葛根素对异丙肾上腺素诱导大鼠的心肌纤维化和心肌结缔组织生长因子表达的影响
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摘要
目的:研究葛根素对异丙肾上腺素(isoprenaline,ISO)诱导大鼠的心肌纤维化和心肌结缔组织生长因子(connective tissue growth factor,CTGF)表达的影响。
方法:采用ISO(5mg·kg-1·d-1×10d)皮下注射制作大鼠心肌纤维化模型,分早期和后期给予葛根素(100mg·kg-1·d-1)腹腔注射56天和46天,实验共8周。48只雄性SD大鼠随机分成四组:模型组(M组)16只;空白对照组(C组)8只;葛根素早期干预组(Pa组)12只;葛根素后期干预组(Pp组)12只。于实验末,大鼠处死的前一天进行超声心动图检查,检测左室舒张末内径(left ventricular internal diameter at end-diastole, LVIDd)、左室收缩末内径(left ventricular internal diameter at end-systole, LVIDs)、左室舒张末容积(left ventricle end-diastole volume, LVEDV)、左室收缩末容积(left ventricle end-systole volume, LVESV)、左室射血分数(left ventricle ejection fraction, LVEF)及缩短分数(fractional shortening, FS)。计算左室指数(左室重量/体重),进行VG(Van Gieson)染色、免疫组化染色,分别测算胶原容积积分(collagen volume fraction, CVF)、CTGF蛋白和转化生长因子β1(transforming growth factor beta1,TGF-β1)蛋白含量,检测左室游离壁心肌组织中羟脯氨酸浓度,运用RT-PCR半定量分析左室游离壁心肌组织中CTGF mRNA和TGF-β1 mRNA水平。
结果:实验末存活SD大鼠32只。
①超声心动图结果:模型组大鼠LVEF和FS较空白对照组显著降低(P<0.01),模型组大鼠左室心腔明显扩大,葛根素明显改善模型组大鼠左室收缩功能和减小模型组LVEDV,葛根素早期干预组大鼠LVEF和FS提高幅度较葛根素后期干预组更明显(分别P<0.05和P<0.01),葛根素干预组大鼠LVIDd、LVEDV与空白对照组无显著差异。
②心肌纤维化:模型组大鼠左室指数、左室心肌组织CVF和羟脯氨酸浓度均较空白对照组明显增加(P<0.01),葛根素减少模型组大鼠左室指数、左室心肌组织CVF及羟脯氨酸浓度(P<0.01),葛根素早期干预组大鼠左室指数、左室心肌组织CVF和羟脯氨酸浓度均较葛根素后期干预组减少(分别P<0.05、P<0.01和P<0.05)。
③促纤维化细胞因子:与空白对照组比较,模型组大鼠左室心肌组织的CTGF和TGF-β1表达均明显增加(P<0.01),葛根素降低模型组大鼠左室心肌组织CTGF和TGF-β1的过度表达,葛根素早期干预组大鼠左室心肌组织中CTGF和TGF-β1的表达均较葛根素后期干预组少。
④相关分析:四组大鼠的左室心肌组织CTGF蛋白与左室心肌组织CVF和羟脯氨酸浓度呈正相关(P<0.05)。
结论:葛根素减少ISO诱导大鼠的左室心肌间质胶原沉积和左室心肌组织中羟脯氨酸浓度,减轻和延缓ISO诱导大鼠的心肌纤维化,从而改善左心室收缩功能,这种作用机制可能是通过抑制左室心肌组织中CTGF、TGF-β1——促纤维化细胞因子的过度表达来实现。葛根素早期干预较后期干预效果更好。
Objective: To investigate the effects of puerarin on myocardial fibrosis and the expression of connective tissue growth factor (CTGF) in myocardial tissue of the rats induced by isoproterenol (ISO).
Methods: In this study, the model of myocardial fibrosis was established by subcutaneous injection (s.c.) with ISO (0.05% ISO, 5 mg/kg per day for ten days) in male Sprague-Dawley rats. Meanwhile, the rats were administrated by intraperitoneal injection (i.p.) with peurarin (100mg/kg per day for 56 or 46 days). The period of the present study of animals was 8 weeks. 48 male Sprague-Dawley rats weighting 150 to 170 g were devided into four groups randomly: model group (n=16, 0.05% ISO 5 mg/kg per day s.c. for ten days, NS 1ml per day i.p. for 56 days), control group ( n=8, NS 10 ml/kg per day s.c. for ten days, NS 1ml per day i.p. for 56 days), early administration with puerarin group (early puerarin-treated group, n=12, 0.05% ISO 5mg/kg per day s.c. for ten days, puerarin 100mg/kg per day i.p. for 56 days) , later administration with puerarin group (later puerarin-treated group, n=12, 0.05% ISO 5mg/kg per day s.c. for ten days, NS 1ml per day i.p. for ten days, puerarin 100mg/kg per day i.p. for 46 days after ten days). At the end of study, left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricle end-diastole volume (LVEDV), left ventricle end-systole volume (LVESV), left ventricle ejection fraction (LVEF) and fractional shortening (FS) of rats were detected by GE vivid7 diasonography. Then rats were anesthetized with 3% pentobarbital, and left ventricle (LV) weight to body weight ratio was assessed. The cross serial transverse sections of LV of the rats were examined microscopically after Van Gieson (VG) collagen staining, CTGF-antibody immunohistochemstry staining and transforming growth factor beta1 (TGF-β1)-antibody immunohistochemstry staining. The quantitative analyses of collagen volume fraction (CVF) , CTGF protein and TGF-β1 protein were performed using an image analysis computer system. CTGF mRNA level, TGF-β1 mRNA level and ratio of hydroxyproline to the total protein in LV myocardial tissue were measured.
Results: There were 32 survival rats at the end of the present experiment.
①parameters of echocardiogram: In comparison with control group, the LVEF and FS of model group were decreased obviously (P<0.01) and the LVIDd, LVIDs, LVEDV and LVESV of model group was increased markedly (P<0.01). The LVEDV and LVESV of model group was increased by tow- and eight-fold , respectively, compared to the control group. Comparing with model group, the LVEF and FS of the treatment with puerarin groups were increased (P<0.01). The LVEF and FS of early puerarin-treated group were more increased than later puerarin-treated group (P<0.05, P<0.01, respectively). However, comparing with model group, the LVIDd, LVEDV, LVIDs, LVESV of later puerarin-treated group were decreased (P<0.05, P<0.05, P<0.01, P<0.01, respectively). The LVIDs, LVESV of early puerarin-treated group were decreased in comparison with later puerarin-treated group(P<0.01, P<0.05, respectively). Furthermore, nonsignificant was the difference in the LVIDd and LVEDV in early puerarin-treated group, later puerarin-treated group and control group.
②Myocardial fibrosis: It was observed that excessive collagen deposited in LV myocardial interstitium of the model rats after VG collagen staining. In comparison with control group, LV weight/ body weight ratio, CVF and ratio of hydroxyproline/ total protein in LV myocardial tissue of model group were significantly increased (P<0.01). LV weight/ body weight ratio, CVF and ratio of hydroxyproline/total protein in LV myocardial tissue of early puerarin-treated group were 2.3825±0.0755 mg/g, 0.1286±0.0097, 0.4873±0.0267μg/mg, respectively. In the same time, those of later puerarin-treated group were 2.4863±0.1131 mg/g, 0.1674±0.0158, 0.5304±0.0334μg/mg, respectively. Comparing with model group, LV weight/ body weight ratio, CVF and ratio of hydroxyproline/total protein in LV myocardial tissue of the treatment with puerarin groups were decreased (P<0.01). LV weight/ body weight ratio, CVF and ratio of hydroxyproline/total protein in LV myocardial tissue of early puerarin-treated group were lower than later puerarin-treated group (P<0.05, P<0.01, P<0.05, respectively).
③Profibrotic cytokines: In comparison with control group, the CTGF mRNA and TGF-β1 mRNA in LV myocardial tissue of model group were upregulated noticeably (P<0.01), and those were increased by three- and two-fold respectively. In this study, puerarin downregulated the overexpression of CTGF gene and TGF-β1 gene in LV myocardial tissue induced by ISO in rats. Comparing with model group, the CTGF mRNA in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were significantly downregulated (P<0.01), and the TGF-β1 mRNA in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were downregulated (P<0.01, P<0.05, respectively). The CTGF mRNA and TGF-β1 mRNA in LV myocardial tissue of early puerarin-treated group were lower than those of later puerarin-treated group (P<0.05, P<0.01, respectively). The proteins of CTGF and TGF-β1 in LV myocardial tissue of model group were markedly increased compared to control group (P<0.01), and those were increased by sevene- and three-fold respectively. When compared with model group, the CTGF protein in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were markedly decreased (P<0.01), and the TGF-β1 protein in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were decreased (P<0.01, P<0.05, respectively). The CTGF protein and TGF-β1 protein in LV myocardial tissue of early puerarin-treated group were lower than those of later puerarin-treated group (P<0.05, P<0.01, respectively).
④correlation analyze: CTGF protein was correlated with ratio of hydroxyproline/ total protein and CVF in LV of rats of every group (P<0.05).
Conclusions: These data demonstrated that peurarin reduced the excessive collagen deposition in cardiac interstitial, and improved LV systolic dysfunction, and reduced LV dilatation of rats with chronic myocardial fibrosis induced by ISO. One of the mechanisms of the effects is related to downregulate the overexpression of CTGF and TGF-β1, two profibrotic cytokins, in LV myocardial tissue. Furthermore, the effects of early treatment with puerarin are better than those of later treatment with puerarin.
方法:采用ISO(5mg·kg-1·d-1×10d)皮下注射制作大鼠心肌纤维化模型,分早期和后期给予葛根素(100mg·kg-1·d-1)腹腔注射56天和46天,实验共8周。48只雄性SD大鼠随机分成四组:模型组(M组)16只;空白对照组(C组)8只;葛根素早期干预组(Pa组)12只;葛根素后期干预组(Pp组)12只。于实验末,大鼠处死的前一天进行超声心动图检查,检测左室舒张末内径(left ventricular internal diameter at end-diastole, LVIDd)、左室收缩末内径(left ventricular internal diameter at end-systole, LVIDs)、左室舒张末容积(left ventricle end-diastole volume, LVEDV)、左室收缩末容积(left ventricle end-systole volume, LVESV)、左室射血分数(left ventricle ejection fraction, LVEF)及缩短分数(fractional shortening, FS)。计算左室指数(左室重量/体重),进行VG(Van Gieson)染色、免疫组化染色,分别测算胶原容积积分(collagen volume fraction, CVF)、CTGF蛋白和转化生长因子β1(transforming growth factor beta1,TGF-β1)蛋白含量,检测左室游离壁心肌组织中羟脯氨酸浓度,运用RT-PCR半定量分析左室游离壁心肌组织中CTGF mRNA和TGF-β1 mRNA水平。
结果:实验末存活SD大鼠32只。
①超声心动图结果:模型组大鼠LVEF和FS较空白对照组显著降低(P<0.01),模型组大鼠左室心腔明显扩大,葛根素明显改善模型组大鼠左室收缩功能和减小模型组LVEDV,葛根素早期干预组大鼠LVEF和FS提高幅度较葛根素后期干预组更明显(分别P<0.05和P<0.01),葛根素干预组大鼠LVIDd、LVEDV与空白对照组无显著差异。
②心肌纤维化:模型组大鼠左室指数、左室心肌组织CVF和羟脯氨酸浓度均较空白对照组明显增加(P<0.01),葛根素减少模型组大鼠左室指数、左室心肌组织CVF及羟脯氨酸浓度(P<0.01),葛根素早期干预组大鼠左室指数、左室心肌组织CVF和羟脯氨酸浓度均较葛根素后期干预组减少(分别P<0.05、P<0.01和P<0.05)。
③促纤维化细胞因子:与空白对照组比较,模型组大鼠左室心肌组织的CTGF和TGF-β1表达均明显增加(P<0.01),葛根素降低模型组大鼠左室心肌组织CTGF和TGF-β1的过度表达,葛根素早期干预组大鼠左室心肌组织中CTGF和TGF-β1的表达均较葛根素后期干预组少。
④相关分析:四组大鼠的左室心肌组织CTGF蛋白与左室心肌组织CVF和羟脯氨酸浓度呈正相关(P<0.05)。
结论:葛根素减少ISO诱导大鼠的左室心肌间质胶原沉积和左室心肌组织中羟脯氨酸浓度,减轻和延缓ISO诱导大鼠的心肌纤维化,从而改善左心室收缩功能,这种作用机制可能是通过抑制左室心肌组织中CTGF、TGF-β1——促纤维化细胞因子的过度表达来实现。葛根素早期干预较后期干预效果更好。
Objective: To investigate the effects of puerarin on myocardial fibrosis and the expression of connective tissue growth factor (CTGF) in myocardial tissue of the rats induced by isoproterenol (ISO).
Methods: In this study, the model of myocardial fibrosis was established by subcutaneous injection (s.c.) with ISO (0.05% ISO, 5 mg/kg per day for ten days) in male Sprague-Dawley rats. Meanwhile, the rats were administrated by intraperitoneal injection (i.p.) with peurarin (100mg/kg per day for 56 or 46 days). The period of the present study of animals was 8 weeks. 48 male Sprague-Dawley rats weighting 150 to 170 g were devided into four groups randomly: model group (n=16, 0.05% ISO 5 mg/kg per day s.c. for ten days, NS 1ml per day i.p. for 56 days), control group ( n=8, NS 10 ml/kg per day s.c. for ten days, NS 1ml per day i.p. for 56 days), early administration with puerarin group (early puerarin-treated group, n=12, 0.05% ISO 5mg/kg per day s.c. for ten days, puerarin 100mg/kg per day i.p. for 56 days) , later administration with puerarin group (later puerarin-treated group, n=12, 0.05% ISO 5mg/kg per day s.c. for ten days, NS 1ml per day i.p. for ten days, puerarin 100mg/kg per day i.p. for 46 days after ten days). At the end of study, left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricle end-diastole volume (LVEDV), left ventricle end-systole volume (LVESV), left ventricle ejection fraction (LVEF) and fractional shortening (FS) of rats were detected by GE vivid7 diasonography. Then rats were anesthetized with 3% pentobarbital, and left ventricle (LV) weight to body weight ratio was assessed. The cross serial transverse sections of LV of the rats were examined microscopically after Van Gieson (VG) collagen staining, CTGF-antibody immunohistochemstry staining and transforming growth factor beta1 (TGF-β1)-antibody immunohistochemstry staining. The quantitative analyses of collagen volume fraction (CVF) , CTGF protein and TGF-β1 protein were performed using an image analysis computer system. CTGF mRNA level, TGF-β1 mRNA level and ratio of hydroxyproline to the total protein in LV myocardial tissue were measured.
Results: There were 32 survival rats at the end of the present experiment.
①parameters of echocardiogram: In comparison with control group, the LVEF and FS of model group were decreased obviously (P<0.01) and the LVIDd, LVIDs, LVEDV and LVESV of model group was increased markedly (P<0.01). The LVEDV and LVESV of model group was increased by tow- and eight-fold , respectively, compared to the control group. Comparing with model group, the LVEF and FS of the treatment with puerarin groups were increased (P<0.01). The LVEF and FS of early puerarin-treated group were more increased than later puerarin-treated group (P<0.05, P<0.01, respectively). However, comparing with model group, the LVIDd, LVEDV, LVIDs, LVESV of later puerarin-treated group were decreased (P<0.05, P<0.05, P<0.01, P<0.01, respectively). The LVIDs, LVESV of early puerarin-treated group were decreased in comparison with later puerarin-treated group(P<0.01, P<0.05, respectively). Furthermore, nonsignificant was the difference in the LVIDd and LVEDV in early puerarin-treated group, later puerarin-treated group and control group.
②Myocardial fibrosis: It was observed that excessive collagen deposited in LV myocardial interstitium of the model rats after VG collagen staining. In comparison with control group, LV weight/ body weight ratio, CVF and ratio of hydroxyproline/ total protein in LV myocardial tissue of model group were significantly increased (P<0.01). LV weight/ body weight ratio, CVF and ratio of hydroxyproline/total protein in LV myocardial tissue of early puerarin-treated group were 2.3825±0.0755 mg/g, 0.1286±0.0097, 0.4873±0.0267μg/mg, respectively. In the same time, those of later puerarin-treated group were 2.4863±0.1131 mg/g, 0.1674±0.0158, 0.5304±0.0334μg/mg, respectively. Comparing with model group, LV weight/ body weight ratio, CVF and ratio of hydroxyproline/total protein in LV myocardial tissue of the treatment with puerarin groups were decreased (P<0.01). LV weight/ body weight ratio, CVF and ratio of hydroxyproline/total protein in LV myocardial tissue of early puerarin-treated group were lower than later puerarin-treated group (P<0.05, P<0.01, P<0.05, respectively).
③Profibrotic cytokines: In comparison with control group, the CTGF mRNA and TGF-β1 mRNA in LV myocardial tissue of model group were upregulated noticeably (P<0.01), and those were increased by three- and two-fold respectively. In this study, puerarin downregulated the overexpression of CTGF gene and TGF-β1 gene in LV myocardial tissue induced by ISO in rats. Comparing with model group, the CTGF mRNA in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were significantly downregulated (P<0.01), and the TGF-β1 mRNA in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were downregulated (P<0.01, P<0.05, respectively). The CTGF mRNA and TGF-β1 mRNA in LV myocardial tissue of early puerarin-treated group were lower than those of later puerarin-treated group (P<0.05, P<0.01, respectively). The proteins of CTGF and TGF-β1 in LV myocardial tissue of model group were markedly increased compared to control group (P<0.01), and those were increased by sevene- and three-fold respectively. When compared with model group, the CTGF protein in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were markedly decreased (P<0.01), and the TGF-β1 protein in LV myocardial tissue of early puerarin-treated group and later puerarin-treated group were decreased (P<0.01, P<0.05, respectively). The CTGF protein and TGF-β1 protein in LV myocardial tissue of early puerarin-treated group were lower than those of later puerarin-treated group (P<0.05, P<0.01, respectively).
④correlation analyze: CTGF protein was correlated with ratio of hydroxyproline/ total protein and CVF in LV of rats of every group (P<0.05).
Conclusions: These data demonstrated that peurarin reduced the excessive collagen deposition in cardiac interstitial, and improved LV systolic dysfunction, and reduced LV dilatation of rats with chronic myocardial fibrosis induced by ISO. One of the mechanisms of the effects is related to downregulate the overexpression of CTGF and TGF-β1, two profibrotic cytokins, in LV myocardial tissue. Furthermore, the effects of early treatment with puerarin are better than those of later treatment with puerarin.
引文
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