扩张型心肌病心肌细胞外基质的重塑及其调控机制
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摘要
目的:研究基质金属蛋白酶-2(matrix metalloproteinase-2, MMP-2)及金属蛋白酶组织抑制因子-1(tissue inhibitors of metalloproteinase-1, TIMP-1)在阿霉素扩张型心肌病(dilated cardiomyopathy diease, DCM)心肌间质重塑中的作用和意义,观察血管紧张素转化酶抑制剂(angiotensin-coverting enzyme inhibitor, ACEI)干预治疗对MMP-2和TIMP-1在心室组织中表达的影响,以及血浆Ⅰ型前胶原羧基端肽(procollagen typeⅠcarboxylpropetide, PICP)、Ⅲ型前胶原氨基端肽(procollagen typeⅢN-terminalpropetide, PⅢNP)浓度变化及其与心肌纤维化程度的相关性。
方法:雄性SD大鼠分2组(1)正常对照组10只;(2)DCM组50只:阿霉素2mg/Kg腹腔注射,每周1次,连续8周后行心脏超声心动图,将达到DCM标准的大鼠再分为3组:①A组(卡托普利高剂量干预组),50mg/Kg·d灌胃给药,连续3周;②B组(卡托普利低剂量干预组),25mg/Kg·d灌胃给药,连续3周;③C组(DCM对照组)。取各组心脏组织切片行HE染色观察心肌的病理变化,苦味酸天狼星红染色(Van Gieson, VG染色)进行心室胶原特异染色及定量分析,免疫组化染色法对各组大鼠心脏心室组织MMP-2、TIMP-1蛋白的表达进行半定量检测。采用RT-PCR技术检测心室心肌MMP-2及TIMP-1mRNA的表达。ELISA方法对血浆PICP和PⅢNP的浓度进行定量测定。
结果:
1大鼠生存情况:对照组全部存活;腹腔注射阿霉素的50只大鼠,死亡4只。
2超声心动图检测:与正常对照组相比,给予阿霉素腹腔注射的DCM组,心腔明显扩张,左室舒张期末内径(left ventricular enddiastole , LVED)、左室收缩期末内径(left ventricular endsystole, LVDS)明显的增加(P﹤0.05);左室内径缩短率(fraction-shortening , FS)、左室射血分数(left ventricu1ar ejection fraction , EF)明显降低(P﹤0.05)。
3心肌组织病理学检查:①HE染色见正常对照组心肌细胞排列均匀整齐,横纹清楚,细胞大小均一,心肌细胞间隙无变化;DCM各组心脏组织有不同程度的炎性病变,心肌细胞排列紊乱呈多灶性溶解,心肌细胞变性、坏死,相邻细胞间隙增大,排列紊乱、核大深染、异型。DCM组心肌组织形态学的改变符合扩张型心肌病的病理学改变。②VG染色:DCM组较正常对照组的胶原纤维明显增加。DCM组胶原容积分数(collagen volume fraction , CVF)高于正常对照组(P﹤0. 05),而A组和B组的CVF值较C组明显减少(P﹤0. 05)。
4免疫组化染色:结果示MMP-2、TIMP-1蛋白主要表达于心肌细胞的胞质及心肌细胞外基质(extracellular matrix,ECM)中。MMP-2在正常对照组、A组和B组微弱表达,而在C组表达增强。C组MMP-2的表达高于正常对照组(P﹤0.01);而A组MMP-2的表达显著低于C组(P﹤0.01),B组MMP-2的表达低于C组(P﹤0.05)。TIMP-1在正常对照组、A组和B组呈较强的表达,而在C组表达较弱。C组TIMP-1的表达低于正常对照组(P﹤0.01);而A组TIMP-1的表达明显高于C组(P﹤0.01),B组TIMP-1的表达高于C组(P﹤0.05)。
5心室心肌MMP-2、TIMP-1的mRNA表达:MMP-2 mRNA表达C组心室心肌中较正常对照组显著增加(P﹤0. 01),A组较C组有明显的降低(P﹤0. 01),B组低于C组(P﹤0. 05)。TIMP-1mRNA的表达C组较正常对照组有明显的减低(P﹤0. 05),A组较C组有明显的增加(P﹤0. 05),B组与C组无明显差异(P﹥0.05)。
6血浆中PICP、PⅢNP的浓度:C组血浆的PICP、PⅢNP的浓度高于正常对照组(P﹤0. 01);A、B组血浆中PICP、PⅢNP的浓度显著低于C组(P﹤0.01);
结论: MMP和TIMP参与了DCM发生发展过程中心肌细胞外基质的重塑,MMP-2∕TIMP-1比率增高可促进DCM心肌细胞外基质胶原增生,从而影响心肌纤维化程度。血浆中PICP、PⅢNP的浓度与心肌纤维化程度相关。血管紧张素转化酶抑制剂卡托普利可能通过降低心脏心肌细胞外基质MMP-2的表达,减轻MMP-2对ECM的降解和破坏作用;并通过上调TIMP-1而影响MMP-2∕TIMP-1动态平衡,在DCM心肌细胞外基质重塑中起重要调节作用。
PURPOSES: To research the effect and significance about MMPs-2 and TIMPs-1 in the model of DCM rats. To investigate the expression of MMP-2,TIMP-1 and collagen fiber during the course of DCM treated with ACEI and without. To explore the the relation between MMPs and PICP, PⅢNP.
METHODS: 60 SD rats were divided randomly into two groups: normal control group, the DCM group, the DCM treated with adriamycin intraperitoneally 2.0 mg/kg·week for 8 weeks to estabilsh DCM model. The normal control group was intravitreous injected with normal saline. Transthoracic echocardiography was performed in the DCM group and control guoup rats.DCM who were achieve standard were divided randomly into three groups:(1)A group:the rats who were administered captopril by gavage at a dose of 50mg/kg·d for 3 weeks (2)B group: the rats who were administered captopril by gavage at a dose of 25 mg/kg·d for 3 weeks (3)C group(DCM control group).HE stain was used to observe the change of the Histopathological characteristics . The semiquantitative analysis was used to evaluate the CVF.The expression of MMP-2 and TIMP-1 were quailtative and semiquantitative analysised with immunohistochemistry and RT-PCR .The qualitative analysis was used to evaluate the PICP and PⅢNP in blood plasm.
RESULTS:
1 Living condition of rats: the normal control group were all survival;the DCM group has been died four rats.
2 Compared with the normol control group, venticular interior diameter was enlarge. LVED and LVES were increased significantly(P < 0.05),whereas the FS and EF were decreased(P < 0.05).
3 Pathological examination demonstrated that the cardiac muscular tissue of the DCM group were harmed , which characteristic were consistented with dilated cardio- myopathy in the human patients.Compare with the normol group,DCM group’s Van Gien stain display that CVF was increased significantly(P < 0.05). Compare with the C group,the A and B group’s Van Gien stain display that CVF was decreased significantly (P < 0.05).
4 Immunohistochemistry showed that the expression of MMP-2 and TIMP-1 were mainly located in the endochylema and extracellular matrix.The expression of MMP-2 in the normal group,the A and B group were weak at all time. The expression of MMP- 2 in the C group was stronger then normal group (P <0.01). The differences were statistical significance as compared with the A group and the C group (P <0.01). The expression of MMP-2 in the B group was weaker then the C group (P <0.05). The expression of TIMP-1 in the DCM group was weaker then normal group (P<0.01). The differences were statistical significance as compared with the A group and the C group (P <0.01). The differences were statistical significance as compared with the B group and the C group (P <0.05).
5 RT-PCR showed that the expression of MMP-2 mRNA in the C group was stronger then the normal group (P<0.01). The differences were statistical significance decrease as compared with the A group and the C group (P <0.01). The expression of MMP-2 in the B group was weaker then the C group (P <0.05).The expression of TIMP-1mRNA in the DCM group was weaker then normal group (P<0.05). The differences were statistical significance as compared with the A group and the C group (P <0.05). There was no statistical significance as compared with the B group and the C group (P﹥0.05).
6 ELISA showede that PICP and PⅢNP in blood plasm of the DCM group was increased significantly (P<0.01). The differences were statistical significance as compared with the A,B group and the C group (P <0.01).
CONCLUSION: MMP and TIMP involved in the course of the remoding about extra- cellular matrix in dilated cardiomyopathy diease. The higher rate of MMP-2/ TIMP-1 can promote the collegen proliferation and effect the level of myocardial fibrosis.The concentration of PICP and PⅢNP in blood plasm is correlated to the myo- cardial fibrosis .Captopril may be reduced the expression of MMP-2 and up-regulation the level of TIMP-1,then the effect of degradation ECM about MMP-2 can be relief. Captopril played an important role in the treatment of the remoding about extracellular matrix in dilated cardiomyopathy diease .
方法:雄性SD大鼠分2组(1)正常对照组10只;(2)DCM组50只:阿霉素2mg/Kg腹腔注射,每周1次,连续8周后行心脏超声心动图,将达到DCM标准的大鼠再分为3组:①A组(卡托普利高剂量干预组),50mg/Kg·d灌胃给药,连续3周;②B组(卡托普利低剂量干预组),25mg/Kg·d灌胃给药,连续3周;③C组(DCM对照组)。取各组心脏组织切片行HE染色观察心肌的病理变化,苦味酸天狼星红染色(Van Gieson, VG染色)进行心室胶原特异染色及定量分析,免疫组化染色法对各组大鼠心脏心室组织MMP-2、TIMP-1蛋白的表达进行半定量检测。采用RT-PCR技术检测心室心肌MMP-2及TIMP-1mRNA的表达。ELISA方法对血浆PICP和PⅢNP的浓度进行定量测定。
结果:
1大鼠生存情况:对照组全部存活;腹腔注射阿霉素的50只大鼠,死亡4只。
2超声心动图检测:与正常对照组相比,给予阿霉素腹腔注射的DCM组,心腔明显扩张,左室舒张期末内径(left ventricular enddiastole , LVED)、左室收缩期末内径(left ventricular endsystole, LVDS)明显的增加(P﹤0.05);左室内径缩短率(fraction-shortening , FS)、左室射血分数(left ventricu1ar ejection fraction , EF)明显降低(P﹤0.05)。
3心肌组织病理学检查:①HE染色见正常对照组心肌细胞排列均匀整齐,横纹清楚,细胞大小均一,心肌细胞间隙无变化;DCM各组心脏组织有不同程度的炎性病变,心肌细胞排列紊乱呈多灶性溶解,心肌细胞变性、坏死,相邻细胞间隙增大,排列紊乱、核大深染、异型。DCM组心肌组织形态学的改变符合扩张型心肌病的病理学改变。②VG染色:DCM组较正常对照组的胶原纤维明显增加。DCM组胶原容积分数(collagen volume fraction , CVF)高于正常对照组(P﹤0. 05),而A组和B组的CVF值较C组明显减少(P﹤0. 05)。
4免疫组化染色:结果示MMP-2、TIMP-1蛋白主要表达于心肌细胞的胞质及心肌细胞外基质(extracellular matrix,ECM)中。MMP-2在正常对照组、A组和B组微弱表达,而在C组表达增强。C组MMP-2的表达高于正常对照组(P﹤0.01);而A组MMP-2的表达显著低于C组(P﹤0.01),B组MMP-2的表达低于C组(P﹤0.05)。TIMP-1在正常对照组、A组和B组呈较强的表达,而在C组表达较弱。C组TIMP-1的表达低于正常对照组(P﹤0.01);而A组TIMP-1的表达明显高于C组(P﹤0.01),B组TIMP-1的表达高于C组(P﹤0.05)。
5心室心肌MMP-2、TIMP-1的mRNA表达:MMP-2 mRNA表达C组心室心肌中较正常对照组显著增加(P﹤0. 01),A组较C组有明显的降低(P﹤0. 01),B组低于C组(P﹤0. 05)。TIMP-1mRNA的表达C组较正常对照组有明显的减低(P﹤0. 05),A组较C组有明显的增加(P﹤0. 05),B组与C组无明显差异(P﹥0.05)。
6血浆中PICP、PⅢNP的浓度:C组血浆的PICP、PⅢNP的浓度高于正常对照组(P﹤0. 01);A、B组血浆中PICP、PⅢNP的浓度显著低于C组(P﹤0.01);
结论: MMP和TIMP参与了DCM发生发展过程中心肌细胞外基质的重塑,MMP-2∕TIMP-1比率增高可促进DCM心肌细胞外基质胶原增生,从而影响心肌纤维化程度。血浆中PICP、PⅢNP的浓度与心肌纤维化程度相关。血管紧张素转化酶抑制剂卡托普利可能通过降低心脏心肌细胞外基质MMP-2的表达,减轻MMP-2对ECM的降解和破坏作用;并通过上调TIMP-1而影响MMP-2∕TIMP-1动态平衡,在DCM心肌细胞外基质重塑中起重要调节作用。
PURPOSES: To research the effect and significance about MMPs-2 and TIMPs-1 in the model of DCM rats. To investigate the expression of MMP-2,TIMP-1 and collagen fiber during the course of DCM treated with ACEI and without. To explore the the relation between MMPs and PICP, PⅢNP.
METHODS: 60 SD rats were divided randomly into two groups: normal control group, the DCM group, the DCM treated with adriamycin intraperitoneally 2.0 mg/kg·week for 8 weeks to estabilsh DCM model. The normal control group was intravitreous injected with normal saline. Transthoracic echocardiography was performed in the DCM group and control guoup rats.DCM who were achieve standard were divided randomly into three groups:(1)A group:the rats who were administered captopril by gavage at a dose of 50mg/kg·d for 3 weeks (2)B group: the rats who were administered captopril by gavage at a dose of 25 mg/kg·d for 3 weeks (3)C group(DCM control group).HE stain was used to observe the change of the Histopathological characteristics . The semiquantitative analysis was used to evaluate the CVF.The expression of MMP-2 and TIMP-1 were quailtative and semiquantitative analysised with immunohistochemistry and RT-PCR .The qualitative analysis was used to evaluate the PICP and PⅢNP in blood plasm.
RESULTS:
1 Living condition of rats: the normal control group were all survival;the DCM group has been died four rats.
2 Compared with the normol control group, venticular interior diameter was enlarge. LVED and LVES were increased significantly(P < 0.05),whereas the FS and EF were decreased(P < 0.05).
3 Pathological examination demonstrated that the cardiac muscular tissue of the DCM group were harmed , which characteristic were consistented with dilated cardio- myopathy in the human patients.Compare with the normol group,DCM group’s Van Gien stain display that CVF was increased significantly(P < 0.05). Compare with the C group,the A and B group’s Van Gien stain display that CVF was decreased significantly (P < 0.05).
4 Immunohistochemistry showed that the expression of MMP-2 and TIMP-1 were mainly located in the endochylema and extracellular matrix.The expression of MMP-2 in the normal group,the A and B group were weak at all time. The expression of MMP- 2 in the C group was stronger then normal group (P <0.01). The differences were statistical significance as compared with the A group and the C group (P <0.01). The expression of MMP-2 in the B group was weaker then the C group (P <0.05). The expression of TIMP-1 in the DCM group was weaker then normal group (P<0.01). The differences were statistical significance as compared with the A group and the C group (P <0.01). The differences were statistical significance as compared with the B group and the C group (P <0.05).
5 RT-PCR showed that the expression of MMP-2 mRNA in the C group was stronger then the normal group (P<0.01). The differences were statistical significance decrease as compared with the A group and the C group (P <0.01). The expression of MMP-2 in the B group was weaker then the C group (P <0.05).The expression of TIMP-1mRNA in the DCM group was weaker then normal group (P<0.05). The differences were statistical significance as compared with the A group and the C group (P <0.05). There was no statistical significance as compared with the B group and the C group (P﹥0.05).
6 ELISA showede that PICP and PⅢNP in blood plasm of the DCM group was increased significantly (P<0.01). The differences were statistical significance as compared with the A,B group and the C group (P <0.01).
CONCLUSION: MMP and TIMP involved in the course of the remoding about extra- cellular matrix in dilated cardiomyopathy diease. The higher rate of MMP-2/ TIMP-1 can promote the collegen proliferation and effect the level of myocardial fibrosis.The concentration of PICP and PⅢNP in blood plasm is correlated to the myo- cardial fibrosis .Captopril may be reduced the expression of MMP-2 and up-regulation the level of TIMP-1,then the effect of degradation ECM about MMP-2 can be relief. Captopril played an important role in the treatment of the remoding about extracellular matrix in dilated cardiomyopathy diease .
引文
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[34] Spinale FG,Coker ML , Krombach SR ,et al. Matrix metalloproteinase inhibition during the development of congestive heart failure : effects on left ventricular dimensions and function[J] . Circ Res ,1999 ;85:364-376
[35] Bai P ,Mabley J G, Liaudet L , et al . Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol Rep,2004;11:505-508.
[36]Kim H E,Dalal S S ,Young E ,et al. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction[J]. Clin Invest ,2000 ;106:857-866.
[37]Roonqsritonq C,Sadhu A,Pierce M,et al. Plasma carboxy-terminal peptide of procollagen type I is an independent predictor of diastolic function in patients with advanced systolic heart failure.Conqest Heart Fail,2008 Nov-Dec;14(6):302-306.
[38] Zamaneh Kassiri,Gavin Y. Oudit, Otto Sanchez ,et al . Combination of tumor necrosis factor-аablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 Knock-Out Mice[J]. Circulation Research, 2005; 97:380.
[39]Vellaichamy E,Khurana ML,Fink J,et al.Involvement of the NF-kB/matrix metallo- proteinase pathway in cardiac fibrosis of mice lacking guanylyl cyclase/natriuretic peptide receptor-A[J]. Biol Chem,2005;280:19230-19242.
[40] Sivakumar P,Gupta S,Sarkar S,et al. Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Mol Cell Biochem,2008 Jan;307(1-2):159-167.
[41]Maquart FX,Bellon G,Chaqour B,et al.In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex wounds[J]. Clin Invest,1993;92: 2368-2376.
[42] Ergul A, Portik - Dobos V, Hutchinson J,et al. Downregulation of vascular matrixmetalloproteinase inducer and activator proteins in hypertensive patients[J]. Am J Hypertens, 2004;17(9):775-782.
[43] Ji? Kuka?kaa, Richard Pr??aa, Karel Kota?kaa,et al . Matrix Metalloproteinases and their function in myocardium[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2005; 149(2):225–236.
[44] Barton PJ ,Birks EJ, Felkin L E,et al. Increased expression of extracellular matrix regulators TIMP1 andMMP1in deteriorating heart failure[J]. Heart Lung Transplant, 2003;22 (7):738-744.
[45] Schulze CJ ,W angW , Suarez P inzonWL ,et al. Imbalance between tissue inhibitor of metalloproteinase-4 and matrix metalloproteinases during acute myocardial correction of myoctardial] ischem ia-reperfusion injury. Circulation, 2003;107 (19) : 2487-2492.
[46]Reinhardt D,Sigusch HH,Hensse J,et al.Cardiac remodeling in end stage heart failure:upregulation of matrix metalloproteinase(MMP) irrespective of the underlying disease,and evidence for a direct inhibitory effect of ACE inhibitors on MMP.Heart, 2002;88:525-530.
[47]Brower GL,Levick SP,Janicki Js. Inhibition of matrix metalloproteinase activity by ACE inhibitorw prevents left ventricular remoding in a rat model of heart failure. Am J Physiol Heart Circ Physilol,2007 Jun;292(6):H3057-64.
[48]Seeland U,Kouchi J,Zolk O,et al. Effect of ramipril and furosemide treatment on interstitial remodeling in post-infarction heart failure rat hearts[J]. Mol Cell Cardiol, 2002;34:151-163.
[49]Radarceanu A,Moulin F,Djaballah W,et al.Residual stress ischaemia is associated with blood markers of myocardial structural remodelling.Eur J Heart Fail, 2007 Apr; 9(4):370-376.
[50]Papadopoulos DP,Econmou EV,Makris TK,et al.Effect of angiotensin-converting enzyme inhibitor on collagenolytic enzyme activity in patients with acute myocardial infarction.Drugs Exp Clin Res,2004;30(2):55-65.
[51]Sakata Y,Yamamoto K,Mano T,et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats:its inhibition as a primary effect of angiotensin-coverting enzyme inhibitor.Circulation,2004;109:2143- 2149.
[52] Hayashi H,Kovara M,Abe M,et al.Aldosteron nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptasis[J].Hypertens Res,2008;31(2):363-375.
[53] Chow AK,Cena J,Schulz R.Acute actions and novel targets of matrix metallo- proteinases in the heart and vascculatur[J].Br J Pharmacol,2007,152(2):189-205.
[54]Verrecchia F,Mauviel A.Transforminag growth factor-beta and fibrosis[J].World J Gastroenterol,2007;13(22):3056-3062.
[1] Visse, Robert. Matrix Metalloproteinases and TissueInhibitors of Metalloproteinases: Structure, Function, and Biochem istry[J]. Circ Res, 2003 ; 92: 827-839.
[2] Maata M, Soini Y,Liakka A, et a1. Localization of MMP,TIMP-1,TIMP-2,TIMP-3 and TIMP-3 messenger RNA in normal hyperplastic and neoplastic endo- metrium.Enhanced expression by endometrial adenocarcinomas is associated with low differetiation[J].Am J Clin Pathol, 2000; 114(3):402.
[3] Kugler A.Matrix metalloproteinases and their inhibitors [J].Anticancer Rse,1999,19 (20):1589.
[4] Laura S, Abigail S, Robert E et al . Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy[J]. Physiol Cell Physiol, 2007 Aug 1; 293: C1362-C1373.
[5] F Picard, M Brehm, M Fassbach et al . Increased cardiac mRNA expression of matrix metalloproteinase-1 (MMP-1) and its inhibitor (TIMP-1) in DCM patients[J].Clin Res Cardiol , 2006 May 1; 95(5):261-269.
[6] Sivakumar P, Gupta S, Sarkar S et al . Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy[J]. Mol Cell Biochem , 2007; 9:12.
[7] Zamaneh Kassiri, Gavin Y. Oudit, Otto Sanchez et al . Combination of tumor necrosis factor-аablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 Knock-Out Mice[J]. Circulation Research, 2005; 97:380.
[8] Ji? Kuka?kaa, Richard Pr??aa, Karel Kota?kaa et al . Matrix Metalloproteinases and their function in myocardium[J]. Biomed Pap Med Fac Univ Palacky Olomouc CzechRepub, 2005; 149(2):225–236.
[9] Ye S. Polymorphism in matrix metalloproteinase genepromotors implication in regulation of gene expression and susceptibility of various diseases[J].Matrix Biol ,2000 ; 19:623– 629.
[10] Mizon-Gerard F, de Groote P, Lamblin N et al. Prognostic impact ofmatrixmetallo- proteinase gene polymorphisms in patients with heart failure according to the aetiology of left ventricular systolic dysfunction [J]. Eur Heart J , 2004; 25 (8) :688-693.
[11] M Fassbach and B Schwartzkopff. Elevated serum markers for collagen synthesis in patients with hypertrophic cardiomyopathy and diastolic dysfunction[J]. Z Kardiol, 2005 May 1; 94(5):328-335.
[12] Noji Y, Shimizu M, Ino H,et al. Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction[J].Circ J , 2004 Apr; 68(4):355-60.
[13] Lombardi R, Betocchi S, Losi MA et al. Myocardial collagen turnover in hypertrophic cardiomyopathy[J]. Circulation, 2003 Sep23; 108(12):1455-1460.
[14] Meng XH, Wang Y, Zhuang Jx et al . Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis[J]. Chin Med J, 2004, Aug; 117(8):1195-1199.
[15] Matthias Pauschinger, Kumaran Chandrasekharan. Myocardial Remodeling in Viral Heart Disease:Possible Interactions Between Inflammatory Mediators and MMP-TIMP Sysem[J]. Heart Failure Review. 2004; 9:21-31.
[16] Cheung C,Luo H,Yanagawa B et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis[J]. Cardiovasc Pathol, 2006 Mar-Apr;15(2):63-74.
[17] Hidenori Matsusaka, Masaki Ikeuchi, Shouji Matsushima et al.Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy[J]. Am J Physiol Heart Circ Physiol, 2005; 289: H1858-H1864.
[18] Stephen J, Croker, Ricardo F et al. Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1[J]. American Journal of Pathology , 2007; 171:1762-1773.
[2] Bai P, Mabley JG, LiaudetL, et al. Matrixmetalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity[J]. Oncol Rep,2004;11(2):505-508.
[3]刘洪智,戚本玲,曹林生,等。基质金属蛋白酶在阿霉素心肌病左室重构中的表达与意义[J]。临床心血管病杂志,2005;21(1):26-29。
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[7] F Picard, M Brehm, M Fassbach et al . Increased cardiac mRNA expression of matrix metallproteinase-1 (MMP-1) and its inhibitor (TIMP-1) in DCM patients[J].Clin Res Cardiol , 2006 May 1;95(5):261-269.
[8] Sivakumar P, Gupta S, Sarkar S et al . Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy[J]. Mol Cell Biochem, 2007;9:12.
[9] Kugler A.Matrix metalloproteinases and their inhibitors [J].Anticancer Rse, 1999;19 (20):1589.
[10]Selman M, Ruiz V, Cabrera S, et al. TIMP-1,-2,-3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment. Am J Physiol lung cell mol Physiol,2000; 279(3):562-574.
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[21] Teraoka K,Hirano M,Yamaguchi K,et al. Progressive cardiac dysfunction in adriamycin-induced cardiomyopathy rats.Eur J Heart Fail,2000;2(4):373-378.
[22] Laura S,Abigail S, Robert E et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy[J]. Physiol Cell Physiol, 2007 Aug 1; 293: C1362-C1373.
[23] Gunja-Smith Z,Morales AR,Romanelli R,et al. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy:role of metalloproteinases and pyri- dimoline cross links. Am J Pathol,1996;148(5):1639-1648.
[24]Jen Chin Wang. Importance of Plasma Matrix Metalloproteinases (MMP) and Tissue Inhibitors of Metalloproteinase (TIMP) in development of fibrosis in agnogenic myeloid metaplasia.Leukemia & Lymphoma,2005 Sep; 46(9):1261-1268. Review.
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[26] Spinale F G,Coker M L,Thomas C V,et al. Timedependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure. Circ Res,1998;82: 482-495.
[27]Sakata Y,Yamamoto K,Mano T,et al. Activation of Matrix Metalloproteinases Precedes Left Vent ricular Remodeling in Hypertensive Heart failure Rats. Circulation , 2004;109:2143-2149.
[28]Boixel C,Fontaine V,Rucker-Martin C,et al.Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinase in the rat[J].Am Coll Cardiol,2003 Jul 16;42(2):336-44.
[29] Herpel E,Pritsch M,Koch A,et al.Interstitial fibrosis in the heart:differences in extracellular proteins and matrix metalloproteinases in end-stage dilated,ischaemic and valvular cardiomyopathy. Histopathology,2006 May;48(6):736-47.
[30]George J,Patal S,Wexler D,et al.Circulating matrix metalloproteinase-2 but not metalloproteinase-3,matrix metalloproteinase-9,or tissue inhibitor of metalloproteinase- 1 predicts outcome in patiedts with congestive heart failure.Am Heart J,2005 Sep;150 (3):484-487.
[31] Jayasankar V,Woo YJ,Bish L T, et al. Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treat s ischemic cardiomyopathy. Circu- lation, 2004 ;110:SⅡ180-186.
[32]Hayashidani S,Tsut sui H,Ikeuchi M , et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction.Am J Physiol Heart Circ Physiol ,2003;285:H1229 -1235.
[33] Ducharme A ,Frantz S ,Aikawa M ,et al. Targeted deletion of matrix metallo- proteinase- 9 attenuates left ventricular enlargement and collagen accumulation afterexperimental myocardial infarction[J]. Clin Invest ,2000;106:55-62
[34] Spinale FG,Coker ML , Krombach SR ,et al. Matrix metalloproteinase inhibition during the development of congestive heart failure : effects on left ventricular dimensions and function[J] . Circ Res ,1999 ;85:364-376
[35] Bai P ,Mabley J G, Liaudet L , et al . Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol Rep,2004;11:505-508.
[36]Kim H E,Dalal S S ,Young E ,et al. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction[J]. Clin Invest ,2000 ;106:857-866.
[37]Roonqsritonq C,Sadhu A,Pierce M,et al. Plasma carboxy-terminal peptide of procollagen type I is an independent predictor of diastolic function in patients with advanced systolic heart failure.Conqest Heart Fail,2008 Nov-Dec;14(6):302-306.
[38] Zamaneh Kassiri,Gavin Y. Oudit, Otto Sanchez ,et al . Combination of tumor necrosis factor-аablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 Knock-Out Mice[J]. Circulation Research, 2005; 97:380.
[39]Vellaichamy E,Khurana ML,Fink J,et al.Involvement of the NF-kB/matrix metallo- proteinase pathway in cardiac fibrosis of mice lacking guanylyl cyclase/natriuretic peptide receptor-A[J]. Biol Chem,2005;280:19230-19242.
[40] Sivakumar P,Gupta S,Sarkar S,et al. Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Mol Cell Biochem,2008 Jan;307(1-2):159-167.
[41]Maquart FX,Bellon G,Chaqour B,et al.In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex wounds[J]. Clin Invest,1993;92: 2368-2376.
[42] Ergul A, Portik - Dobos V, Hutchinson J,et al. Downregulation of vascular matrixmetalloproteinase inducer and activator proteins in hypertensive patients[J]. Am J Hypertens, 2004;17(9):775-782.
[43] Ji? Kuka?kaa, Richard Pr??aa, Karel Kota?kaa,et al . Matrix Metalloproteinases and their function in myocardium[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2005; 149(2):225–236.
[44] Barton PJ ,Birks EJ, Felkin L E,et al. Increased expression of extracellular matrix regulators TIMP1 andMMP1in deteriorating heart failure[J]. Heart Lung Transplant, 2003;22 (7):738-744.
[45] Schulze CJ ,W angW , Suarez P inzonWL ,et al. Imbalance between tissue inhibitor of metalloproteinase-4 and matrix metalloproteinases during acute myocardial correction of myoctardial] ischem ia-reperfusion injury. Circulation, 2003;107 (19) : 2487-2492.
[46]Reinhardt D,Sigusch HH,Hensse J,et al.Cardiac remodeling in end stage heart failure:upregulation of matrix metalloproteinase(MMP) irrespective of the underlying disease,and evidence for a direct inhibitory effect of ACE inhibitors on MMP.Heart, 2002;88:525-530.
[47]Brower GL,Levick SP,Janicki Js. Inhibition of matrix metalloproteinase activity by ACE inhibitorw prevents left ventricular remoding in a rat model of heart failure. Am J Physiol Heart Circ Physilol,2007 Jun;292(6):H3057-64.
[48]Seeland U,Kouchi J,Zolk O,et al. Effect of ramipril and furosemide treatment on interstitial remodeling in post-infarction heart failure rat hearts[J]. Mol Cell Cardiol, 2002;34:151-163.
[49]Radarceanu A,Moulin F,Djaballah W,et al.Residual stress ischaemia is associated with blood markers of myocardial structural remodelling.Eur J Heart Fail, 2007 Apr; 9(4):370-376.
[50]Papadopoulos DP,Econmou EV,Makris TK,et al.Effect of angiotensin-converting enzyme inhibitor on collagenolytic enzyme activity in patients with acute myocardial infarction.Drugs Exp Clin Res,2004;30(2):55-65.
[51]Sakata Y,Yamamoto K,Mano T,et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats:its inhibition as a primary effect of angiotensin-coverting enzyme inhibitor.Circulation,2004;109:2143- 2149.
[52] Hayashi H,Kovara M,Abe M,et al.Aldosteron nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptasis[J].Hypertens Res,2008;31(2):363-375.
[53] Chow AK,Cena J,Schulz R.Acute actions and novel targets of matrix metallo- proteinases in the heart and vascculatur[J].Br J Pharmacol,2007,152(2):189-205.
[54]Verrecchia F,Mauviel A.Transforminag growth factor-beta and fibrosis[J].World J Gastroenterol,2007;13(22):3056-3062.
[1] Visse, Robert. Matrix Metalloproteinases and TissueInhibitors of Metalloproteinases: Structure, Function, and Biochem istry[J]. Circ Res, 2003 ; 92: 827-839.
[2] Maata M, Soini Y,Liakka A, et a1. Localization of MMP,TIMP-1,TIMP-2,TIMP-3 and TIMP-3 messenger RNA in normal hyperplastic and neoplastic endo- metrium.Enhanced expression by endometrial adenocarcinomas is associated with low differetiation[J].Am J Clin Pathol, 2000; 114(3):402.
[3] Kugler A.Matrix metalloproteinases and their inhibitors [J].Anticancer Rse,1999,19 (20):1589.
[4] Laura S, Abigail S, Robert E et al . Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy[J]. Physiol Cell Physiol, 2007 Aug 1; 293: C1362-C1373.
[5] F Picard, M Brehm, M Fassbach et al . Increased cardiac mRNA expression of matrix metalloproteinase-1 (MMP-1) and its inhibitor (TIMP-1) in DCM patients[J].Clin Res Cardiol , 2006 May 1; 95(5):261-269.
[6] Sivakumar P, Gupta S, Sarkar S et al . Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy[J]. Mol Cell Biochem , 2007; 9:12.
[7] Zamaneh Kassiri, Gavin Y. Oudit, Otto Sanchez et al . Combination of tumor necrosis factor-аablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 Knock-Out Mice[J]. Circulation Research, 2005; 97:380.
[8] Ji? Kuka?kaa, Richard Pr??aa, Karel Kota?kaa et al . Matrix Metalloproteinases and their function in myocardium[J]. Biomed Pap Med Fac Univ Palacky Olomouc CzechRepub, 2005; 149(2):225–236.
[9] Ye S. Polymorphism in matrix metalloproteinase genepromotors implication in regulation of gene expression and susceptibility of various diseases[J].Matrix Biol ,2000 ; 19:623– 629.
[10] Mizon-Gerard F, de Groote P, Lamblin N et al. Prognostic impact ofmatrixmetallo- proteinase gene polymorphisms in patients with heart failure according to the aetiology of left ventricular systolic dysfunction [J]. Eur Heart J , 2004; 25 (8) :688-693.
[11] M Fassbach and B Schwartzkopff. Elevated serum markers for collagen synthesis in patients with hypertrophic cardiomyopathy and diastolic dysfunction[J]. Z Kardiol, 2005 May 1; 94(5):328-335.
[12] Noji Y, Shimizu M, Ino H,et al. Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction[J].Circ J , 2004 Apr; 68(4):355-60.
[13] Lombardi R, Betocchi S, Losi MA et al. Myocardial collagen turnover in hypertrophic cardiomyopathy[J]. Circulation, 2003 Sep23; 108(12):1455-1460.
[14] Meng XH, Wang Y, Zhuang Jx et al . Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis[J]. Chin Med J, 2004, Aug; 117(8):1195-1199.
[15] Matthias Pauschinger, Kumaran Chandrasekharan. Myocardial Remodeling in Viral Heart Disease:Possible Interactions Between Inflammatory Mediators and MMP-TIMP Sysem[J]. Heart Failure Review. 2004; 9:21-31.
[16] Cheung C,Luo H,Yanagawa B et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis[J]. Cardiovasc Pathol, 2006 Mar-Apr;15(2):63-74.
[17] Hidenori Matsusaka, Masaki Ikeuchi, Shouji Matsushima et al.Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy[J]. Am J Physiol Heart Circ Physiol, 2005; 289: H1858-H1864.
[18] Stephen J, Croker, Ricardo F et al. Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1[J]. American Journal of Pathology , 2007; 171:1762-1773.