重组腺病毒Ad-hBNP对慢性心力衰竭大鼠治疗作用的研究
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摘要
目的：
本研究旨在探索BNP治疗心力衰竭的新途径。通过构建重组腺病毒Ad-hBNP，制备CHF大鼠模型，观察外源基因hBNP导入动物机体后在动物体内的分布及表达，探讨BNP对CHF治疗作用及其机制，为今后BNP基因治疗的临床应用提供基础研究的理论依据。
方法：
1．构建重组腺病毒Ad-hBNP RT-PCR方法从人心肌组织获得hBNP片段，与pUCm-T载体连接构成pUC-hBNP重组质粒；KpnⅠ、SalⅠ分别双酶切pUC-hBNP和pAdTrack-CMV，将目的片段插入pAdTrack-CMV构建pAdTrack-hBNP重组质粒；pAdTrack-hBNP重组质粒经PmeⅠ酶切线性化后，电转法转入含有腺病毒骨架质粒的E．coilBJ5183感受态细胞中，同源重组获得重组质粒pAdEasy-hBNP；经BamHI、PacⅠ酶切鉴定及基因序列检测后，重组成功的pAdEasy-hBNP经阳离子脂质体法转染293T细胞，经过包装、扩增和纯化后，获得可用于实验性基因治疗的重组腺病毒Ad-hBNP。
2．制备CHF大鼠模型采用腹主动脉缩窄法制备CHF大鼠模型。于右肾动脉分支处上方缩窄腹主动脉至0．6mm，同时设立假手术组及正常对照组。12周后行超声心动图及血液动力学检测心脏结构和功能、放射免疫分析测定血清AgⅡ和Ald水平、HE染色及Masson染色检测心肌病理学变化、RT-PCR分析心肌胶原mRNA表达，综合评价CHF大鼠心功能。确定动物实验CHF大鼠入选标准。
3．研究重组腺病毒Ad-hBNP对CHF大鼠的治疗作用
(1)观察CHF大鼠接受Ad-hBNP治疗后，hBNP在体内的分布与表达CHF大鼠24只，18只单次腹腔注射重组腺病毒Ad-hBNP后，随机均分为1天组、4天组和7天组；另6只CHF大鼠不予以重组腺病毒，记为0点组。各实验组动物于相应的时间处死，ELISA检测血清hBNP水平，免疫组化检测CHF大鼠各脏器hBNP的表达，RT-PCR检测各组织hBNP mRNA的表达。
(2)观察Ad-hBNP对CHF大鼠的治疗效果30只CHF大鼠，随机分为Ad-hBNP组、Ad-Track组、NS组，另设假手术组不予任何治疗作为对照组，分别经腹腔注射予以相应治疗，每周一次，共4周。4周后实验动物行超声心动图及血液动力学检测，ELISA检测血清hBNP水平，放射免疫分析测定血清AgⅡ、Ald、ET及TNF-α含量，RT-PCR分析心肌胶原mRNA表达水平。
结果：
1．应用Ad-Easy缺陷性腺病毒载体系统成功构建重组腺病毒Ad-hBNP，纯化后Ad-hBNP病毒滴度达到4．4275×10~(12)VP／ml。透射电镜观察Ad-hBNP呈多面体结构，颗粒直径在90nm左右。
2．腹主动脉缩窄术12周后，经超声心动图和血液动力学检测、神经内分泌指标、病理学及RT-PCR测定心肌胶原mRNA表达等多种途径，并结合临床表现综合评价，证实CHF动物模型造模成功。确定在体动物实验CHF大鼠的入选标准：(1)大鼠腹主动脉结扎术后12周，出现进食量减少，精神萎靡，少活动，被毛无光泽、蓬松。(2)超声心动图检测指标：LVESD＞0．32cm、VLEDD＞0．65cm，EF＜75％，FS＜40％。
3．单次腹腔注射Ad-hBNP，CHF大鼠心脏、肝脏、肺脏、肾脏、脾脏及小肠均检测到hBNP表达，外源性hBNP在CHF大鼠体内的表达至少可持续7天。
4．间断重组腺病毒Ad-hBNP治疗，CHF大鼠IVS、LVEDD、LVESD、LVPW显著降低，而EF、FS显著增高；同时CHF大鼠心功能明显改善，表现为HR显著降低，LVSP和+dP／dt_(max)显著升高及LVEDP降低和-dP／dt_(max)绝对值升高。
5．与Ad-Track组及NS组比较，Ad-hBNP组血清AgⅡ、Ald、ET及TNF-α水平较明显下降；心肌组织Ⅰ、Ⅲ型胶原mRNA表达显著降低。
结论：
1．应用Ad-Easy缺陷性腺病毒载体系统可成功构建重组腺病毒Ad-hBNP。
2．利用腹主动脉缩窄术可成功制备CHF大鼠模型。
3．单次腹腔注射Ad-hBNP，外源hBNP基因可在CHF大鼠多脏器中得到有效表达，其生物学效应时间显著长于BNP的生物半衰期。
4．间断给予Ad-hBNP能够有效地改善CHF大鼠心脏结构、功能及心室重构。BNP可能在抑制循环或局部神经内分泌—细胞因子水平发挥作用，对抗心室重构。
应用BNP治疗CHF是否有益目前尚存争议，本研究就此问题得出了初步结果，认为BNP基因治疗心力衰竭是一种新的尝试，为开展BNP基因治疗临床应用提供了基础研究的理论参考。目前国内外尚无BNP基因治疗CHF的相关报道。
Objective
To explore a new way of CHF treatment by BNP.Ad-hBNP were constructed andCHF rats were also prepared for observing the distribution and the expression of hBNPgene in CHF rats and evaluating the therapeutic effect of BNP on CHF rats through thegene therapy in vivo.This may lead to elaborate the CHF treatment by BNP and itsmechanism and provide a reference of basic research for BNP in gene therapy.
Methods
1.The target gene hBNP were obstained by reverse transcription polymerasechain reaction from human heart.The product of RT-PCR were ligated with pUCm-Tvectors to form pUC-hBNP.After pUC-hBNP were digested with KpnI and SalI,thetarget fragments were subcloned into shuttle plasimid pAdTrack-CMV.The resultantplasmid pAdTrack-hBNP,after linearized by PmeI,were transformed intoE.coilBJ5183 including adenoviral backbone plasmid pAdEasy-1,then therecombinant plasmid pAdEasy-hBNP were constructed.The pAdEasy-hBNP wereconfirmed by BamHI and PacI,then by DNA sequencing.Recombinant plasmidpAdEasy-hBNP linearized by PacI were transfected into 293T cells.The recombinantadenovirus Ad-hBNP were packaged and amplified in 293T cells.Determin the titer ofpurified recombinant adenovirus and observe the shape of recombinant adenovirus.
2.The CHF rats were prepared by abdominal aorta constriction to 0.6mm.After12 weeks,echocadiagraphy,hemodynamics parameters,radioimmunoassay of serumlevels of AgII and Ald,pathological HE staining and Masson staining,RT-PCRanalysis of the expression of myocardial collagen mRNA were all performed toevaluate the cardiac function of CHF rats.
3.To observe the distribution and the expression of hBNP gene in CHF rats 24CHF rats were randomly divided into 4 groups for detecting the serum levels of hBNPwith ELISA,the expression of hBNP with RT-PCR and immunohistochemistry indifferent groups.To elaborate the CHF treatment by BNP and its mechanism 30 CHFrats were randomly divided into Ad-hBNP group,Ad-Track group,NS group and 10sham-operated rats as control group.After 4 weeks treatment,echocadiagraphy, hemodynamics parameters,radioimmunoassay of serum levels of AgII,Ald,ET,TNF-αand RT-PCR analysis of the expression of myocardial collagen mRNA wereperformed to evaluate the cardiac function and the ventricular remodeling.
Result
Ad-hBNP were constructed successfully and the titer of purified adenovirus was4.4275×10~(12)VP/ml.Recombinant adenoviruses were showed as polyhedron shapeunder electron microscopy.CHF rats were prepared and CHF rats for the experiment invivo must show symptoms of CHF,at the same time the criterions of echocadiagraphywere LVESD＞0.32cm,VLEDD＞0.65cm,EF＜75% and FS＜40%.The expression ofhBNP gene were detected in CHF rats by intraperitoneal injection Ad-hBNP and itcontinued at least 7 days.By the treatment of Ad-hBNP,the LVPW,IVS,LVEDD andLVESD of the Ad-hBNP group were significantly smaller than the Ad-Track group andthe NS group.Compared with the Ad-Track group and the NS group,hemodynamicsshowed HR,LVEDP decreased and LVSP,+dP/dt_(max) and the absolute of-dP/dt_(max)increased,while the serum levels of AgII,Ald,ET and TNF-α,as well the expressionof myocardial collagen mRNA of CHF rats were reduced.
Conclusion
1.Ad-hBNP were constructed successfully by using Ad-Easy defective adenovirussystem.
2.CHF rats were prepared for the experiment in vivo by abdominal aortaconstriction.
3.Exogenous hBNP were effectively expressed in CHF rats.Compared with thehalf life of BNP,the prosses that at least continued 7 days were significantly extended.
4.BNP improved the cardiac structure and function.It may be play an importantrole in ventricular remodeling by controlling the neuroendocrine and cytokines.
The research showed that Ad-hBNP had a therapeutic role on CHF rats both incardiac function and ventricular remodeling and tried a new way of CHF treatment byBNP.It also provided a reference of basic research for BNP in gene therapy.
本研究旨在探索BNP治疗心力衰竭的新途径。通过构建重组腺病毒Ad-hBNP，制备CHF大鼠模型，观察外源基因hBNP导入动物机体后在动物体内的分布及表达，探讨BNP对CHF治疗作用及其机制，为今后BNP基因治疗的临床应用提供基础研究的理论依据。
方法：
1．构建重组腺病毒Ad-hBNP RT-PCR方法从人心肌组织获得hBNP片段，与pUCm-T载体连接构成pUC-hBNP重组质粒；KpnⅠ、SalⅠ分别双酶切pUC-hBNP和pAdTrack-CMV，将目的片段插入pAdTrack-CMV构建pAdTrack-hBNP重组质粒；pAdTrack-hBNP重组质粒经PmeⅠ酶切线性化后，电转法转入含有腺病毒骨架质粒的E．coilBJ5183感受态细胞中，同源重组获得重组质粒pAdEasy-hBNP；经BamHI、PacⅠ酶切鉴定及基因序列检测后，重组成功的pAdEasy-hBNP经阳离子脂质体法转染293T细胞，经过包装、扩增和纯化后，获得可用于实验性基因治疗的重组腺病毒Ad-hBNP。
2．制备CHF大鼠模型采用腹主动脉缩窄法制备CHF大鼠模型。于右肾动脉分支处上方缩窄腹主动脉至0．6mm，同时设立假手术组及正常对照组。12周后行超声心动图及血液动力学检测心脏结构和功能、放射免疫分析测定血清AgⅡ和Ald水平、HE染色及Masson染色检测心肌病理学变化、RT-PCR分析心肌胶原mRNA表达，综合评价CHF大鼠心功能。确定动物实验CHF大鼠入选标准。
3．研究重组腺病毒Ad-hBNP对CHF大鼠的治疗作用
(1)观察CHF大鼠接受Ad-hBNP治疗后，hBNP在体内的分布与表达CHF大鼠24只，18只单次腹腔注射重组腺病毒Ad-hBNP后，随机均分为1天组、4天组和7天组；另6只CHF大鼠不予以重组腺病毒，记为0点组。各实验组动物于相应的时间处死，ELISA检测血清hBNP水平，免疫组化检测CHF大鼠各脏器hBNP的表达，RT-PCR检测各组织hBNP mRNA的表达。
(2)观察Ad-hBNP对CHF大鼠的治疗效果30只CHF大鼠，随机分为Ad-hBNP组、Ad-Track组、NS组，另设假手术组不予任何治疗作为对照组，分别经腹腔注射予以相应治疗，每周一次，共4周。4周后实验动物行超声心动图及血液动力学检测，ELISA检测血清hBNP水平，放射免疫分析测定血清AgⅡ、Ald、ET及TNF-α含量，RT-PCR分析心肌胶原mRNA表达水平。
结果：
1．应用Ad-Easy缺陷性腺病毒载体系统成功构建重组腺病毒Ad-hBNP，纯化后Ad-hBNP病毒滴度达到4．4275×10~(12)VP／ml。透射电镜观察Ad-hBNP呈多面体结构，颗粒直径在90nm左右。
2．腹主动脉缩窄术12周后，经超声心动图和血液动力学检测、神经内分泌指标、病理学及RT-PCR测定心肌胶原mRNA表达等多种途径，并结合临床表现综合评价，证实CHF动物模型造模成功。确定在体动物实验CHF大鼠的入选标准：(1)大鼠腹主动脉结扎术后12周，出现进食量减少，精神萎靡，少活动，被毛无光泽、蓬松。(2)超声心动图检测指标：LVESD＞0．32cm、VLEDD＞0．65cm，EF＜75％，FS＜40％。
3．单次腹腔注射Ad-hBNP，CHF大鼠心脏、肝脏、肺脏、肾脏、脾脏及小肠均检测到hBNP表达，外源性hBNP在CHF大鼠体内的表达至少可持续7天。
4．间断重组腺病毒Ad-hBNP治疗，CHF大鼠IVS、LVEDD、LVESD、LVPW显著降低，而EF、FS显著增高；同时CHF大鼠心功能明显改善，表现为HR显著降低，LVSP和+dP／dt_(max)显著升高及LVEDP降低和-dP／dt_(max)绝对值升高。
5．与Ad-Track组及NS组比较，Ad-hBNP组血清AgⅡ、Ald、ET及TNF-α水平较明显下降；心肌组织Ⅰ、Ⅲ型胶原mRNA表达显著降低。
结论：
1．应用Ad-Easy缺陷性腺病毒载体系统可成功构建重组腺病毒Ad-hBNP。
2．利用腹主动脉缩窄术可成功制备CHF大鼠模型。
3．单次腹腔注射Ad-hBNP，外源hBNP基因可在CHF大鼠多脏器中得到有效表达，其生物学效应时间显著长于BNP的生物半衰期。
4．间断给予Ad-hBNP能够有效地改善CHF大鼠心脏结构、功能及心室重构。BNP可能在抑制循环或局部神经内分泌—细胞因子水平发挥作用，对抗心室重构。
应用BNP治疗CHF是否有益目前尚存争议，本研究就此问题得出了初步结果，认为BNP基因治疗心力衰竭是一种新的尝试，为开展BNP基因治疗临床应用提供了基础研究的理论参考。目前国内外尚无BNP基因治疗CHF的相关报道。
Objective
To explore a new way of CHF treatment by BNP.Ad-hBNP were constructed andCHF rats were also prepared for observing the distribution and the expression of hBNPgene in CHF rats and evaluating the therapeutic effect of BNP on CHF rats through thegene therapy in vivo.This may lead to elaborate the CHF treatment by BNP and itsmechanism and provide a reference of basic research for BNP in gene therapy.
Methods
1.The target gene hBNP were obstained by reverse transcription polymerasechain reaction from human heart.The product of RT-PCR were ligated with pUCm-Tvectors to form pUC-hBNP.After pUC-hBNP were digested with KpnI and SalI,thetarget fragments were subcloned into shuttle plasimid pAdTrack-CMV.The resultantplasmid pAdTrack-hBNP,after linearized by PmeI,were transformed intoE.coilBJ5183 including adenoviral backbone plasmid pAdEasy-1,then therecombinant plasmid pAdEasy-hBNP were constructed.The pAdEasy-hBNP wereconfirmed by BamHI and PacI,then by DNA sequencing.Recombinant plasmidpAdEasy-hBNP linearized by PacI were transfected into 293T cells.The recombinantadenovirus Ad-hBNP were packaged and amplified in 293T cells.Determin the titer ofpurified recombinant adenovirus and observe the shape of recombinant adenovirus.
2.The CHF rats were prepared by abdominal aorta constriction to 0.6mm.After12 weeks,echocadiagraphy,hemodynamics parameters,radioimmunoassay of serumlevels of AgII and Ald,pathological HE staining and Masson staining,RT-PCRanalysis of the expression of myocardial collagen mRNA were all performed toevaluate the cardiac function of CHF rats.
3.To observe the distribution and the expression of hBNP gene in CHF rats 24CHF rats were randomly divided into 4 groups for detecting the serum levels of hBNPwith ELISA,the expression of hBNP with RT-PCR and immunohistochemistry indifferent groups.To elaborate the CHF treatment by BNP and its mechanism 30 CHFrats were randomly divided into Ad-hBNP group,Ad-Track group,NS group and 10sham-operated rats as control group.After 4 weeks treatment,echocadiagraphy, hemodynamics parameters,radioimmunoassay of serum levels of AgII,Ald,ET,TNF-αand RT-PCR analysis of the expression of myocardial collagen mRNA wereperformed to evaluate the cardiac function and the ventricular remodeling.
Result
Ad-hBNP were constructed successfully and the titer of purified adenovirus was4.4275×10~(12)VP/ml.Recombinant adenoviruses were showed as polyhedron shapeunder electron microscopy.CHF rats were prepared and CHF rats for the experiment invivo must show symptoms of CHF,at the same time the criterions of echocadiagraphywere LVESD＞0.32cm,VLEDD＞0.65cm,EF＜75% and FS＜40%.The expression ofhBNP gene were detected in CHF rats by intraperitoneal injection Ad-hBNP and itcontinued at least 7 days.By the treatment of Ad-hBNP,the LVPW,IVS,LVEDD andLVESD of the Ad-hBNP group were significantly smaller than the Ad-Track group andthe NS group.Compared with the Ad-Track group and the NS group,hemodynamicsshowed HR,LVEDP decreased and LVSP,+dP/dt_(max) and the absolute of-dP/dt_(max)increased,while the serum levels of AgII,Ald,ET and TNF-α,as well the expressionof myocardial collagen mRNA of CHF rats were reduced.
Conclusion
1.Ad-hBNP were constructed successfully by using Ad-Easy defective adenovirussystem.
2.CHF rats were prepared for the experiment in vivo by abdominal aortaconstriction.
3.Exogenous hBNP were effectively expressed in CHF rats.Compared with thehalf life of BNP,the prosses that at least continued 7 days were significantly extended.
4.BNP improved the cardiac structure and function.It may be play an importantrole in ventricular remodeling by controlling the neuroendocrine and cytokines.
The research showed that Ad-hBNP had a therapeutic role on CHF rats both incardiac function and ventricular remodeling and tried a new way of CHF treatment byBNP.It also provided a reference of basic research for BNP in gene therapy.
引文
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