电针预处理对家兔心肌缺血再灌注损伤的延迟相保护及基于多家族热休克蛋白的机理研究
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摘要
目的：通过观察电针预处理对家兔心肌缺血再灌注损伤的延迟相保护效应、家兔血清CK的含量、心肌保护重要中介物质(PKC)、效应物质(HSP27mRNA, HSP70mRNA, HSP90mRNA)及细胞凋亡死亡受体通路蛋白(Fas/FasL)的表达,探讨针灸防病保健理论的分子生物学基础,研究电针预处理对家兔心肌缺血再灌注损伤诱导延迟相保护的机制。
方法：新西兰大耳白兔随机分为3组,即假手术组、缺血再灌注组、电针预处理组,并设定0h、24h及48h三个时相。采用自拟改良法制备家兔心肌缺血再灌注损伤模型,以电针内关预处理为被试因素,光镜下观察左心室缺血区组织病理形态学变化；电镜下观察左心室缺血区组织超微结构的变化；采用ELISA法检测血清CK含量；Vestern Blot技术检测心肌组织PKC表达；RT-PCR技术检测心肌组织各家族热休克蛋白基因表达(HSP27mRNA, HSP70mRNA, HSP90mRNA); TUNEL法检测心肌细胞凋亡指数；免疫组化法检测心肌组织Fas/FasL蛋白表达。
结果：
(1)造模后,缺血再灌注组家兔心肌组织形态学改变最明显,假手术组家兔心肌组织形态学改变最轻,三个时相下血清CK浓度在两组间的差异均有统计学意义(P<0.05或P<0.01),说明造模成功；电针预处理组家兔心肌组织形态学较缺血再灌注组明显改善,其血清CK浓度在24h与48h两个时相与缺血再灌注组比较有显著性差异(P<0.05),但本组两时相(24h、48h)之间比较无显著性差异(P>0.05)
(2)与假手术组比较,缺血再灌注组家兔心肌PKC的表达增加(P<0.05)；同样与假手术组比较,电针预处理组则增加更为显著(P<0.01),且高于缺血再灌注组(P<0.05)。
(3)与假手术组比较,缺血再灌注组家兔心肌HSP70mRNA的表达增加(P<0.05)；同样与假手术组比较,电针预处理组则增加更为显著(P<0.01),且高于缺血再灌注组5), HSP70mRNA表达水平在各组间的变化趋势与PKC完全一致。HSP27mRNA及HSP90mRNA表达水平在各组有类似HSP70mRNA的变化趋势,但无统计学支持(P>0.05)。
(4)与假手术组比较,缺血再灌注组心肌细胞凋亡指数显著升高(P<0.01)；与缺血再灌注组比较,电针预处理组心肌凋亡指数有明显降低(P<0.05)。
(5)与假手术组比较,缺血再灌注组Fas、FasL的表达均显著增加(P<0.05)；与缺血再灌注组比较,电针预处理组Fas、FasL勺表达均有显著下降(P<0.05)。
结论：
(1)改良法制备家兔心肌缺血再灌注损伤模型的流程有效、可行,能保证研究的需要。
(2)电针预处理可明显改善缺血再灌注损伤家兔心肌组织形态学,能在24h、48h两个时相降低血清CK浓度,显示出良好的延迟相保护效应。
(3)施以本研究设定的刺激量后,电针预处理未能诱导出快速相保护效应。
(4)电针预处理可在延迟时相进一步激活因缺血再灌注损伤而升高的PKC活性,并能有效诱导HSP70mRNA的表达,提示：激活"PKC磷酸化-HSP70"是电针启动延迟相保护的关键步骤。
(5)在HSP各家族中,HSP70对电针预处理的应答具有相对特异性。
(6)电针预处理可在延迟时相有效抑制缺血再灌注损伤条件下的心肌细胞凋亡,并能下调死亡受体通路Fas/FasL系统的表达,提示：下调"Fas/FasL—细胞凋亡”是电针实现延迟相保护的重要途径。
Object:To explore the molecular biology basis of the theory on disease prevention and health protection of acupuncture pretreatment and to study the mechanism of delayed protection about electroacupuncture pretreatment on rabbit's myocardial ischemia reperfusion injury by observing the prevention effects, the contents of CK in rabbit's blood, the expression of important intermediary material in myocardial protection (PKC)、effect material (HSP27mRNA、HSP70mRNA、HSP90mRNA) and the proteins of death receptor pathway in cell apoptosis(Fas/FasL)
Methods:New Zealand big ear white rabbits were randomly allocated to sham operation(sham), ischemia reperfusion(IR) and electroacupuncture pretreatment (EP) groups,setting three phase(0h、24h、48h). The animal model of rabbits with myocardial ischemia reperfusion injury was established by improved method.The electroacupuncture pretreatment at acupoints Neiguan was used as the test factor.The pathological morphology changes in ischemia tissue of left ventricular were observed under the light microscope. The ultrastructure changes in ischemia tissue of left ventricular were observed under the electron microscope.The contents of CK in blood serum were detected by ELISA. The expressions of PKC in myocardial tissue were detected by Western Blot. The gene expressions of HSP from multi-family (HSP27mRNA、 HSP70mRNA. HSP90mRNA) in myocardial tissue were detected by RT-PCR. The apoptotic index of myocardium were detected by TUNEL. The expressions of Fas/FasL in myocardial tissue were detected by immunohistochemistry.
Results:
(1)After modeled, the morphology change of myocardial tissue in IR group rabbit is most obvious,those in sham group is most light, the concentration of serum CK is statistically different in three phase between the two groups (P<0.05or P<0.01), indicating the molding's success; the myocardial tissue morphology in EP group is obviously improved than those in IR group, and its serum CK concentration has significant difference with IR group in24h and48h (P<0.05), but those in two phase (24、48h) have no significant difference (P>0.05)..
(2) Compared with sham group, the expression of PKC was obviously increased in IR group (P<0.05); similarly compared with sham group,those in EP group increased more significantly (P<0.01), and higher than those in IR group (P<0.05).
(3) Compared with sham group, the expression of HSP70mRNA was obviously increased in IR group (P<0.05); similarly compared with sham group,those in EP group increased more significantly (P<0.01), and higher than those in IR group (P<0.05), the change trend of HSP70mRNA in each group was completely consistent with those of PKC. The change trend of HSP27mRNA and HSP90mRNA was similar with HSP70mRNA, but had no statistical support (P>0.05)..
(4) Compared with sham group, the apoptosis index of myocardial cell in IR group increased significantly (P<0.01); And compared with IR group,those in EP group dropped significantly (P<0.05)..
(5)Compared with sham group, the expression of Fas/FasL in IR group was significantly increased (P<0.05); And compared with IR group,those in EP group dropped significantly (P<0.05).
Conclusion:
(1) The improved methods of making rabbit model on myocardial ischemia reperfusion injury is effective and feasible, and can guarantee the need of research..
(2)Electroacupuncture pretreatment can obviously improve the morphology of rabbit myocardial tissue in ischemia reperfusion injury, can reduce the concentration of serum CK in24h and48h,showing good delayed protection.
(3)With the stimulus quantity setted in this research set, electroacupuncture pretreatment can not induce a fast phase protection.
(4) Electroacupuncture pretreatment can further the activation of PKC improved by ischemia reperfusion injury in delayed time, and can effectively induce the expression of HSP70mRNA.Activating"PKC phosphorylation-HSP70" is the key step of electroacupuncture starting delayed protection.
(5)In multi-family of HSP,HSP70has specific response with electroacupunc-ture pretreatment.
(6)In delayed time,electroacupuncture pretreatment can inhibit myocardial cell apoptosis in ischemia reperfusion injury, and can down-regulate the expression of death receptor pathway Fas/FasL system. Down-regulating "Fas/FasL-cell apoptosis" is the important way of electroacupuncture pretreatment realizing delayed protection.
方法：新西兰大耳白兔随机分为3组,即假手术组、缺血再灌注组、电针预处理组,并设定0h、24h及48h三个时相。采用自拟改良法制备家兔心肌缺血再灌注损伤模型,以电针内关预处理为被试因素,光镜下观察左心室缺血区组织病理形态学变化；电镜下观察左心室缺血区组织超微结构的变化；采用ELISA法检测血清CK含量；Vestern Blot技术检测心肌组织PKC表达；RT-PCR技术检测心肌组织各家族热休克蛋白基因表达(HSP27mRNA, HSP70mRNA, HSP90mRNA); TUNEL法检测心肌细胞凋亡指数；免疫组化法检测心肌组织Fas/FasL蛋白表达。
结果：
(1)造模后,缺血再灌注组家兔心肌组织形态学改变最明显,假手术组家兔心肌组织形态学改变最轻,三个时相下血清CK浓度在两组间的差异均有统计学意义(P<0.05或P<0.01),说明造模成功；电针预处理组家兔心肌组织形态学较缺血再灌注组明显改善,其血清CK浓度在24h与48h两个时相与缺血再灌注组比较有显著性差异(P<0.05),但本组两时相(24h、48h)之间比较无显著性差异(P>0.05)
(2)与假手术组比较,缺血再灌注组家兔心肌PKC的表达增加(P<0.05)；同样与假手术组比较,电针预处理组则增加更为显著(P<0.01),且高于缺血再灌注组(P<0.05)。
(3)与假手术组比较,缺血再灌注组家兔心肌HSP70mRNA的表达增加(P<0.05)；同样与假手术组比较,电针预处理组则增加更为显著(P<0.01),且高于缺血再灌注组5), HSP70mRNA表达水平在各组间的变化趋势与PKC完全一致。HSP27mRNA及HSP90mRNA表达水平在各组有类似HSP70mRNA的变化趋势,但无统计学支持(P>0.05)。
(4)与假手术组比较,缺血再灌注组心肌细胞凋亡指数显著升高(P<0.01)；与缺血再灌注组比较,电针预处理组心肌凋亡指数有明显降低(P<0.05)。
(5)与假手术组比较,缺血再灌注组Fas、FasL的表达均显著增加(P<0.05)；与缺血再灌注组比较,电针预处理组Fas、FasL勺表达均有显著下降(P<0.05)。
结论：
(1)改良法制备家兔心肌缺血再灌注损伤模型的流程有效、可行,能保证研究的需要。
(2)电针预处理可明显改善缺血再灌注损伤家兔心肌组织形态学,能在24h、48h两个时相降低血清CK浓度,显示出良好的延迟相保护效应。
(3)施以本研究设定的刺激量后,电针预处理未能诱导出快速相保护效应。
(4)电针预处理可在延迟时相进一步激活因缺血再灌注损伤而升高的PKC活性,并能有效诱导HSP70mRNA的表达,提示：激活"PKC磷酸化-HSP70"是电针启动延迟相保护的关键步骤。
(5)在HSP各家族中,HSP70对电针预处理的应答具有相对特异性。
(6)电针预处理可在延迟时相有效抑制缺血再灌注损伤条件下的心肌细胞凋亡,并能下调死亡受体通路Fas/FasL系统的表达,提示：下调"Fas/FasL—细胞凋亡”是电针实现延迟相保护的重要途径。
Object:To explore the molecular biology basis of the theory on disease prevention and health protection of acupuncture pretreatment and to study the mechanism of delayed protection about electroacupuncture pretreatment on rabbit's myocardial ischemia reperfusion injury by observing the prevention effects, the contents of CK in rabbit's blood, the expression of important intermediary material in myocardial protection (PKC)、effect material (HSP27mRNA、HSP70mRNA、HSP90mRNA) and the proteins of death receptor pathway in cell apoptosis(Fas/FasL)
Methods:New Zealand big ear white rabbits were randomly allocated to sham operation(sham), ischemia reperfusion(IR) and electroacupuncture pretreatment (EP) groups,setting three phase(0h、24h、48h). The animal model of rabbits with myocardial ischemia reperfusion injury was established by improved method.The electroacupuncture pretreatment at acupoints Neiguan was used as the test factor.The pathological morphology changes in ischemia tissue of left ventricular were observed under the light microscope. The ultrastructure changes in ischemia tissue of left ventricular were observed under the electron microscope.The contents of CK in blood serum were detected by ELISA. The expressions of PKC in myocardial tissue were detected by Western Blot. The gene expressions of HSP from multi-family (HSP27mRNA、 HSP70mRNA. HSP90mRNA) in myocardial tissue were detected by RT-PCR. The apoptotic index of myocardium were detected by TUNEL. The expressions of Fas/FasL in myocardial tissue were detected by immunohistochemistry.
Results:
(1)After modeled, the morphology change of myocardial tissue in IR group rabbit is most obvious,those in sham group is most light, the concentration of serum CK is statistically different in three phase between the two groups (P<0.05or P<0.01), indicating the molding's success; the myocardial tissue morphology in EP group is obviously improved than those in IR group, and its serum CK concentration has significant difference with IR group in24h and48h (P<0.05), but those in two phase (24、48h) have no significant difference (P>0.05)..
(2) Compared with sham group, the expression of PKC was obviously increased in IR group (P<0.05); similarly compared with sham group,those in EP group increased more significantly (P<0.01), and higher than those in IR group (P<0.05).
(3) Compared with sham group, the expression of HSP70mRNA was obviously increased in IR group (P<0.05); similarly compared with sham group,those in EP group increased more significantly (P<0.01), and higher than those in IR group (P<0.05), the change trend of HSP70mRNA in each group was completely consistent with those of PKC. The change trend of HSP27mRNA and HSP90mRNA was similar with HSP70mRNA, but had no statistical support (P>0.05)..
(4) Compared with sham group, the apoptosis index of myocardial cell in IR group increased significantly (P<0.01); And compared with IR group,those in EP group dropped significantly (P<0.05)..
(5)Compared with sham group, the expression of Fas/FasL in IR group was significantly increased (P<0.05); And compared with IR group,those in EP group dropped significantly (P<0.05).
Conclusion:
(1) The improved methods of making rabbit model on myocardial ischemia reperfusion injury is effective and feasible, and can guarantee the need of research..
(2)Electroacupuncture pretreatment can obviously improve the morphology of rabbit myocardial tissue in ischemia reperfusion injury, can reduce the concentration of serum CK in24h and48h,showing good delayed protection.
(3)With the stimulus quantity setted in this research set, electroacupuncture pretreatment can not induce a fast phase protection.
(4) Electroacupuncture pretreatment can further the activation of PKC improved by ischemia reperfusion injury in delayed time, and can effectively induce the expression of HSP70mRNA.Activating"PKC phosphorylation-HSP70" is the key step of electroacupuncture starting delayed protection.
(5)In multi-family of HSP,HSP70has specific response with electroacupunc-ture pretreatment.
(6)In delayed time,electroacupuncture pretreatment can inhibit myocardial cell apoptosis in ischemia reperfusion injury, and can down-regulate the expression of death receptor pathway Fas/FasL system. Down-regulating "Fas/FasL-cell apoptosis" is the important way of electroacupuncture pretreatment realizing delayed protection.
引文
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