Caveolin-3在病毒性心肌炎小鼠中的作用及银杏叶提取物干预的研究
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摘要
病毒性心肌炎（viral myocarditis，VMC）是小儿最常见心血管系统疾病，病情轻重不一，多数患儿预后良好，部分患儿可发展为扩张型心肌病、致残性心律失常。VMC的发病机制尚不明确，涉及病毒的直接损伤、免疫机制、细胞凋亡、心肌纤维化、生化机制等，免疫机制一直以来是研究的热点。小凹（caveolae）是定位于细胞质膜上的膜结构，可从细胞质膜上脱落下来形成囊泡，把细胞外的生物活性分子通过吞饮作用向胞内转移、参与多种信号转导过程。小凹蛋白-3（Caveolin-3）主要表达在心脏，骨骼和平滑肌的肌细胞中。研究表明， TGF-β1及其下游蛋白smad3构成的信号通路在心肌纤维化的发生中具有重要作用；Caveolin参与冠心病、心肌病、糖尿病大血管病变等多种疾病的发展过程。在病毒性心肌炎发生机制中，Caveolin-3的作用以及Caveolin-3是否可调控TGF-β1/smad3信号通路的表达目前尚未见报道。银杏叶提取物具有广泛的药理作用，如具有改善毛细血管的通透性、扩张冠状动脉、改善心肌血液循环、降低心肌细胞耗氧量等多种功能，临床已用于心血管疾病、肾病综合征、糖尿病、老年痴呆等心脑血管疾病的预防和治疗。
本研究用CVB3感染大鼠原代心肌细胞，同时加入银杏叶提取物，检测银杏叶提取物对大鼠心肌细胞的保护作用及毒性作用，同时通过western-blot、免疫组化方法检测大鼠心肌细胞内Cav-3、TGF-β1、smad3蛋白表达量变化。另外，通过CVB3感染Balb/C小鼠建立病毒性心肌炎小鼠模型，通过HE染色观察小鼠心肌病理变化，通过Masson染色观察各组小鼠心肌纤维化程度；然后分别通过RT-PCR、western-blot、免疫组化方法检测小鼠心肌Cav-3、TGF-β1、smad3蛋白表达量及mRNA变化。体内、体外实验结果显示，Cav-3、TGF-β1及smad3蛋白在病毒感染后表达增加，银杏叶提取物能够改善小鼠心肌病理变化，降低心肌纤维化程度，银杏叶提取物是通过下调Cav-3、TGF-β1及其下游蛋白smad3的表达，以实现治疗病毒性心肌炎的作用，其治疗效果与参麦注射液相当，为临床应用银杏叶提取物治疗VMC提供了理论和实验依据。
本研究创新点：（1）Cav-3、TGF-β1及smad3蛋白在病毒性心肌炎中的作用少见报道，本研究显示其在病毒性心肌炎发病中具有一定的作用；（2）本研究探讨了银杏提取物对病毒性心肌炎中的Cav-3、TGF-β1和smad3蛋白表达的影响，及其对病毒性心肌炎的治疗作用。
Viral myocarditis is one common cardiovascular disease of Clinical Pediatrics,which caused by Virus infection, can lead to cardiac muscle degeneration necrosis andits incidence rising rencently, the VMC has become one of the main causes ofunexplained sudden death among teenagers,further more the chronic VMC candevelop to dilated cardiomyopathy，and threaten children’s health severely. Thepathogenesis of VMC is not yet fully understood, which refers to myocardial directinjury caused by virus, inflammatory reaction and immune response in common. Asmyocardial fibrosis is one most important pathological process of VMC, and theCav-3-TGF-β1-smad3signal pathway plays an important role in fibrosis, so weinferred that this signal pathway also has an important role in VMC, if regulatedtheir expression, we may can cure VMC, and this signal pathway maybe a clinicalcare target of VMC.
Extract of ginkgo biloba(EGB) has widely pharmacological value, such asantagonist of platelet active factor, scavenge harmful free radicals, anti-inflammatory,antianaphylaxis, and so on.EGB is used in the clinical treatment of cerebral vascular function obstacles andperipheral vascular disease, include alzheimer’s disease, parkinson’s disease, brainand retina ischemia, memory loss and intermittent limp, and so on. So we inferred thatEGB can antagonize CVB3infection, improve mice heart pathological changes, andEGB is expected to cure VMC.
（1）Vitro experimental study of the role of Caveolin-3in viral myocarditis and the therapeutic efficacy of EGB
Materials and methods: We get the fetal rats which are borned in24hours, andgained the cardiocytes, then exposed to the EGB, tested the activity of cardiocytesthrough MMT method to check toxicity of EGB, then infected cardiocytes with CVB3,and tested the activity of cardiocytes through MMT method to determine theconcentration of CVB3, then we infected cardiocytes with this concentration of CVB3,and added EGB, then tested the activity of cardiocytes through MMT method to checkthe protective activity of EGB, meanwhile we tested the expression of Cav-3、TGF-β1、smad3through western blot, immunohistochemical staining methods, thenwe can observe whether EGB can affect the expression of Cav-3,TGF-β1and smad3,so we can offer basis for viral myocarditis pathogenesis research and clinicaltreatment.
Result: First we isolated and got cardiocytes successfully, each concentration ofEGB has no toxicity on cardiocytes, the cell survival rate of cardiocytes was morethan75%after exposed to EGB for24h and48h, so we selected1750μg/mL of EGBfor next research. When the concentration of EGB is reach to54μg/mL,it hasprotective effect against the CVB3infection, and the cell survival rate of cardiocyteswas more than75%, so we select selected1750μg/mL of EGB for next research. Afterdetected the expression of Cav-3、 TGF-β1、 smad3through western blot,immunohistochemical staining methods, we found that EGB can down regulate theexpression of this signal pathway, which was much lower than virus model group withstatistically significant difference, P<0.05.
Conclusions: EGB has no toxicity on cardiocytes, but has protective effect against theCVB3infection, which through reducing the expression of Cav-3,TGF-β1,smad3, itsugges that EGB can down regulate the signal pathway to protect cardiocytes againstCVB3infection, which can offer basis for viral myocarditis pathogenesis research andclinical treatment.
（2）Vivo experimental study of the role of Caveolin-3in viral myocarditis and thetherapeutic efficacy of EGB
Materials and methods: We choose160pure bred Balb/c mice aged4weeks and divide their into control group statistically up (n=40) and VMC group (n=120)randomly, the VMC group: VMC model was established by injecting intraperitoneallyo.1mL102TCID50CVB3solution, while the control group was injected with0.1mLEngeal’s fluid excluding virus, then divided the120VMC modle into3groupsrandomly, they are VMC-control group (n=40), the EGB group (n=40), the shenmaiinjection group (n=40), the VMC-control group was injected intraperitoneally o.5mLphysiological saline for21days continuously since the day injected the CVB3, theEGB group and the shenmai injection group mice were injected with1ml/kg.d EGB,shenmai injection1ml/kg.d separately for21days continuously since the day injectedthe CVB3. In the day5,day10,day15,day21of injection, we take part of mice ineach group randomly, then killed by cutting necks, obtained the hearts to examinPathological integral and myocardial fibrosis stage of cardiomyocyte through HEstain and Masson stain, then examined the expression of Cav-3,TGF-β1,smad3byRT-PCR and immunohistochemical staining and western-blot separately. Then we canobserve whether EGB can effect Cav-3,TGF-β1and smad3signal pathway, so we canoffer basis for viral myocarditis pathogenesis research and clinical treatment.
Result: The pathological integral of cardiomyocyte of VMC-control group miceincreased with the extension of time, which was much higher than the control group ateach stage, difference was significant, P<0.01. After injected with EGB, thepathological integral of EGB group mice decreased, and much lower thanVMC-control group, difference was significant, P<0.01, but difference of pathologicalintegral of EGB group and shenmai injection group was not significant,P>0.05. TheVMC-control group mice emerged collagen at day5, and myocardial cell gapincreases, the CVF increased with the extension of time, which was much higher thanthe control group at each stage, difference was significant, P<0.01. The CVF of EGBgroup and shenmai injection group also increased with the extension of time, but wasmuch lower than the VMC-control group at each stage, difference was significant,P<0.01, but the difference of pathological integral of EGB group and shenmaiinjection group was not significant,P>0.05. The expression of Cav-3、TGF-β1、smad3of VMC-control group mice was much higher than the control group at each stage detected by RT-PCR and immunohistochemical staining and western-blot, differencewas significant, P<0.01. After injected with EGB, the pathological integral of EGBgroup mice decreased, and much lower than VMC-control group, difference at eachstage was significant excepted at day5and day10, P<0.05,, but the expression ofthis signal pathway in EGB group and shenmai injection group has no difference,P>0.05.
Conclusions: EGB can improve the pathological integral of VMC micecardiomyocyte, decrease CVF, and also improve VMC mice heart fouction. EGB canantagonize VMC through regulate the expression of Cav-3, TGF-β1and smad3signalpathway. EGB can be used for the clinical treatment of VMC.
本研究用CVB3感染大鼠原代心肌细胞，同时加入银杏叶提取物，检测银杏叶提取物对大鼠心肌细胞的保护作用及毒性作用，同时通过western-blot、免疫组化方法检测大鼠心肌细胞内Cav-3、TGF-β1、smad3蛋白表达量变化。另外，通过CVB3感染Balb/C小鼠建立病毒性心肌炎小鼠模型，通过HE染色观察小鼠心肌病理变化，通过Masson染色观察各组小鼠心肌纤维化程度；然后分别通过RT-PCR、western-blot、免疫组化方法检测小鼠心肌Cav-3、TGF-β1、smad3蛋白表达量及mRNA变化。体内、体外实验结果显示，Cav-3、TGF-β1及smad3蛋白在病毒感染后表达增加，银杏叶提取物能够改善小鼠心肌病理变化，降低心肌纤维化程度，银杏叶提取物是通过下调Cav-3、TGF-β1及其下游蛋白smad3的表达，以实现治疗病毒性心肌炎的作用，其治疗效果与参麦注射液相当，为临床应用银杏叶提取物治疗VMC提供了理论和实验依据。
本研究创新点：（1）Cav-3、TGF-β1及smad3蛋白在病毒性心肌炎中的作用少见报道，本研究显示其在病毒性心肌炎发病中具有一定的作用；（2）本研究探讨了银杏提取物对病毒性心肌炎中的Cav-3、TGF-β1和smad3蛋白表达的影响，及其对病毒性心肌炎的治疗作用。
Viral myocarditis is one common cardiovascular disease of Clinical Pediatrics,which caused by Virus infection, can lead to cardiac muscle degeneration necrosis andits incidence rising rencently, the VMC has become one of the main causes ofunexplained sudden death among teenagers,further more the chronic VMC candevelop to dilated cardiomyopathy，and threaten children’s health severely. Thepathogenesis of VMC is not yet fully understood, which refers to myocardial directinjury caused by virus, inflammatory reaction and immune response in common. Asmyocardial fibrosis is one most important pathological process of VMC, and theCav-3-TGF-β1-smad3signal pathway plays an important role in fibrosis, so weinferred that this signal pathway also has an important role in VMC, if regulatedtheir expression, we may can cure VMC, and this signal pathway maybe a clinicalcare target of VMC.
Extract of ginkgo biloba(EGB) has widely pharmacological value, such asantagonist of platelet active factor, scavenge harmful free radicals, anti-inflammatory,antianaphylaxis, and so on.EGB is used in the clinical treatment of cerebral vascular function obstacles andperipheral vascular disease, include alzheimer’s disease, parkinson’s disease, brainand retina ischemia, memory loss and intermittent limp, and so on. So we inferred thatEGB can antagonize CVB3infection, improve mice heart pathological changes, andEGB is expected to cure VMC.
（1）Vitro experimental study of the role of Caveolin-3in viral myocarditis and the therapeutic efficacy of EGB
Materials and methods: We get the fetal rats which are borned in24hours, andgained the cardiocytes, then exposed to the EGB, tested the activity of cardiocytesthrough MMT method to check toxicity of EGB, then infected cardiocytes with CVB3,and tested the activity of cardiocytes through MMT method to determine theconcentration of CVB3, then we infected cardiocytes with this concentration of CVB3,and added EGB, then tested the activity of cardiocytes through MMT method to checkthe protective activity of EGB, meanwhile we tested the expression of Cav-3、TGF-β1、smad3through western blot, immunohistochemical staining methods, thenwe can observe whether EGB can affect the expression of Cav-3,TGF-β1and smad3,so we can offer basis for viral myocarditis pathogenesis research and clinicaltreatment.
Result: First we isolated and got cardiocytes successfully, each concentration ofEGB has no toxicity on cardiocytes, the cell survival rate of cardiocytes was morethan75%after exposed to EGB for24h and48h, so we selected1750μg/mL of EGBfor next research. When the concentration of EGB is reach to54μg/mL,it hasprotective effect against the CVB3infection, and the cell survival rate of cardiocyteswas more than75%, so we select selected1750μg/mL of EGB for next research. Afterdetected the expression of Cav-3、 TGF-β1、 smad3through western blot,immunohistochemical staining methods, we found that EGB can down regulate theexpression of this signal pathway, which was much lower than virus model group withstatistically significant difference, P<0.05.
Conclusions: EGB has no toxicity on cardiocytes, but has protective effect against theCVB3infection, which through reducing the expression of Cav-3,TGF-β1,smad3, itsugges that EGB can down regulate the signal pathway to protect cardiocytes againstCVB3infection, which can offer basis for viral myocarditis pathogenesis research andclinical treatment.
（2）Vivo experimental study of the role of Caveolin-3in viral myocarditis and thetherapeutic efficacy of EGB
Materials and methods: We choose160pure bred Balb/c mice aged4weeks and divide their into control group statistically up (n=40) and VMC group (n=120)randomly, the VMC group: VMC model was established by injecting intraperitoneallyo.1mL102TCID50CVB3solution, while the control group was injected with0.1mLEngeal’s fluid excluding virus, then divided the120VMC modle into3groupsrandomly, they are VMC-control group (n=40), the EGB group (n=40), the shenmaiinjection group (n=40), the VMC-control group was injected intraperitoneally o.5mLphysiological saline for21days continuously since the day injected the CVB3, theEGB group and the shenmai injection group mice were injected with1ml/kg.d EGB,shenmai injection1ml/kg.d separately for21days continuously since the day injectedthe CVB3. In the day5,day10,day15,day21of injection, we take part of mice ineach group randomly, then killed by cutting necks, obtained the hearts to examinPathological integral and myocardial fibrosis stage of cardiomyocyte through HEstain and Masson stain, then examined the expression of Cav-3,TGF-β1,smad3byRT-PCR and immunohistochemical staining and western-blot separately. Then we canobserve whether EGB can effect Cav-3,TGF-β1and smad3signal pathway, so we canoffer basis for viral myocarditis pathogenesis research and clinical treatment.
Result: The pathological integral of cardiomyocyte of VMC-control group miceincreased with the extension of time, which was much higher than the control group ateach stage, difference was significant, P<0.01. After injected with EGB, thepathological integral of EGB group mice decreased, and much lower thanVMC-control group, difference was significant, P<0.01, but difference of pathologicalintegral of EGB group and shenmai injection group was not significant,P>0.05. TheVMC-control group mice emerged collagen at day5, and myocardial cell gapincreases, the CVF increased with the extension of time, which was much higher thanthe control group at each stage, difference was significant, P<0.01. The CVF of EGBgroup and shenmai injection group also increased with the extension of time, but wasmuch lower than the VMC-control group at each stage, difference was significant,P<0.01, but the difference of pathological integral of EGB group and shenmaiinjection group was not significant,P>0.05. The expression of Cav-3、TGF-β1、smad3of VMC-control group mice was much higher than the control group at each stage detected by RT-PCR and immunohistochemical staining and western-blot, differencewas significant, P<0.01. After injected with EGB, the pathological integral of EGBgroup mice decreased, and much lower than VMC-control group, difference at eachstage was significant excepted at day5and day10, P<0.05,, but the expression ofthis signal pathway in EGB group and shenmai injection group has no difference,P>0.05.
Conclusions: EGB can improve the pathological integral of VMC micecardiomyocyte, decrease CVF, and also improve VMC mice heart fouction. EGB canantagonize VMC through regulate the expression of Cav-3, TGF-β1and smad3signalpathway. EGB can be used for the clinical treatment of VMC.
引文
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