Notch信号通路在心肌成纤维细胞向肌成纤维细胞转分化中的作用
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摘要
【研究背景】
心肌成纤维细胞(CFs)过度增殖、转分化为肌成纤维细胞(MFB)而表达α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)导致胶原合成分泌过多是心肌纤维化的重要病理基础。转化生长因子-β1 (TGF-β1)具有促进CFs向MFB转分化,上调α-SMA和促进胶原合成等作用,是重要的促心肌纤维化细胞因子。心脏中肾素-血管紧张素系统( rennin-angiotensin system, RAS)的主要产物血管紧张素Ⅱ( angiotensinⅡ,AngⅡ)也能促进心肌纤维化的形成。Notch信号通路通过受体与配体相互作用来精确调控细胞分化,在心血管发育生理、病理过程中起重要作用,已证实其参与调节了成纤维细胞向MFB的分化,但其在CFs向MFB转分化过程中作用如何尚缺乏明确报道。
【研究目的】
1.观察基础状态下CFs表达Notch各受体情况以及DAPT对CFs的α-SMA,HYP的作用,初步阐明Notch通路是否参与心肌纤维化。
2.明确TGF-β1诱导CFs的α-SMA、HYP变化过程中Notch各受体的变化情况。
3.明确AngⅡ诱导CFs的α-SMA、HYP变化过程中Notch各受体的变化情况。
【研究内容】
1.检测基础状态下CFs表达Notch各受体情况以及分别使用DAPT不同作用浓度和不同作用时间对CFs的α-SMA、HYP的影响:分别采用实时定量PCR和蛋白印迹的方法检测Notch各受体的基因和蛋白水平;采用免疫荧光细胞化学和蛋白印迹的方法检测α-SMA的表达;采用消化法测定HYP含量。
2. TGF-β1不同作用时间和作用浓度对CFs的α-SMA、HYP的影响以及在TGF-β1诱导CFs向MFB转分化中Notch各受体的表达变化:采用免疫荧光细胞化学和蛋白印迹的方法检测α-SMA的表达;采用消化法测定HYP含量;采用实时荧光定量PCR和蛋白印迹的方法检测Notch各受体的基因和蛋白水平。
3. AngⅡ不同作用时间和作用浓度对CFs的α-SMA、HYP的影响以及在AngⅡ诱导CFs向MFB转分化中Notch各受体的表达变化:采用免疫荧光细胞化学和蛋白印迹的方法检测α-SMA的表达;采用消化法测定HYP含量;采用实时荧光定量PCR和蛋白印迹的方法检测Notch各受体的基因和蛋白水平。
【研究结果】
1.基础状态下CFs有Notch各受体基因和蛋白的表达;随着DAPT作用浓度的增加和作用时间的延长CFs的α-SMA、HYP均呈递增趋势。
2. TGF-β1可以上调CFs的α-SMA、HYP表达量,随着TGF-β1作用浓度的增加和作用时间的延长α-SMA、HYP均呈递增趋势。但Notch1、Notch3、Notch4随着TGF-β1作用时间的延长呈递减趋势,Notch2则无明显变化。
3. AngⅡ可以上调CFs的α-SMA、HYP表达量,随着AngⅡ作用浓度的增加和作用时间的延长α-SMA、HYP均呈递增趋势。但Notch1、Notch3、Notch4随着AngⅡ作用时间的延长呈递减趋势,Notch2表达则无明显变化。
【研究结论】
1. Notch各受体基因和蛋白在基础状态下CFs上均有表达。DAPT阻断Notch通路后,可以引起α-SMA、HYP的增加,导致CFs向MFB发生转分化。Notch通路在CFs向MFB转分化过程中可能具有重要作用。
2. TGF-β1能够显著增加CFsα-SMA、HYP的表达量,并且呈时间和剂量依赖效应,可以诱导CFs向MFB转分化。在TGF-β1诱导CFs向MFB转分化过程中Notch1、Notch3、Notch4呈递减趋势,Notch2则无明显变化。
3. AngⅡ能够显著增加CFsα-SMA、HYP的表达量,而且呈时间和剂量依赖效应,可以诱导CFs向MFB转分化。在AngⅡ诱导CFs向MFB转分化过程中Notch1、Notch3、Notch4逐渐降低,Notch2变化不显著。
【Background】
The excessive proliferation and transdifferentiation of cardiac fibroblasts (CFs) into myofibroblasts, which expressedα-smooth muscle actin and led to excessive collagen synthesis and secretion, are essential pathology of cardiac fibrosis. Transforming growth factor -β1 (TGF-β1), which can promote the differentiation of CFs to the MFB and up-regulate the expression ofα-SMA and collagen synthesis, is an important profibrotic cytokine. AngiotensinⅡ(angiotensinⅡ, AngⅡ), main product of cardiac renin-angiotensin system (rennin-angiotensin system, RAS) can promote myocardial fibrosis either. Notch signaling pathway, which controls the cell differentiation by interaction of ligands and receptors, plays an key role in the development and pathology of cardiovascular system. Although it has been proved that Notch signaling regulated the differentiation of fibroblasts into myofibroblasts, its effects in the differentiation of CFs into MFB remains unclear.
【Purposes】
1. To detect the expression level of Notch receptors in the CFs in basic state, investigate the effects of DAPT on the expression level ofα-SMA and HYP. To clarify if Notch signaling pathway participated in the pathology of myocardial fibrosis preliminarily.
2. To investigate the change of Notch receptors expression in the transdifferentiation of cardiac fibroblasts (CFs) into myofibroblasts (MFB) induced by TGF-β1.
3. To investigate the change of Notch receptors expression in the transdifferentiation of CFs into MFB induced by AngⅡ.
【Contents】
1. Detect the expression level of Notch receptors in the CFs in basic state and the expression level ofα-SMA and HYP stimulated by DAPT at different concentration and for different time length. Real-time quantitative PCR and Western blot were used to detect the expression level of Notch receptors mRNA and protein. Cytochemical immunofluorescence and Western blot were used to detect the expression ofα-SMA. Digestion method was used to detect the content of HYP.
2. The effects stimulation by TGF-β1 at different concentration and time length on the expression levelα-SMA and HYP in the CFs and the change of Notch receptors expression during the transdifferentiation of CFs into MFB. Cytochemical immunofluorescence and Western blot were used to detect the expression ofα-SMA. Digestion method was used to detect the content of HYP. Real-time quantitative PCR and Western blot were used to detect the expression level of Notch receptors mRNA and protein.
3. The effects stimulation by AngⅡat different concentration and time length on the expression levelα-SMA and HYP in the CFs and the change of Notch receptors expression during the transdifferentiation of CFs into MFB. Cytochemical immunofluorescence and Western blot were used to detect the expression ofα-SMA. Digestion method was used to detect the content of HYP. Real-time quantitative PCR and Western blot were used to detect the expression level of Notch receptors mRNA and protein.
【Results】
1. In basic state, the mRNA and protein of Notch receptors were expressed in CFs. The expression levels ofα-SMA and HYP showed uptrend as the concentration and the time length of DAPT increased.
2. TGF-β1 could up-regulate the expression ofα-SMA and HYP in CFs. The expression levels ofα-SMA and HYP showed increasing trend as the concentration and the time length of TGF-β1 stimulation increased. However, the expression levels of Notch1, Notch3 and Notch4 decreased with the increase of TGF-β1 concentration and extension of time. The expression of Notch2 did not change significantly.
3. AngⅡcould up-regulate the expression ofα-SMA and HYP in CFs. The expression levels ofα-SMA and HYP was up-regulated with the increase of AngⅡconcentration and extension of time. However, the expression levels of Notch1, Notch3 and Notch4 decreased with the increase of AngⅡconcentration and extension of time. The expression of Notch2 did not change significantly.
【Conclusion】
1. In basic state, the mRNA and protein of Notch receptors were expressed in CFs. Blockade of Notch signaling by DAPT up-regulated the expression ofα-SMA and HYP and resulted in the trandifferentiation of CFs into MFB.
2. TGF-β1 could up-regulate the expression ofα-SMA and HYP significantly in a time- and dose-dependent manner and induce the trandifferentiation of CFs into MFB. During the trandifferentiation, the expression levels of Notch1, Notch3 and Notch4 decreased gradually, while the expression level of Notch2 did not change significantly.
3. AngⅡ, which could up-regulate the expression ofα-SMA and HYP significantly in a time- and dose-dependent manner, could induce the trandifferentiation of CFs into MFB. During the trandifferentiation, the expression levels of Notch1, Notch3 and Notch4 decreased gradually, while the expression level of Notch2 did not change significantly.
心肌成纤维细胞(CFs)过度增殖、转分化为肌成纤维细胞(MFB)而表达α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)导致胶原合成分泌过多是心肌纤维化的重要病理基础。转化生长因子-β1 (TGF-β1)具有促进CFs向MFB转分化,上调α-SMA和促进胶原合成等作用,是重要的促心肌纤维化细胞因子。心脏中肾素-血管紧张素系统( rennin-angiotensin system, RAS)的主要产物血管紧张素Ⅱ( angiotensinⅡ,AngⅡ)也能促进心肌纤维化的形成。Notch信号通路通过受体与配体相互作用来精确调控细胞分化,在心血管发育生理、病理过程中起重要作用,已证实其参与调节了成纤维细胞向MFB的分化,但其在CFs向MFB转分化过程中作用如何尚缺乏明确报道。
【研究目的】
1.观察基础状态下CFs表达Notch各受体情况以及DAPT对CFs的α-SMA,HYP的作用,初步阐明Notch通路是否参与心肌纤维化。
2.明确TGF-β1诱导CFs的α-SMA、HYP变化过程中Notch各受体的变化情况。
3.明确AngⅡ诱导CFs的α-SMA、HYP变化过程中Notch各受体的变化情况。
【研究内容】
1.检测基础状态下CFs表达Notch各受体情况以及分别使用DAPT不同作用浓度和不同作用时间对CFs的α-SMA、HYP的影响:分别采用实时定量PCR和蛋白印迹的方法检测Notch各受体的基因和蛋白水平;采用免疫荧光细胞化学和蛋白印迹的方法检测α-SMA的表达;采用消化法测定HYP含量。
2. TGF-β1不同作用时间和作用浓度对CFs的α-SMA、HYP的影响以及在TGF-β1诱导CFs向MFB转分化中Notch各受体的表达变化:采用免疫荧光细胞化学和蛋白印迹的方法检测α-SMA的表达;采用消化法测定HYP含量;采用实时荧光定量PCR和蛋白印迹的方法检测Notch各受体的基因和蛋白水平。
3. AngⅡ不同作用时间和作用浓度对CFs的α-SMA、HYP的影响以及在AngⅡ诱导CFs向MFB转分化中Notch各受体的表达变化:采用免疫荧光细胞化学和蛋白印迹的方法检测α-SMA的表达;采用消化法测定HYP含量;采用实时荧光定量PCR和蛋白印迹的方法检测Notch各受体的基因和蛋白水平。
【研究结果】
1.基础状态下CFs有Notch各受体基因和蛋白的表达;随着DAPT作用浓度的增加和作用时间的延长CFs的α-SMA、HYP均呈递增趋势。
2. TGF-β1可以上调CFs的α-SMA、HYP表达量,随着TGF-β1作用浓度的增加和作用时间的延长α-SMA、HYP均呈递增趋势。但Notch1、Notch3、Notch4随着TGF-β1作用时间的延长呈递减趋势,Notch2则无明显变化。
3. AngⅡ可以上调CFs的α-SMA、HYP表达量,随着AngⅡ作用浓度的增加和作用时间的延长α-SMA、HYP均呈递增趋势。但Notch1、Notch3、Notch4随着AngⅡ作用时间的延长呈递减趋势,Notch2表达则无明显变化。
【研究结论】
1. Notch各受体基因和蛋白在基础状态下CFs上均有表达。DAPT阻断Notch通路后,可以引起α-SMA、HYP的增加,导致CFs向MFB发生转分化。Notch通路在CFs向MFB转分化过程中可能具有重要作用。
2. TGF-β1能够显著增加CFsα-SMA、HYP的表达量,并且呈时间和剂量依赖效应,可以诱导CFs向MFB转分化。在TGF-β1诱导CFs向MFB转分化过程中Notch1、Notch3、Notch4呈递减趋势,Notch2则无明显变化。
3. AngⅡ能够显著增加CFsα-SMA、HYP的表达量,而且呈时间和剂量依赖效应,可以诱导CFs向MFB转分化。在AngⅡ诱导CFs向MFB转分化过程中Notch1、Notch3、Notch4逐渐降低,Notch2变化不显著。
【Background】
The excessive proliferation and transdifferentiation of cardiac fibroblasts (CFs) into myofibroblasts, which expressedα-smooth muscle actin and led to excessive collagen synthesis and secretion, are essential pathology of cardiac fibrosis. Transforming growth factor -β1 (TGF-β1), which can promote the differentiation of CFs to the MFB and up-regulate the expression ofα-SMA and collagen synthesis, is an important profibrotic cytokine. AngiotensinⅡ(angiotensinⅡ, AngⅡ), main product of cardiac renin-angiotensin system (rennin-angiotensin system, RAS) can promote myocardial fibrosis either. Notch signaling pathway, which controls the cell differentiation by interaction of ligands and receptors, plays an key role in the development and pathology of cardiovascular system. Although it has been proved that Notch signaling regulated the differentiation of fibroblasts into myofibroblasts, its effects in the differentiation of CFs into MFB remains unclear.
【Purposes】
1. To detect the expression level of Notch receptors in the CFs in basic state, investigate the effects of DAPT on the expression level ofα-SMA and HYP. To clarify if Notch signaling pathway participated in the pathology of myocardial fibrosis preliminarily.
2. To investigate the change of Notch receptors expression in the transdifferentiation of cardiac fibroblasts (CFs) into myofibroblasts (MFB) induced by TGF-β1.
3. To investigate the change of Notch receptors expression in the transdifferentiation of CFs into MFB induced by AngⅡ.
【Contents】
1. Detect the expression level of Notch receptors in the CFs in basic state and the expression level ofα-SMA and HYP stimulated by DAPT at different concentration and for different time length. Real-time quantitative PCR and Western blot were used to detect the expression level of Notch receptors mRNA and protein. Cytochemical immunofluorescence and Western blot were used to detect the expression ofα-SMA. Digestion method was used to detect the content of HYP.
2. The effects stimulation by TGF-β1 at different concentration and time length on the expression levelα-SMA and HYP in the CFs and the change of Notch receptors expression during the transdifferentiation of CFs into MFB. Cytochemical immunofluorescence and Western blot were used to detect the expression ofα-SMA. Digestion method was used to detect the content of HYP. Real-time quantitative PCR and Western blot were used to detect the expression level of Notch receptors mRNA and protein.
3. The effects stimulation by AngⅡat different concentration and time length on the expression levelα-SMA and HYP in the CFs and the change of Notch receptors expression during the transdifferentiation of CFs into MFB. Cytochemical immunofluorescence and Western blot were used to detect the expression ofα-SMA. Digestion method was used to detect the content of HYP. Real-time quantitative PCR and Western blot were used to detect the expression level of Notch receptors mRNA and protein.
【Results】
1. In basic state, the mRNA and protein of Notch receptors were expressed in CFs. The expression levels ofα-SMA and HYP showed uptrend as the concentration and the time length of DAPT increased.
2. TGF-β1 could up-regulate the expression ofα-SMA and HYP in CFs. The expression levels ofα-SMA and HYP showed increasing trend as the concentration and the time length of TGF-β1 stimulation increased. However, the expression levels of Notch1, Notch3 and Notch4 decreased with the increase of TGF-β1 concentration and extension of time. The expression of Notch2 did not change significantly.
3. AngⅡcould up-regulate the expression ofα-SMA and HYP in CFs. The expression levels ofα-SMA and HYP was up-regulated with the increase of AngⅡconcentration and extension of time. However, the expression levels of Notch1, Notch3 and Notch4 decreased with the increase of AngⅡconcentration and extension of time. The expression of Notch2 did not change significantly.
【Conclusion】
1. In basic state, the mRNA and protein of Notch receptors were expressed in CFs. Blockade of Notch signaling by DAPT up-regulated the expression ofα-SMA and HYP and resulted in the trandifferentiation of CFs into MFB.
2. TGF-β1 could up-regulate the expression ofα-SMA and HYP significantly in a time- and dose-dependent manner and induce the trandifferentiation of CFs into MFB. During the trandifferentiation, the expression levels of Notch1, Notch3 and Notch4 decreased gradually, while the expression level of Notch2 did not change significantly.
3. AngⅡ, which could up-regulate the expression ofα-SMA and HYP significantly in a time- and dose-dependent manner, could induce the trandifferentiation of CFs into MFB. During the trandifferentiation, the expression levels of Notch1, Notch3 and Notch4 decreased gradually, while the expression level of Notch2 did not change significantly.
引文
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45 Hao J ,Ju H ,Zhao S , et al . Elevation of expression of Smads 2、3、and4,decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J Mol Cell Cardiol .1999 ,31 (3) :667-678.
46 Ruiz-Ortega M, Ruperez M, Esteban V, Egido J. Molecular mechanisms of angiotensin II-induced vascular injury. Curr Hypertens Rep. 2003, 5: 73–9.
47 Li JH, Huang XR, Zhu HJ, et al. Role of TGF-βsignaling in extracellular matrix production under high glucose conditions. KidneyInt. 2003,63:2010–9.
48 Li JH, Huang XR, Zhu HJ, et al. Advanced glycation end products activate Smad signaling via TGF-β-dependent and independent mechanisms: implications for diabetic renal and vascular disease. FASEB J.2004,18:176–8.
49 Dixon IM, Hao J ,Keid NL , et al . Effect of chronic AT1 receptor blockade on cardiac Smad overexpression in hereditary cardiomyo- pathic hamsters.Cardiovasc Res.2000,46 (2):286-297.
50 Leask A, Abraham DJ. TGF-βsignaling and the fibrotic response.FASEB J. 2004,18:816–7.
51 Verrecchia F, Mauviel A. Transforming growth factor-beta signaling thr- ough the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol. 2002,118:211–5.
52 Shah M, Foreman DM, Ferguson MW. Neutralisation of TGF-beta 1 and TGF-beta2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci.1995,108(Pt 3):985-1002.
53 Hosokawa R, Nonaka K, Morifuji M, et al. TGF-beta 3 decreases type I collagen and scarring after labioplasty. J Dent Res.2003, 82(7):558-642.
54 Eghbali FJ ,Sieck GC ,Prakash YS , et al . Type 1 procollagen production and cell proliferation is mediated by transforming growth factor-βin a model of hepatic fibrosis.Endocrinology.1996,137 (5) :1894-1903.
55 Sun Y,Zhang J ,Zhang JQ , et al .Local angiotensinⅡand transforming growth factor-β1 in renal fibrosis of rats. Hypertension.2000,35(5): 1078-1084.
56 Kuwahara F , Kai H ,Tokuda K, et al . Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloade rats.Circulation.2002,106 (1):130- 135.
57 Yu HCM, Burrell LM,Black MJ,et al . Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation. 1998,98 (23) :2621-2628.
58 Tsujita-Kyutoku M, Uehara N, Matsuoka Y, et al. Comparison of transforming growth factor-beta/Smad signaling between normal dermal fibroblasts and fibroblasts derived from central and peripheral areas of keloid lesions. In Vivo. 2005,19(6):959-63.
59 Li JP , Petrov V , Rumilla K, et al . Transforming growth factor-beta1 promotes contraction of collagen gel by cardia fibroblasts through their differentiation into myofibroblasts. Methods Find Exp Clin Pharmacol.2003,25 (2):79-86.
60 Colwell AS, Phan TT, Kong W, et al. Hypertrophic scar fibroblasts have increased connective tissue growth factor expression after transforming growth factor-beta stimulation. Plast Reconstr Surg. 2005,116(5):1387-90; discussion 1391-2.
61 GriffinM, Lee HW, Zhao L, et al. Gender-related differences in prolifera- tive response of cardiac fibroblasts to hypoxia: effects of estrogen. Mol Cell Biochem. 2000,215 (2):21-30.
62 Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone.J Lab Clin Med.1993,122:395–403.
63 Ratajska A, Campbell SE, Sun Y, Weber KT. Angiotenin II associatedcardiac myocyte necrosis: role of adrenal catecholamines. Cardiovasc Res.1994,28:684–690.
64 Lu L, Quinn MT, Sun Y. Oxidative stress in the infarcted heart: role of de novo angiotensin II production. Biochem Biophys Res Commun. 2004,325:943–951.
65 Cleutjens JPM, Kandala JC, Guarda E,et al. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol. 1995,27:1281–1292.
66 Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol. 1997,17:467–491.
67 Yu CM, Tipoe GL, Wing-Hon Lai K, Lau CP. Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagoniston inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction. J Am Coll Cardiol. 2001,38:1207–1215.
68 Jugdutt BI. Effect of captopril and enalapril on left ventricular geometry,function and collagen during healing after anterior and inferior myocardial infarction in a dog model. J Am Coll Cardiol. 1995,25:1718–1725.
69 . Frimm Cde C, Sun Y, Weber KT. Angiotensin II receptor blockade and myocardial fibrosis of the infarcted rat heart. J Lab Clin Med .1997,129:439–446.
70 Michel JB, Lattion AL, Salzmann JL, et al. Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction. Circ Res .1988,62:641–650.
71 Van Krimpen C, Smits JFM, Cleutjens JPM, et al. DNA synthesis in thenon-infarcted cardiac interstitium after left coronary artery ligation in the rat heart: effects of captopril. J Mol Cell Cardiol. 1991, 23: 1245–1253.
72 Schieffer B, Wirger A, Meybrunn M, et al. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation. 1994,89:2273–2282.
73 Kim S, Ohta K, Hamaguchi A, et al. Contribution of renal angiotensin II type I receptor to gene expressions in hypertension-induced renal injury. Kidney Int .1994,46:1346–1358.
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44 Rodriguez-Vita J, Sanchez-Lopez E, Esteban V,et al. Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism.Circulation. 2005,111:2509–17.
45 Hao J ,Ju H ,Zhao S , et al . Elevation of expression of Smads 2、3、and4,decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J Mol Cell Cardiol .1999 ,31 (3) :667-678.
46 Ruiz-Ortega M, Ruperez M, Esteban V, Egido J. Molecular mechanisms of angiotensin II-induced vascular injury. Curr Hypertens Rep. 2003, 5: 73–9.
47 Li JH, Huang XR, Zhu HJ, et al. Role of TGF-βsignaling in extracellular matrix production under high glucose conditions. KidneyInt. 2003,63:2010–9.
48 Li JH, Huang XR, Zhu HJ, et al. Advanced glycation end products activate Smad signaling via TGF-β-dependent and independent mechanisms: implications for diabetic renal and vascular disease. FASEB J.2004,18:176–8.
49 Dixon IM, Hao J ,Keid NL , et al . Effect of chronic AT1 receptor blockade on cardiac Smad overexpression in hereditary cardiomyo- pathic hamsters.Cardiovasc Res.2000,46 (2):286-297.
50 Leask A, Abraham DJ. TGF-βsignaling and the fibrotic response.FASEB J. 2004,18:816–7.
51 Verrecchia F, Mauviel A. Transforming growth factor-beta signaling thr- ough the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol. 2002,118:211–5.
52 Shah M, Foreman DM, Ferguson MW. Neutralisation of TGF-beta 1 and TGF-beta2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci.1995,108(Pt 3):985-1002.
53 Hosokawa R, Nonaka K, Morifuji M, et al. TGF-beta 3 decreases type I collagen and scarring after labioplasty. J Dent Res.2003, 82(7):558-642.
54 Eghbali FJ ,Sieck GC ,Prakash YS , et al . Type 1 procollagen production and cell proliferation is mediated by transforming growth factor-βin a model of hepatic fibrosis.Endocrinology.1996,137 (5) :1894-1903.
55 Sun Y,Zhang J ,Zhang JQ , et al .Local angiotensinⅡand transforming growth factor-β1 in renal fibrosis of rats. Hypertension.2000,35(5): 1078-1084.
56 Kuwahara F , Kai H ,Tokuda K, et al . Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloade rats.Circulation.2002,106 (1):130- 135.
57 Yu HCM, Burrell LM,Black MJ,et al . Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation. 1998,98 (23) :2621-2628.
58 Tsujita-Kyutoku M, Uehara N, Matsuoka Y, et al. Comparison of transforming growth factor-beta/Smad signaling between normal dermal fibroblasts and fibroblasts derived from central and peripheral areas of keloid lesions. In Vivo. 2005,19(6):959-63.
59 Li JP , Petrov V , Rumilla K, et al . Transforming growth factor-beta1 promotes contraction of collagen gel by cardia fibroblasts through their differentiation into myofibroblasts. Methods Find Exp Clin Pharmacol.2003,25 (2):79-86.
60 Colwell AS, Phan TT, Kong W, et al. Hypertrophic scar fibroblasts have increased connective tissue growth factor expression after transforming growth factor-beta stimulation. Plast Reconstr Surg. 2005,116(5):1387-90; discussion 1391-2.
61 GriffinM, Lee HW, Zhao L, et al. Gender-related differences in prolifera- tive response of cardiac fibroblasts to hypoxia: effects of estrogen. Mol Cell Biochem. 2000,215 (2):21-30.
62 Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone.J Lab Clin Med.1993,122:395–403.
63 Ratajska A, Campbell SE, Sun Y, Weber KT. Angiotenin II associatedcardiac myocyte necrosis: role of adrenal catecholamines. Cardiovasc Res.1994,28:684–690.
64 Lu L, Quinn MT, Sun Y. Oxidative stress in the infarcted heart: role of de novo angiotensin II production. Biochem Biophys Res Commun. 2004,325:943–951.
65 Cleutjens JPM, Kandala JC, Guarda E,et al. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol. 1995,27:1281–1292.
66 Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol. 1997,17:467–491.
67 Yu CM, Tipoe GL, Wing-Hon Lai K, Lau CP. Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagoniston inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction. J Am Coll Cardiol. 2001,38:1207–1215.
68 Jugdutt BI. Effect of captopril and enalapril on left ventricular geometry,function and collagen during healing after anterior and inferior myocardial infarction in a dog model. J Am Coll Cardiol. 1995,25:1718–1725.
69 . Frimm Cde C, Sun Y, Weber KT. Angiotensin II receptor blockade and myocardial fibrosis of the infarcted rat heart. J Lab Clin Med .1997,129:439–446.
70 Michel JB, Lattion AL, Salzmann JL, et al. Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction. Circ Res .1988,62:641–650.
71 Van Krimpen C, Smits JFM, Cleutjens JPM, et al. DNA synthesis in thenon-infarcted cardiac interstitium after left coronary artery ligation in the rat heart: effects of captopril. J Mol Cell Cardiol. 1991, 23: 1245–1253.
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