAHAN J F,et al.SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase(ALK)receptors ALK4,ALK5,and ALK7[J].Mol Pharmacol,2002,62(1):65-74.
[28]ZHAI Y,GAO X,WU Q,et al.Fluvastatin decreases cardiac fibrosis possibly through regulation of TGF-beta(1)/Smad 7 expression in the spontaneously hypertensive rats[J].Eur J Pharmacol,2008,587(1-3):196-203.
[29]CHEN P,XIE Y,SHEN E,et al.Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-beta1 signaling in coxsackievirus B3-induced cardiomyopathy[J].Eur J Pharmacol,2011,658(2-3):168-174.
[30]CHEN R,XUE J,XIE M L.Reduction of isoprenaline-induced myocardial TGF-beta1 expression and fibrosis in ostholetreated mice[J].Toxicol Appl Pharmacol,2011,256(2):168-173.
[31]SHEN X C,YANG Y P,XIAO T T,et al.Protective effect of oxymatrine on myocardial fibrosis induced by acute myocardial infarction in rats involved in TGF-beta(1)-Smads signal pathway[J].J Asian Nat Prod Res,2011,13(3):215-224.
[32]ZOU Y,AKAZAWA H,QIN Y,et al.Mechanical stress activates angiotensinⅡtype 1 receptor without the involvement of angiotensin II[J].Nat Cell Biol,2004,6(6):499-506.
[33]ZOU Y,AKAZAWA H,QIN Y,et al.Mechanical stress activates angiotensinⅡtype 1 receptor without the involvement of angiotensinⅡ[J].Nat Cell Biol,2004,6(6):499-506.
[34]MA F,LI Y,JIA L,et al.Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF beta/Smad activation and cardiac fibrosis induced by angiotensinⅡ[J].PLo SOne,2012,7(5):e35144.
[35]MARCINIEC K,PAWELCZAK B,LATOCHA M,et al.Synthesis,anti-breast cancer activity,and molecular docking study of a new group of acetylenic quinolinesulfonamide derivatives[J].Molecules,2017,22(2).pii:E300.
[36]王先梅,杨丽霞,宋武战,等.心脏糜酶活性改变在心肌肥厚患者心肌纤维化中的意义[J].中国病理生理杂志,2007(12):2327-2331.