钙网蛋白及基质金属蛋白酶在扩张型心肌病发病机制中的作用
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摘要
目的:
这项研究旨在阐明扩张型心肌病与钙网蛋白、基质金属蛋白酶(matrix metalloproteinases,MMPs)家族成员中MMP-2和MMP-9之间的关系,以阐明扩张型心肌病的发病机制,为扩张型心肌病的预防和治疗提供理论论据。
方法:
实验分两组:扩张型心肌病组和对照组。分别收集14例扩张型心肌病病人及14例对照组全血及其临床资料(年龄、性别、LA、RA、LVDd、RV及LVEF等),提取血浆,①通过蛋白免疫印迹法(western blotting)测定血浆钙网蛋白的表达水平;②通过明胶酶谱法(Gelatin-PAGE)检测各标本血浆中MMP-2和MMP-9活性。
结果:
1.MMP-9活性在扩张型心肌病组与对照组之间存在显著差异(P<0.05),且在扩张型心肌病组中与左室射血分数呈负相关(r=-0.590, P<0.05),与左室舒张末径呈正相关(非正态分布等级相关:r=0.396,P<0.05),但与左房、右房、右室舒张末径、室间隔厚度均无统计学相关性;而在对照组中MMP9与左房、右房、左室、右室舒张末径、室间隔厚度均无统计学相关性。
2.MMP-2活性在扩张型心肌病组及对照组中无统计学差异,与左房、右房、左室、右室舒张末径、左室射血分数和室间隔厚度之间均无相关关系。
3.钙网蛋白在扩张型心肌病组的表达有升高,但与对照组相比,两者间的表达水平无统计学差异(P>0.05)。
结论:
1. MMP-9在扩张型心肌病患者左室重构中起重要作用,MMP-9的活性可作为评估心功能情况的参考项目。
2.钙网蛋白在扩张型心肌病病理过程中未直接参与其疾病发展,但未排通过其他途径作用于该病理过程。
AIM:
To explore effects of calreticulin and matrix metalloproteinases in the pathogenesis of dilated cardiomyopathy.
METHODS:
The objects of study were divided into two groups: dilated cardiomyopathy group and control group. The persons without heart disease and pulmonary disease were selected in the control group. Both groups’plasma and clinical information were collected. The expression of CRT in both gourps were detected by the western blotting. The enzymatic activity of MMP-2 and MMP-9 in both groups were detected by the Gelatin-PAGE.
RESULTS:
1. The enzymatic activity of MMP-9, left ventricular ejection fraction(LVEF) and the left ventricular end-diastolic diameter(LVDd) in DCM patients had significant difference compared to the control group(P<0.05). The activity of MMP-9 had relationship with the left ventricular end-diastolic diameter (LVDd) and left ventricular ejection fraction(LVEF) compared to the control group(r=0.396,P<0.05). On the contrary, there was no relationship between the activity of MMP-9 and the right ventricular diameter (RV), left atrium (LA), right atrium (RA), intact ventricular septum (IVS).
2. The activity of MMP-2 had no defference between two groups. MMP-2 also had no relationship with patients’LA, RA, RV, LVEF, LVDd and IVS.
3. There was no difference in the expression of CRT between two groups.
CONCLUSION:
1. The plasma MMP-9 had probably played important role in ECM degradation and ventricle remodelling in DCM patient.
2. Calreticulin was not directly involved in the pathogenesis development of DCM, but not exclusive role through other channels in the pathological process.
这项研究旨在阐明扩张型心肌病与钙网蛋白、基质金属蛋白酶(matrix metalloproteinases,MMPs)家族成员中MMP-2和MMP-9之间的关系,以阐明扩张型心肌病的发病机制,为扩张型心肌病的预防和治疗提供理论论据。
方法:
实验分两组:扩张型心肌病组和对照组。分别收集14例扩张型心肌病病人及14例对照组全血及其临床资料(年龄、性别、LA、RA、LVDd、RV及LVEF等),提取血浆,①通过蛋白免疫印迹法(western blotting)测定血浆钙网蛋白的表达水平;②通过明胶酶谱法(Gelatin-PAGE)检测各标本血浆中MMP-2和MMP-9活性。
结果:
1.MMP-9活性在扩张型心肌病组与对照组之间存在显著差异(P<0.05),且在扩张型心肌病组中与左室射血分数呈负相关(r=-0.590, P<0.05),与左室舒张末径呈正相关(非正态分布等级相关:r=0.396,P<0.05),但与左房、右房、右室舒张末径、室间隔厚度均无统计学相关性;而在对照组中MMP9与左房、右房、左室、右室舒张末径、室间隔厚度均无统计学相关性。
2.MMP-2活性在扩张型心肌病组及对照组中无统计学差异,与左房、右房、左室、右室舒张末径、左室射血分数和室间隔厚度之间均无相关关系。
3.钙网蛋白在扩张型心肌病组的表达有升高,但与对照组相比,两者间的表达水平无统计学差异(P>0.05)。
结论:
1. MMP-9在扩张型心肌病患者左室重构中起重要作用,MMP-9的活性可作为评估心功能情况的参考项目。
2.钙网蛋白在扩张型心肌病病理过程中未直接参与其疾病发展,但未排通过其他途径作用于该病理过程。
AIM:
To explore effects of calreticulin and matrix metalloproteinases in the pathogenesis of dilated cardiomyopathy.
METHODS:
The objects of study were divided into two groups: dilated cardiomyopathy group and control group. The persons without heart disease and pulmonary disease were selected in the control group. Both groups’plasma and clinical information were collected. The expression of CRT in both gourps were detected by the western blotting. The enzymatic activity of MMP-2 and MMP-9 in both groups were detected by the Gelatin-PAGE.
RESULTS:
1. The enzymatic activity of MMP-9, left ventricular ejection fraction(LVEF) and the left ventricular end-diastolic diameter(LVDd) in DCM patients had significant difference compared to the control group(P<0.05). The activity of MMP-9 had relationship with the left ventricular end-diastolic diameter (LVDd) and left ventricular ejection fraction(LVEF) compared to the control group(r=0.396,P<0.05). On the contrary, there was no relationship between the activity of MMP-9 and the right ventricular diameter (RV), left atrium (LA), right atrium (RA), intact ventricular septum (IVS).
2. The activity of MMP-2 had no defference between two groups. MMP-2 also had no relationship with patients’LA, RA, RV, LVEF, LVDd and IVS.
3. There was no difference in the expression of CRT between two groups.
CONCLUSION:
1. The plasma MMP-9 had probably played important role in ECM degradation and ventricle remodelling in DCM patient.
2. Calreticulin was not directly involved in the pathogenesis development of DCM, but not exclusive role through other channels in the pathological process.
引文
1. Bielecka-dabrowa A, Wierzbicka M, Dabrowa M, et al. New methods in laboratory diagnostics of dilated cardiomyopathy[J]. Cardiol J, 2008, 15(4):388-395.
2. Nunes VL, R amires FJ, Pimentel WS, et al. The role of storage of interstitial myocardial collagen on the overlife rate of patients with idiopathic and Chagasic dilated cardiomyophthy [J]. Arq Bras cardiol, 2006, 87(6): 757-762.
3. Ashwath ML, Dearmond SJ, Culclasure T. Prion associated dilated cardiomyopathy[J]. Arch Intern Med ,2005 ,165 (3):338-340.
4.付卿卿,王雪楠,袁王景,程鹏,廖玉华;病毒在扩张型心肌病发病中的作用;<中国热带医学2OO7年第7卷第l2期:2274-2275.
5. BradyWJ,Fergusen JD,Unman EA,el a1.Myocarditis:emergencydepartment recognition and management[J].Emerg Med Clin North Am,2OO4,22(4):865-885.
6.马国添.扩张型心肌病免疫发病机制及治疗进展.心血管病学进展, 2005, 26(5): 523-525.
7. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evi2dence for genetic and phenotyp ic heterogeneity. Heart muscle disease studygroup [J]. J Am Coll Cardiol, 1999, 34: 181-190.
8. TaylorMRG, Fain P, Sinagra G, et al. Natural history of dilated cardiomyopathydue to lamin A /C gene mutations[J]. J Am Coll Cardiol, 2003, 41: 771-780.
9. DalakasMC, Park KY, Semino2Mora C, et al. Desmin myopathy, a skeletalmy2opathy with cardiomyopathy caused bymutations in the desmin gene[ J ]. N En2gl J Med, 2000, 342: 770-780.
10. Towbin JA, Hejtmancik JF, B rink P, et al. X2linked dilated cardiomyopathy:molecular genetic evidence of linkage to the Duchenne muscular dystrophy(dystrophin) gene at the Xp21 locus[J]. Circulation, 1997, 95: 2434-2440.
11.龚芸,邓海,曾晶晶.阿霉素诱导制备兔扩张型心肌病模型[J].深圳中西药结合杂志. 2007, 6: 352-354.
12.王连生,吴翔,黄峻;扩张型心肌病病理形态学变化与心功能的关系;中国临床康复2004,3(8):580-581.
13. Klappacher G, Franzen P, haab D, et al. Measuring extracelluar matrix turnover in the serum of patients with idiophthic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Caridol, 1995, 75:913.
14. Krause, K. H. and M. Michalak. Calreticulin. Cell .1997, 88(4): 439-43.
15. Vinet L,Rouet-Benzineb P, Marniquet X, et al. Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction. Am J Physiol Heart Circ Physiol. 2008,295(1):H352-60.
16. Mesaeli N, Nakamura K, Zvaritch E, et al. Calreticulin is essential for cardiac development[J]. J Cell Biol, 1999, 144(5): 857-868.
17. Michalak M, Guo L, Robertson M, et al. Calreticulin in the heart[J]. Mol Cell Biochem, 2004, 263(1-2): 137-142
18. Li J, Puceat M, Perez-Terzic C, et al. Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis[J]. J Cell Biol, 2002, 158(1): 103-113.
19. Robert Visse, Hideaki Nagase. Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure function and biochemistry [J]. Circ Res, 2003, 92: 827-839.
20. Kleiner D E, Stetler-Steverson W G. Quantitative zymography: detection of picogram quantities of gelatinases [J]. Anal. Biochem. 1994, 218(2):235.
21.秦继迅.蛋白质印迹技术在生物医学中的应用方法.遵义科技. 2010, 1: 52-54.
22.张修伟,杨英珍,王齐冰.扩张型心肌病102例临床分析.中华心血管病杂志,2001.29:56-57.
23.王志明,邹玉宝,宋雷,等.超声心电图调查8080例肥厚型心肌病患病率[J].中华心血管杂志,2004,32:1090-1094.
24. Richardson P, Mckenna W, Bristow, et al. Report of the 1995 World health organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation,1996,93(5):841-842.
25. Komajda M, Jais JP, Reeves F, et al. Factors predicting mortrality in idiopathic dilated cardiomyopathy[J]. Eur Heart J, 1990,11: 824-831.
26. Lynch JM, Chilibeck K, Qui Y et al.Assembling pieces of the cardiac puzzle; calreticulin and calcium-dependent pathways in cardiac development, health, and disease.Trends CardiovascMed. 2006;16(3):p65-9.
27. Zwadlo C, Borlak J. Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca2+-handling proteins in heart hypertrophy. Toxicol Appl Pharmacol, 2005, 207: 244-256.
28. Wu Min,Nasrin Mesaeli,Melanie Durston et al.Differential expression and activity of MMP-2 and MMP-9 in calreticulin deficient cells. Matrix Biolo2007,26: 463-472.
29. Gutstein, D.E., Morley, G. E., Tamaddon, H et al., Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res, 2001. 88(3): p. 333-9.
30. Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005; 85: 1-31.
31. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 2002; 90: 520–530.
32. Shah PK. Inflammation, metalloproteinases, and increased proteolysis—an emerging pathophysiological paradigm in aortic aneurysm. Circulation 1997; 96: 2115–2117
33. Wu M, Li YG. The expressions of CD40-CD40L and activities of matrix metalloproteinase in atherosclerotic rats. Molecular and Cellular Biochemistry.2006,282(1-2):141-146.
34. Zhang JS, Nie L, Razavian M, et al. Molecular imaging of activated matrix metalloproteinases in vascular remodeling. Circulation. 2008,118(19):1953-60.
35. D Reinhardt, HH Sigusch, J Henβe, et al Cardiac remodelling 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
36. Sun M, Opavsky MA, Stewart DJ, et al. Temporal response and localization of integrins beta1 and beta3 in the heart failure after myocaidial infarction: regulation by cytokines.Arterioscler Thromb Vasc Biol 2003;23:2146–54.
37. Markus Meyer; Wolfgang Schillinger; Burkert Pieske, et al. Alterations of Sarcoplasmic Reticulum Proteins in Failing Human Dilated Cardiomyopathy. Circulation. 1995;92:778-784.
1.付卿卿,王雪楠,袁王景,等.病毒在扩张型心肌病发病中的作用[J].中国热带医学,2007,7(l2):2274-2275.
2. TaylorMRG, Fain P, Sinagra G, et al. Natural history of dilated cardiomyopathydue to lamin A/C gene mutations[J]. J Am Coll Cardiol, 2003, 41:771-780.
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18. Orlic D, Kajstura J, Chimenti S, et al. mobilized bone marrow cells repair the infarcted heart, improving function and survival[J]. Proc Natl Acad Sci USA, 2001, 98(18): 10344-10349.
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2. Nunes VL, R amires FJ, Pimentel WS, et al. The role of storage of interstitial myocardial collagen on the overlife rate of patients with idiopathic and Chagasic dilated cardiomyophthy [J]. Arq Bras cardiol, 2006, 87(6): 757-762.
3. Ashwath ML, Dearmond SJ, Culclasure T. Prion associated dilated cardiomyopathy[J]. Arch Intern Med ,2005 ,165 (3):338-340.
4.付卿卿,王雪楠,袁王景,程鹏,廖玉华;病毒在扩张型心肌病发病中的作用;<中国热带医学2OO7年第7卷第l2期:2274-2275.
5. BradyWJ,Fergusen JD,Unman EA,el a1.Myocarditis:emergencydepartment recognition and management[J].Emerg Med Clin North Am,2OO4,22(4):865-885.
6.马国添.扩张型心肌病免疫发病机制及治疗进展.心血管病学进展, 2005, 26(5): 523-525.
7. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evi2dence for genetic and phenotyp ic heterogeneity. Heart muscle disease studygroup [J]. J Am Coll Cardiol, 1999, 34: 181-190.
8. TaylorMRG, Fain P, Sinagra G, et al. Natural history of dilated cardiomyopathydue to lamin A /C gene mutations[J]. J Am Coll Cardiol, 2003, 41: 771-780.
9. DalakasMC, Park KY, Semino2Mora C, et al. Desmin myopathy, a skeletalmy2opathy with cardiomyopathy caused bymutations in the desmin gene[ J ]. N En2gl J Med, 2000, 342: 770-780.
10. Towbin JA, Hejtmancik JF, B rink P, et al. X2linked dilated cardiomyopathy:molecular genetic evidence of linkage to the Duchenne muscular dystrophy(dystrophin) gene at the Xp21 locus[J]. Circulation, 1997, 95: 2434-2440.
11.龚芸,邓海,曾晶晶.阿霉素诱导制备兔扩张型心肌病模型[J].深圳中西药结合杂志. 2007, 6: 352-354.
12.王连生,吴翔,黄峻;扩张型心肌病病理形态学变化与心功能的关系;中国临床康复2004,3(8):580-581.
13. Klappacher G, Franzen P, haab D, et al. Measuring extracelluar matrix turnover in the serum of patients with idiophthic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Caridol, 1995, 75:913.
14. Krause, K. H. and M. Michalak. Calreticulin. Cell .1997, 88(4): 439-43.
15. Vinet L,Rouet-Benzineb P, Marniquet X, et al. Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction. Am J Physiol Heart Circ Physiol. 2008,295(1):H352-60.
16. Mesaeli N, Nakamura K, Zvaritch E, et al. Calreticulin is essential for cardiac development[J]. J Cell Biol, 1999, 144(5): 857-868.
17. Michalak M, Guo L, Robertson M, et al. Calreticulin in the heart[J]. Mol Cell Biochem, 2004, 263(1-2): 137-142
18. Li J, Puceat M, Perez-Terzic C, et al. Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis[J]. J Cell Biol, 2002, 158(1): 103-113.
19. Robert Visse, Hideaki Nagase. Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure function and biochemistry [J]. Circ Res, 2003, 92: 827-839.
20. Kleiner D E, Stetler-Steverson W G. Quantitative zymography: detection of picogram quantities of gelatinases [J]. Anal. Biochem. 1994, 218(2):235.
21.秦继迅.蛋白质印迹技术在生物医学中的应用方法.遵义科技. 2010, 1: 52-54.
22.张修伟,杨英珍,王齐冰.扩张型心肌病102例临床分析.中华心血管病杂志,2001.29:56-57.
23.王志明,邹玉宝,宋雷,等.超声心电图调查8080例肥厚型心肌病患病率[J].中华心血管杂志,2004,32:1090-1094.
24. Richardson P, Mckenna W, Bristow, et al. Report of the 1995 World health organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation,1996,93(5):841-842.
25. Komajda M, Jais JP, Reeves F, et al. Factors predicting mortrality in idiopathic dilated cardiomyopathy[J]. Eur Heart J, 1990,11: 824-831.
26. Lynch JM, Chilibeck K, Qui Y et al.Assembling pieces of the cardiac puzzle; calreticulin and calcium-dependent pathways in cardiac development, health, and disease.Trends CardiovascMed. 2006;16(3):p65-9.
27. Zwadlo C, Borlak J. Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca2+-handling proteins in heart hypertrophy. Toxicol Appl Pharmacol, 2005, 207: 244-256.
28. Wu Min,Nasrin Mesaeli,Melanie Durston et al.Differential expression and activity of MMP-2 and MMP-9 in calreticulin deficient cells. Matrix Biolo2007,26: 463-472.
29. Gutstein, D.E., Morley, G. E., Tamaddon, H et al., Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res, 2001. 88(3): p. 333-9.
30. Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005; 85: 1-31.
31. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 2002; 90: 520–530.
32. Shah PK. Inflammation, metalloproteinases, and increased proteolysis—an emerging pathophysiological paradigm in aortic aneurysm. Circulation 1997; 96: 2115–2117
33. Wu M, Li YG. The expressions of CD40-CD40L and activities of matrix metalloproteinase in atherosclerotic rats. Molecular and Cellular Biochemistry.2006,282(1-2):141-146.
34. Zhang JS, Nie L, Razavian M, et al. Molecular imaging of activated matrix metalloproteinases in vascular remodeling. Circulation. 2008,118(19):1953-60.
35. D Reinhardt, HH Sigusch, J Henβe, et al Cardiac remodelling 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
36. Sun M, Opavsky MA, Stewart DJ, et al. Temporal response and localization of integrins beta1 and beta3 in the heart failure after myocaidial infarction: regulation by cytokines.Arterioscler Thromb Vasc Biol 2003;23:2146–54.
37. Markus Meyer; Wolfgang Schillinger; Burkert Pieske, et al. Alterations of Sarcoplasmic Reticulum Proteins in Failing Human Dilated Cardiomyopathy. Circulation. 1995;92:778-784.
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