骨髓间充质干细胞移植联合培哚普利对大鼠急性心梗后心室重塑的影响
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摘要
尽管在过去的几十年医学技术有了飞跃发展，但急性心肌梗死(AMI)仍然是影响公众健康的主要问题。为降低AMI的死亡率，人们一直做着不懈的努力，CCU的建立、肺动脉球囊漂浮导管对血流动力学的监测、冠状动脉或静脉内溶栓治疗、经皮冠状动脉内介入等再灌注治疗的开展、药物治疗的应用使得近十年来的AMI死亡率有所下降，但仍有近1／3的病人不治而亡。上述治疗能够在一定程度上挽救尚未死亡的心肌，而对已经死亡的心肌是无能为力的。因此，如果损失的心肌数达到一定程度可以发生心室的重塑，或心室重构，包括心室的扩张、梗死区的变薄、非梗死区的心肌肥厚，心室重塑后心力衰竭、室壁瘤的发生率增加，影响预后。
SAVE研究表明，血管紧张素转换酶抑制剂(ACEI)被认为是治疗AMI的良好药物，在改善AMI生存率。但基础研究发现，对已有心肌肥厚的大鼠，ACEI只能在一定程度上逆转心室重塑，略微减少肥厚心肌的质量。
干细胞是一种具有自我更新和自我分化的细胞，在医学领域中日益受到重视。心肌坏死后不可逆，能否用干细胞修复损伤心肌?自Orlic首次对急性心梗小鼠进行骨髓干细胞移植后发现，新生的心肌组织占据了68％的病变心肌区，使有活性有功能的心肌代替了坏死心肌。干细胞通过旁分泌作用促进血管生成、抗细胞凋亡，还有直接分化成心肌样细胞的能力。
基于干细胞的这种生物学特性，本研究探讨了骨髓间充质干细胞(MSC)移植对心梗后心室重塑的影响，尤其是心脏间质的影响，包括胶原、基质金属蛋白酶的变化，并对心室重塑相关的基因表达情况进行了研究。已有研究表明血管紧张素转换酶抑制剂(ACEI)对心室重塑有一定作用，MSC与ACEI在逆转心室重塑方面是否存在协同作用?有必要进一步研究。
第一部分骨髓间充质干细胞移植联合培哚普利对大鼠急性心梗后基质重塑的影响
急性心肌梗死后的心室重塑在形态学上发生的改变有心室扩大和非梗死区的延伸，在微观上表现为心肌细胞的凋亡，心肌细胞的肥大，间质胶原含量和基质金属蛋白酶的改变。这种重塑可以导致心功能减退，影响预后。因此，在治疗急性心梗时有必要逆转心室重塑。
循环和组织局部肾素血管紧张素醛固酮系统的激活能引起心室重塑。用血管紧张素转化酶抑制剂治疗对逆转心室重塑有一定作用。Optimization研究说明血管紧张素转化酶抑制剂(ACEI)治疗急性心肌梗死有效。
骨髓间充质干细胞(mesenchymal stem cells，MSC)是存在于骨髓微环境中的多能祖细胞，临床研究证明在急性心肌梗死的患者中通过冠脉内注射MSC能够明显改善左心室射血功能。然而，有关MSC移植治疗急性心梗的具体机制仍不是很清楚。本研究的目的在于：探讨MSC移植能否降低急性心梗后的胶原含量，能否减少MMP的表达，与ACEI治疗相比是否存在差异，两者是否存在协同效应?
材料与方法
1 MSC的准备
取实验用的成年雄性SD大鼠，麻醉，消毒，无菌环境下切取大鼠股骨和髂骨，收集后折断，放入无菌离心管中，离心管内预先放置5ml的PBS磷酸盐缓冲溶液，内含7500U肝素钠针剂。将离心管放入超静台内，把含骨片的液体倒入无菌培养皿中，加入DMEM培养液。无菌镊及无菌眼科剪小心刮取骨髓，将混合物移入离心管中，900g，20分钟离心。将上清液缓慢加入淋巴细胞分离液中，900g，25分钟离心。小心吸取中部液体，加入另一管含DMEM的离心管中，900g，25分钟离心。细胞团块用培养液重悬后种植在培养瓶中，放入37℃，5％CO_2培养箱中培养，48小时后换液，洗去未贴壁细胞，贴壁细胞在含20％胎牛血清及青、链霉素双抗的DMEM培养液中培养。每5天换液一次，细胞长满后传代，取第三代细胞移植用。
2 DAPI标记
当MSC完全占满培养瓶底时，换用含DAPI(4′6-Diamidino-2-Phenylindole，50μg／ml)培养液培养24小时。
3大鼠心梗模型的建立
1．选成年雄性SD大鼠40个，体重200～260g，急性心肌梗死模型建立为左冠状动脉前降支结扎法。
4 MSC的移植：
建模成功的40个大鼠随机进入4个处理组：
对照组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将PBS溶液注入心肌内，每点50μl。术后第二天用生理盐水灌胃，每天一次。共6周。
MSC组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将含MSC的PBS溶液注入心肌内，每点50μl。术后第二天用生理盐水灌胃，每天一次。共6周。
ACEI组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将PBS溶液注入心肌内，每点50μl。术后第二天用培哚普利原药灌胃(2mg／kg体重)，每天一次。共6周。
MSC+ACEI组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将含MSC的PBS溶液注入心肌内，每点50μl。术后第二天用培哚普利原药灌胃(2mg／kg体重)，每天一次。共6周。
5组织学处理
组织标本用4％的PBS多聚甲醛固定后，用石蜡包埋，切成10μm厚的切片，做Masson’s三色染色。纤维组织染成蓝颜色。用液氮冷冻固定(组织学用)后，切成4μm厚的切片，直接在荧光显微镜下观察。
6 Western Blotting
测定MMP2，MMP9蛋白表达水平，一抗结合((用5％脱脂奶粉TBS-T溶液配，MMP2，MMP9滴度为1：200；β-actin滴度为1：1000)
7 RT-PCR
测定MMP2，MMP9、TIMP1mRNA表达水平。
8统计分析
计量资料用均数±标准差表示，四组间差异的总体比较采用单因素方差分析，组间两两比较采用LSD法。以P＜0.05为显著差异。
结果
1心脏胶原含量的变化
Masson’s三色染色显示在缺血心肌区域存在胶原，呈蓝色。MSC+ACEI组、ACEI组、MSC组梗死区胶原面积含量低于PBS组。
2心肌梗死区MMP2和MMP9的蛋白表达水平改变(Western Blotting)
PBS组MMP2和MMP9在梗死区组织高表达。在Western Blotting显示72kDa．和92 kDa条带的位置分别对应于MMP2和MMP9。MSC+ACEI组和ACEI组MMP2蛋白表达降低，两组间差异不明显。MSC组的MMP2表达有降低趋势，但未达到统计学差异。MSC+ACEI组、ACEI组、MSC组梗死区的MMP9蛋白表达降低。
3 RT-PCR测定心肌梗死区MMP2，MMP9、TIMP1mRNA表达水平。
统计分析表明3个治疗组的MMP2，MMP9的mRNA表达水平与对照组相比有差异。MSC+ACEI，ACEI，MSC和PBS组的灰度比值MMP2／β-actin分别为0.43±0.20，0.45±0.19，0.46±0.14，和0.78±0.22(P＜0.05)，MMP9／β-actin的灰度比值分别为0.40±0.13，0.51±0.10，0.48±0.09，and 0.70±0.20(P＜0.05)。而各组TIMP1的mRNA水平无明显改变。MSC组和ACEI组都能降低MMP2和MMP9的表达。
结论
血管紧张素转换酶抑制剂培哚普利能减少心梗大鼠心脏基质的重塑，降低MMP2，MMP9表达。
本研究发现，骨髓间充质干细胞可降低基质金属蛋白酶表达，有利于改善心室重塑。其机制有待进一步探讨。
骨髓间充质干细胞移植联合血管紧张素转换酶抑制剂能进一步减少MMP9表达，对梗死后心室重塑的治疗有潜在的协同效应。
第二部分骨髓间充质干细胞与培哚普利对晚期心梗后心室重塑相关基因表达的影响
骨髓间充质干细胞移植除了对急性心肌梗死后胶原、基质金属蛋白酶有影响外，对心室重塑的其他方面是否有影响。急性心肌梗死后，如果梗死面积比较大，可使心室舒张末期的压力负荷和容量负荷增加，出现梗死区的变薄和非梗死区的肥厚，心室腔径扩大，还能启动再激活生长因子刺激的即时-早期基因反应，促使蛋白质合成加速，而出现胎儿肌肉特异性基因产物的表达，如c-myc。MSC移植能够使心室腔径发生明显改变吗?对胎儿肌肉特异性基因产物的表达又会产生何种影响?体外研究发现，骨髓来源的基质细胞可不通过与血管内皮整合，可直接通过旁分泌多种促血管生成的因子，如VEGF，从而有利于侧支循环的建立。在急性心梗的缺氧微环境中，骨髓来源的基质细胞分泌VEGF增多。那么，在陈旧性心梗中，MSC能否继续分泌VEGF?骨髓间充质干细胞移植对急性心肌梗死后胶原、基质金属蛋白酶有影响，对调控胶原及纤维化过程的TGFβ-Smad通路有无变化?
材料与方法：
1模型制备：同第一部分。
2细胞准备：同第一部分。
3细胞标记：同第一部分。
4细胞回输：同第一部分。
5药物组给药方法：同第一部分。
6实验分组：同第一部分。
7超声心动图检查：采用GE公司HDE5000超声诊断仪，经胸高频超声探头频率12MHz。
图像采集：心梗后6周行超声心动图检查。大鼠称重，4％水合氯醛溶液按0.8ml／100g体重腹腔注射麻醉，大鼠仰卧，探头置心前区，M超测量左室舒张末期内径、收缩末期内径。
8 Western Blotting
总蛋白提取及定量基本同第一部分。
一抗结合(用5％脱脂奶粉TBS-T溶液配，VEGF，TGFβ1滴度为1：200；β-actin滴度为1：1000)低温过夜。
9 RT-PCR：
组织总RNA提取，RNA定量，逆转录：同第一部分。PCR引物为c-myc、Smad2。
结果
各组大鼠心梗6周后超声心动图M超测得左室舒张末期容积(LVIDd)，左室收缩末期容积(LVIDs)，4组间LVIDd，LVIDs无明显差异，MSC+ACEI组LVIDd最小，但统计学差异不明显。
大鼠心梗后6周后MSC+ACEI组、ACEI组及MSC组梗死区VEGF蛋白表达水平略高于PBS组，但未达统计学差异。
非梗死区c-myc表达高低，与非梗死区心肌代偿性增生程度有关，MSC+ACEI组、ACEI组及MSC组非梗死区c-mycmRNA表达水平低于PBS组，但未达到统计学差异。
TGFβ、Smads表达水平与纤维化程度有关，TGFβ、Smads表达水平增高，纤维化程度程度较重。大鼠心梗后6周后MSC+ACEI组、ACEI组及MSC组梗死区TGFβ蛋白表达水平略低于PBS组，各组Smad2的mRNA表达水平无明显差异。
结论
本研究的治疗组非梗死区心肌组织c-mycmRNA表达有降低趋势，可能有利于抑制心梗后非梗死区的肥厚，减小心梗厚心室重塑。心梗后移植骨髓间充质干细胞或于ACEI药物治疗，有可能部分减小了心梗后心室超负荷状态，从而降低了原癌基因的表达。
大鼠心梗后6周后梗死区VEGF蛋白表达差异不明显。
大鼠心梗6周后左心室腔大小，尤其是左室舒张末期内径与对照组相比有减小趋势，但未达统计学差异。
细胞移植后可能通过降低炎症反应，减少了TGF-beta的表达，从而减少了梗死区的纤维化程度。
Despite enormous progress in the medical technology in the past decade, acute myocardial infarction(AMI) remains the major cardiovascular disease which affect public health.To reduce the mortality rate of AMI,people make afforts to study, with the establishment of CCU.the technique for placing pulmonary artery catheter to hemodynamic monitoring .thrombolytic therapy,percutaneous transluminal coronary angioplasty ,multidrug therapy,but there are still approximately one thirds patients died from AMI.Althrough those therapy might save the myocardical cell, but in vain for myocardical cell died.When the myocardical infarction occured ,the heart adapts through structural changes ,called remodeling ,which include ventricular dilation ,compensatory opposite ventricular wall hypertrophies,and myocardium would continue to deteriorate, and affect the prognosis .
The Survival and Ventricular Enlargement trial(SAVE) show,angiotensin-converting enzyme(ACEI) could improve survival.But fundamental study display that ACEI only partial improve ventricular remodeling.
Stem cell is a kind of cell that has self-renewal and/or differentiation properties.and become importance in regenerative medicine.Cardiiomyocyte injury is irreversible after infarction,does it possible to repalace myocardial scar with functional tissue?In vitro studies in animals show myoblasts merge into myotubes in the scar. Marrow stromal cells(MSCs) augment collateral and anti-apotosis through release of several cytokine.
On the basis of the property of the stem cell,We study the affection of bone marrow mesenchymal stem cell transplantiation on infarction remodeling, especially for matrix remolding ,include collagen and matrix metalloproteinase,we also explore the expression of gene
relate to arteriogensis and hypertrophy in myocardial infarction.In this study,we compare the effection on attenuate infarction remodeling between MSC and ACEI.
Part one Bone marrow mesenchymal stem cell transplantiation combined with perindopril treatment attenuates infarction matrix remodelling in a rat model of acute myocardial infarction
Ventricular remodeling after acute myocardial infarction include the topography change ,for example, ventricular enlargement and lengthening of the noncontractile region; in the view of microstructure , include myocardial apoptosis , myocardial hypertrophy .increasing content of collagen and expression of MMP . This remodelling can lead to decline of ventricular function and advesely affect the prognosis for survival. Thus ,reversing the procedure of ventricular remodelling would be desirable for the treatment of AMI.
Activation of the circulating and tissure rennin-angiotensin-aldosterone system(RAAS) could lead to ventricular remodelling.The therapeutic use of ACEI is beneficial for reducing ventricular remodeling. Optimization studies demonstrated that angiotensin-converting enzyme inhibitors attenuate ventricular remodelling after acute myocardial infarction.
MSCs are pluripotent stem cells within the marrow microenvironment. Clinical studies showed that MSC significantly improved left ventricular function after intracoronary injection of patient with AMI.However,little information is available about the infarction remodelling after bone marrow mesenchymal stem cell transplantiation .The purpose of this study was to investigate: (1) whether transplantation of MSC could reduce the fibrillar collagen content the expression of MMP as compared to treatment of ACEI; (2)whether transplantation of MSC could enhance the beneficial effect of ACEI in reducing ventricular remodelling.
MATERIALS AND METHODS 1 Preparation of MSC
The experimental rats were anesthetized with intraperitonneal injection of 4% chloral hydrate solution (1 ml/100g) .Tibia and thigh bone were collected and pulverized,then transferred to a sterile tube and mixed with 5 ml phosphate-buffered saline (PBS) solution containing 7500 U heparin ,then added into Dulbcco's Modifed Eagle Medium
(DMEM). The tube was centrifuged at 900g for 20 min .The cell suspension was loaded on Percoll solution. The cells were centrifuged at 900g for 25 min. The middle one third of total volume were transferred into a tube containing DMEM, and centrifuged at 900g for 25 min.The cell pellet was then resuspended in culture medium and seeded in culture flasks,and maintained at 37℃ in 5% CO_2 humidified air..After washing off the unattached cells during the period of 48 hours ,the adherent cells were cultured in DMEM containing 20% fetal bovine serum and antibiotics .The medium was changed once every 5 d.
2 DAPI labelling
When MSCs completely occupied the flask bottom ,they were incubated in medium containing DAPI (4'6-Diamidino-2-Phenylindole, 50 μg/ml, Sigma, USA) for 24 h .
3 AMI model were made by ligation of the left anterior descending coronary artery. Forty rats were divided into four groups: control group, MSC group, ACEI group, MSC+ACEI
group.. PBS was injected into control group and ACEI group. Perindopril was administered( p.o. 2mg/kg body weight) to ACEI group ,and MSC+ACEI group.
PBS medium containing MSC (total 10~7 cells, 3 sites×0.05 ml per site ) or medium alone was injected into the left anterior descending coronary artery risk area (ischemic border) with a 24-gauge needle. Six weeks after MSC implantation,the rats were killed and tissure from ischemic area were collected.
4 Histology
Tissure samples from the infraction area were collected at 6 weeks after transplantation and fixed in 4% PBS formaldehyde for histological study. The samples were embedded and cut to yield 10-μm thick sections and stained with meliorative Masson's trichome stain .Interstitial fibrosis was stained blue. Some samples were frozened and cut into 4-μm thick sections.then observed under the fluorescence microscopy.
5 Western Blotting
primary antibodies diluted in TBST (1:200 for MMP2,MMP9; 1:1000 for β-actin).
6 RT-PCR
Detection expression of MMP2,MMP9 and TIMP1 mRNA
7 Statistical Analysis
Numerical data presented as mean ± SD.Comparisons among groups were performed with one-way ANOVA and LSD comparison. Statistical significance was accepted while the null hypothesis was rejected at P value<0.05.
RESULTS
Masson's trichrome staining revealed that collagen(blue) existed in the ischemic area. The area of collagen was decreased in MSC+ACEI group ACEI group MSC group compared with PBS group.
MMP2, MMP9 were highly expressed in the infraction area in the PBS group. The Western blot for MMP2, MMP9 showed the band of 72 kDa. and 92 kDa.The band of 72kDa was barely seen in the MSC +ACEI group.MMP2 Expression was also reduced by ACEI. MSC, ACEI and MSC +ACEI lowered MMP9 expression.
The PCR products of MMP2.MMP9 and TIMP1 were observed at the expected locations on agarose gels. Statistical analysis indicated that the expression of MMP2,MMP9mRNA in 3 treatment groups was significant different from that in the control group.In the MSC+ACEI,ACEI,MSC and PBS groups,the densitometry ratio of MMP2/β-actin was 0.43 ± 0.20, 0.45 ±0.19,0.46 ±0.14 and 0.78 ± 0.22,respectively,P<0.05), the densitometry ratio of MMP9/β-actin was 0.40 ± 0.13,0.51 ± 0.10, 0.48 ± 0.09,and 0.70 ± 0.20 .respectively, P<0.05).However, no significant difference was detected in the expression of TIMP1mRNA among the 4 groups.
Conclusion
Both ACEI and MSC could attenuates infarction matrix remodling in a rat model of AMI by reducing the expression of mRNA of MMP2 MMP9,ACEI could enhance the effect of MSC .
Part Two
The Effection of Bone Marrow Mesenchymal Stem Cell Transplantiation Combine Perindopril Treatment on Gene Expression Associate With Remodeling in a Rat Model of Acute Myocardial Infarction
This study was performed to evalute the effection of bone marrow mesenchymal stem cell and ACEI on the expression of oncogenne in noninfaction tissure,arteriogenic cytokine genes in infaction tissure and TGFβ-smad pathway n infaction tissure during acute myocardial infarction.
Methods
As described at the first part of the paper, 40 rats were divided into four groups:group control,group MSC,group ACEI,group MSC+ACEI.Bone marrow stem cell derived rat were injected immediately into a zone made ischemic by coronary artery ligation in group MSC and group MSC+ACEI . Phosphate-buffered saline (PBS) were injected in Group control. Perindopril was administered p.o.in group ACEI and group MSC+ACEI. Six weeks after implantation,rat were killed and sample of heart were collected, and echo were performed to evaluate the left ventricular geometry before killed the rats.Western blot was employed to evaluated the protein expression of VEGF and TGFβ, the transcriptional level of c-myc and smad2 was detected by reverse transcriptase PCR(RT-PCR) analysis.
Result
The transcriptional level of c-myc mRNA in noninfarction zone increased in PBS group,but seems to no significance. The expression of TGFβ also increased in PBS group.While smad2 seems to no change.There were no significant difference of left ventricular geometry by echo examination and the expression of VEGF among 4 groups by western blot six months after acute myocardial infarction.
Conclusion
Both MSC and ACEI could reduce the expression of TGFβ,therefore,reduce the fibrosis in infarction area.
SAVE研究表明，血管紧张素转换酶抑制剂(ACEI)被认为是治疗AMI的良好药物，在改善AMI生存率。但基础研究发现，对已有心肌肥厚的大鼠，ACEI只能在一定程度上逆转心室重塑，略微减少肥厚心肌的质量。
干细胞是一种具有自我更新和自我分化的细胞，在医学领域中日益受到重视。心肌坏死后不可逆，能否用干细胞修复损伤心肌?自Orlic首次对急性心梗小鼠进行骨髓干细胞移植后发现，新生的心肌组织占据了68％的病变心肌区，使有活性有功能的心肌代替了坏死心肌。干细胞通过旁分泌作用促进血管生成、抗细胞凋亡，还有直接分化成心肌样细胞的能力。
基于干细胞的这种生物学特性，本研究探讨了骨髓间充质干细胞(MSC)移植对心梗后心室重塑的影响，尤其是心脏间质的影响，包括胶原、基质金属蛋白酶的变化，并对心室重塑相关的基因表达情况进行了研究。已有研究表明血管紧张素转换酶抑制剂(ACEI)对心室重塑有一定作用，MSC与ACEI在逆转心室重塑方面是否存在协同作用?有必要进一步研究。
第一部分骨髓间充质干细胞移植联合培哚普利对大鼠急性心梗后基质重塑的影响
急性心肌梗死后的心室重塑在形态学上发生的改变有心室扩大和非梗死区的延伸，在微观上表现为心肌细胞的凋亡，心肌细胞的肥大，间质胶原含量和基质金属蛋白酶的改变。这种重塑可以导致心功能减退，影响预后。因此，在治疗急性心梗时有必要逆转心室重塑。
循环和组织局部肾素血管紧张素醛固酮系统的激活能引起心室重塑。用血管紧张素转化酶抑制剂治疗对逆转心室重塑有一定作用。Optimization研究说明血管紧张素转化酶抑制剂(ACEI)治疗急性心肌梗死有效。
骨髓间充质干细胞(mesenchymal stem cells，MSC)是存在于骨髓微环境中的多能祖细胞，临床研究证明在急性心肌梗死的患者中通过冠脉内注射MSC能够明显改善左心室射血功能。然而，有关MSC移植治疗急性心梗的具体机制仍不是很清楚。本研究的目的在于：探讨MSC移植能否降低急性心梗后的胶原含量，能否减少MMP的表达，与ACEI治疗相比是否存在差异，两者是否存在协同效应?
材料与方法
1 MSC的准备
取实验用的成年雄性SD大鼠，麻醉，消毒，无菌环境下切取大鼠股骨和髂骨，收集后折断，放入无菌离心管中，离心管内预先放置5ml的PBS磷酸盐缓冲溶液，内含7500U肝素钠针剂。将离心管放入超静台内，把含骨片的液体倒入无菌培养皿中，加入DMEM培养液。无菌镊及无菌眼科剪小心刮取骨髓，将混合物移入离心管中，900g，20分钟离心。将上清液缓慢加入淋巴细胞分离液中，900g，25分钟离心。小心吸取中部液体，加入另一管含DMEM的离心管中，900g，25分钟离心。细胞团块用培养液重悬后种植在培养瓶中，放入37℃，5％CO_2培养箱中培养，48小时后换液，洗去未贴壁细胞，贴壁细胞在含20％胎牛血清及青、链霉素双抗的DMEM培养液中培养。每5天换液一次，细胞长满后传代，取第三代细胞移植用。
2 DAPI标记
当MSC完全占满培养瓶底时，换用含DAPI(4′6-Diamidino-2-Phenylindole，50μg／ml)培养液培养24小时。
3大鼠心梗模型的建立
1．选成年雄性SD大鼠40个，体重200～260g，急性心肌梗死模型建立为左冠状动脉前降支结扎法。
4 MSC的移植：
建模成功的40个大鼠随机进入4个处理组：
对照组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将PBS溶液注入心肌内，每点50μl。术后第二天用生理盐水灌胃，每天一次。共6周。
MSC组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将含MSC的PBS溶液注入心肌内，每点50μl。术后第二天用生理盐水灌胃，每天一次。共6周。
ACEI组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将PBS溶液注入心肌内，每点50μl。术后第二天用培哚普利原药灌胃(2mg／kg体重)，每天一次。共6周。
MSC+ACEI组(n=10)：在心梗建模后1小时，在梗死周边区选3个点，包括心尖、梗死区的左侧和右侧。用微量注射器(针头为24G)将含MSC的PBS溶液注入心肌内，每点50μl。术后第二天用培哚普利原药灌胃(2mg／kg体重)，每天一次。共6周。
5组织学处理
组织标本用4％的PBS多聚甲醛固定后，用石蜡包埋，切成10μm厚的切片，做Masson’s三色染色。纤维组织染成蓝颜色。用液氮冷冻固定(组织学用)后，切成4μm厚的切片，直接在荧光显微镜下观察。
6 Western Blotting
测定MMP2，MMP9蛋白表达水平，一抗结合((用5％脱脂奶粉TBS-T溶液配，MMP2，MMP9滴度为1：200；β-actin滴度为1：1000)
7 RT-PCR
测定MMP2，MMP9、TIMP1mRNA表达水平。
8统计分析
计量资料用均数±标准差表示，四组间差异的总体比较采用单因素方差分析，组间两两比较采用LSD法。以P＜0.05为显著差异。
结果
1心脏胶原含量的变化
Masson’s三色染色显示在缺血心肌区域存在胶原，呈蓝色。MSC+ACEI组、ACEI组、MSC组梗死区胶原面积含量低于PBS组。
2心肌梗死区MMP2和MMP9的蛋白表达水平改变(Western Blotting)
PBS组MMP2和MMP9在梗死区组织高表达。在Western Blotting显示72kDa．和92 kDa条带的位置分别对应于MMP2和MMP9。MSC+ACEI组和ACEI组MMP2蛋白表达降低，两组间差异不明显。MSC组的MMP2表达有降低趋势，但未达到统计学差异。MSC+ACEI组、ACEI组、MSC组梗死区的MMP9蛋白表达降低。
3 RT-PCR测定心肌梗死区MMP2，MMP9、TIMP1mRNA表达水平。
统计分析表明3个治疗组的MMP2，MMP9的mRNA表达水平与对照组相比有差异。MSC+ACEI，ACEI，MSC和PBS组的灰度比值MMP2／β-actin分别为0.43±0.20，0.45±0.19，0.46±0.14，和0.78±0.22(P＜0.05)，MMP9／β-actin的灰度比值分别为0.40±0.13，0.51±0.10，0.48±0.09，and 0.70±0.20(P＜0.05)。而各组TIMP1的mRNA水平无明显改变。MSC组和ACEI组都能降低MMP2和MMP9的表达。
结论
血管紧张素转换酶抑制剂培哚普利能减少心梗大鼠心脏基质的重塑，降低MMP2，MMP9表达。
本研究发现，骨髓间充质干细胞可降低基质金属蛋白酶表达，有利于改善心室重塑。其机制有待进一步探讨。
骨髓间充质干细胞移植联合血管紧张素转换酶抑制剂能进一步减少MMP9表达，对梗死后心室重塑的治疗有潜在的协同效应。
第二部分骨髓间充质干细胞与培哚普利对晚期心梗后心室重塑相关基因表达的影响
骨髓间充质干细胞移植除了对急性心肌梗死后胶原、基质金属蛋白酶有影响外，对心室重塑的其他方面是否有影响。急性心肌梗死后，如果梗死面积比较大，可使心室舒张末期的压力负荷和容量负荷增加，出现梗死区的变薄和非梗死区的肥厚，心室腔径扩大，还能启动再激活生长因子刺激的即时-早期基因反应，促使蛋白质合成加速，而出现胎儿肌肉特异性基因产物的表达，如c-myc。MSC移植能够使心室腔径发生明显改变吗?对胎儿肌肉特异性基因产物的表达又会产生何种影响?体外研究发现，骨髓来源的基质细胞可不通过与血管内皮整合，可直接通过旁分泌多种促血管生成的因子，如VEGF，从而有利于侧支循环的建立。在急性心梗的缺氧微环境中，骨髓来源的基质细胞分泌VEGF增多。那么，在陈旧性心梗中，MSC能否继续分泌VEGF?骨髓间充质干细胞移植对急性心肌梗死后胶原、基质金属蛋白酶有影响，对调控胶原及纤维化过程的TGFβ-Smad通路有无变化?
材料与方法：
1模型制备：同第一部分。
2细胞准备：同第一部分。
3细胞标记：同第一部分。
4细胞回输：同第一部分。
5药物组给药方法：同第一部分。
6实验分组：同第一部分。
7超声心动图检查：采用GE公司HDE5000超声诊断仪，经胸高频超声探头频率12MHz。
图像采集：心梗后6周行超声心动图检查。大鼠称重，4％水合氯醛溶液按0.8ml／100g体重腹腔注射麻醉，大鼠仰卧，探头置心前区，M超测量左室舒张末期内径、收缩末期内径。
8 Western Blotting
总蛋白提取及定量基本同第一部分。
一抗结合(用5％脱脂奶粉TBS-T溶液配，VEGF，TGFβ1滴度为1：200；β-actin滴度为1：1000)低温过夜。
9 RT-PCR：
组织总RNA提取，RNA定量，逆转录：同第一部分。PCR引物为c-myc、Smad2。
结果
各组大鼠心梗6周后超声心动图M超测得左室舒张末期容积(LVIDd)，左室收缩末期容积(LVIDs)，4组间LVIDd，LVIDs无明显差异，MSC+ACEI组LVIDd最小，但统计学差异不明显。
大鼠心梗后6周后MSC+ACEI组、ACEI组及MSC组梗死区VEGF蛋白表达水平略高于PBS组，但未达统计学差异。
非梗死区c-myc表达高低，与非梗死区心肌代偿性增生程度有关，MSC+ACEI组、ACEI组及MSC组非梗死区c-mycmRNA表达水平低于PBS组，但未达到统计学差异。
TGFβ、Smads表达水平与纤维化程度有关，TGFβ、Smads表达水平增高，纤维化程度程度较重。大鼠心梗后6周后MSC+ACEI组、ACEI组及MSC组梗死区TGFβ蛋白表达水平略低于PBS组，各组Smad2的mRNA表达水平无明显差异。
结论
本研究的治疗组非梗死区心肌组织c-mycmRNA表达有降低趋势，可能有利于抑制心梗后非梗死区的肥厚，减小心梗厚心室重塑。心梗后移植骨髓间充质干细胞或于ACEI药物治疗，有可能部分减小了心梗后心室超负荷状态，从而降低了原癌基因的表达。
大鼠心梗后6周后梗死区VEGF蛋白表达差异不明显。
大鼠心梗6周后左心室腔大小，尤其是左室舒张末期内径与对照组相比有减小趋势，但未达统计学差异。
细胞移植后可能通过降低炎症反应，减少了TGF-beta的表达，从而减少了梗死区的纤维化程度。
Despite enormous progress in the medical technology in the past decade, acute myocardial infarction(AMI) remains the major cardiovascular disease which affect public health.To reduce the mortality rate of AMI,people make afforts to study, with the establishment of CCU.the technique for placing pulmonary artery catheter to hemodynamic monitoring .thrombolytic therapy,percutaneous transluminal coronary angioplasty ,multidrug therapy,but there are still approximately one thirds patients died from AMI.Althrough those therapy might save the myocardical cell, but in vain for myocardical cell died.When the myocardical infarction occured ,the heart adapts through structural changes ,called remodeling ,which include ventricular dilation ,compensatory opposite ventricular wall hypertrophies,and myocardium would continue to deteriorate, and affect the prognosis .
The Survival and Ventricular Enlargement trial(SAVE) show,angiotensin-converting enzyme(ACEI) could improve survival.But fundamental study display that ACEI only partial improve ventricular remodeling.
Stem cell is a kind of cell that has self-renewal and/or differentiation properties.and become importance in regenerative medicine.Cardiiomyocyte injury is irreversible after infarction,does it possible to repalace myocardial scar with functional tissue?In vitro studies in animals show myoblasts merge into myotubes in the scar. Marrow stromal cells(MSCs) augment collateral and anti-apotosis through release of several cytokine.
On the basis of the property of the stem cell,We study the affection of bone marrow mesenchymal stem cell transplantiation on infarction remodeling, especially for matrix remolding ,include collagen and matrix metalloproteinase,we also explore the expression of gene
relate to arteriogensis and hypertrophy in myocardial infarction.In this study,we compare the effection on attenuate infarction remodeling between MSC and ACEI.
Part one Bone marrow mesenchymal stem cell transplantiation combined with perindopril treatment attenuates infarction matrix remodelling in a rat model of acute myocardial infarction
Ventricular remodeling after acute myocardial infarction include the topography change ,for example, ventricular enlargement and lengthening of the noncontractile region; in the view of microstructure , include myocardial apoptosis , myocardial hypertrophy .increasing content of collagen and expression of MMP . This remodelling can lead to decline of ventricular function and advesely affect the prognosis for survival. Thus ,reversing the procedure of ventricular remodelling would be desirable for the treatment of AMI.
Activation of the circulating and tissure rennin-angiotensin-aldosterone system(RAAS) could lead to ventricular remodelling.The therapeutic use of ACEI is beneficial for reducing ventricular remodeling. Optimization studies demonstrated that angiotensin-converting enzyme inhibitors attenuate ventricular remodelling after acute myocardial infarction.
MSCs are pluripotent stem cells within the marrow microenvironment. Clinical studies showed that MSC significantly improved left ventricular function after intracoronary injection of patient with AMI.However,little information is available about the infarction remodelling after bone marrow mesenchymal stem cell transplantiation .The purpose of this study was to investigate: (1) whether transplantation of MSC could reduce the fibrillar collagen content the expression of MMP as compared to treatment of ACEI; (2)whether transplantation of MSC could enhance the beneficial effect of ACEI in reducing ventricular remodelling.
MATERIALS AND METHODS 1 Preparation of MSC
The experimental rats were anesthetized with intraperitonneal injection of 4% chloral hydrate solution (1 ml/100g) .Tibia and thigh bone were collected and pulverized,then transferred to a sterile tube and mixed with 5 ml phosphate-buffered saline (PBS) solution containing 7500 U heparin ,then added into Dulbcco's Modifed Eagle Medium
(DMEM). The tube was centrifuged at 900g for 20 min .The cell suspension was loaded on Percoll solution. The cells were centrifuged at 900g for 25 min. The middle one third of total volume were transferred into a tube containing DMEM, and centrifuged at 900g for 25 min.The cell pellet was then resuspended in culture medium and seeded in culture flasks,and maintained at 37℃ in 5% CO_2 humidified air..After washing off the unattached cells during the period of 48 hours ,the adherent cells were cultured in DMEM containing 20% fetal bovine serum and antibiotics .The medium was changed once every 5 d.
2 DAPI labelling
When MSCs completely occupied the flask bottom ,they were incubated in medium containing DAPI (4'6-Diamidino-2-Phenylindole, 50 μg/ml, Sigma, USA) for 24 h .
3 AMI model were made by ligation of the left anterior descending coronary artery. Forty rats were divided into four groups: control group, MSC group, ACEI group, MSC+ACEI
group.. PBS was injected into control group and ACEI group. Perindopril was administered( p.o. 2mg/kg body weight) to ACEI group ,and MSC+ACEI group.
PBS medium containing MSC (total 10~7 cells, 3 sites×0.05 ml per site ) or medium alone was injected into the left anterior descending coronary artery risk area (ischemic border) with a 24-gauge needle. Six weeks after MSC implantation,the rats were killed and tissure from ischemic area were collected.
4 Histology
Tissure samples from the infraction area were collected at 6 weeks after transplantation and fixed in 4% PBS formaldehyde for histological study. The samples were embedded and cut to yield 10-μm thick sections and stained with meliorative Masson's trichome stain .Interstitial fibrosis was stained blue. Some samples were frozened and cut into 4-μm thick sections.then observed under the fluorescence microscopy.
5 Western Blotting
primary antibodies diluted in TBST (1:200 for MMP2,MMP9; 1:1000 for β-actin).
6 RT-PCR
Detection expression of MMP2,MMP9 and TIMP1 mRNA
7 Statistical Analysis
Numerical data presented as mean ± SD.Comparisons among groups were performed with one-way ANOVA and LSD comparison. Statistical significance was accepted while the null hypothesis was rejected at P value<0.05.
RESULTS
Masson's trichrome staining revealed that collagen(blue) existed in the ischemic area. The area of collagen was decreased in MSC+ACEI group ACEI group MSC group compared with PBS group.
MMP2, MMP9 were highly expressed in the infraction area in the PBS group. The Western blot for MMP2, MMP9 showed the band of 72 kDa. and 92 kDa.The band of 72kDa was barely seen in the MSC +ACEI group.MMP2 Expression was also reduced by ACEI. MSC, ACEI and MSC +ACEI lowered MMP9 expression.
The PCR products of MMP2.MMP9 and TIMP1 were observed at the expected locations on agarose gels. Statistical analysis indicated that the expression of MMP2,MMP9mRNA in 3 treatment groups was significant different from that in the control group.In the MSC+ACEI,ACEI,MSC and PBS groups,the densitometry ratio of MMP2/β-actin was 0.43 ± 0.20, 0.45 ±0.19,0.46 ±0.14 and 0.78 ± 0.22,respectively,P<0.05), the densitometry ratio of MMP9/β-actin was 0.40 ± 0.13,0.51 ± 0.10, 0.48 ± 0.09,and 0.70 ± 0.20 .respectively, P<0.05).However, no significant difference was detected in the expression of TIMP1mRNA among the 4 groups.
Conclusion
Both ACEI and MSC could attenuates infarction matrix remodling in a rat model of AMI by reducing the expression of mRNA of MMP2 MMP9,ACEI could enhance the effect of MSC .
Part Two
The Effection of Bone Marrow Mesenchymal Stem Cell Transplantiation Combine Perindopril Treatment on Gene Expression Associate With Remodeling in a Rat Model of Acute Myocardial Infarction
This study was performed to evalute the effection of bone marrow mesenchymal stem cell and ACEI on the expression of oncogenne in noninfaction tissure,arteriogenic cytokine genes in infaction tissure and TGFβ-smad pathway n infaction tissure during acute myocardial infarction.
Methods
As described at the first part of the paper, 40 rats were divided into four groups:group control,group MSC,group ACEI,group MSC+ACEI.Bone marrow stem cell derived rat were injected immediately into a zone made ischemic by coronary artery ligation in group MSC and group MSC+ACEI . Phosphate-buffered saline (PBS) were injected in Group control. Perindopril was administered p.o.in group ACEI and group MSC+ACEI. Six weeks after implantation,rat were killed and sample of heart were collected, and echo were performed to evaluate the left ventricular geometry before killed the rats.Western blot was employed to evaluated the protein expression of VEGF and TGFβ, the transcriptional level of c-myc and smad2 was detected by reverse transcriptase PCR(RT-PCR) analysis.
Result
The transcriptional level of c-myc mRNA in noninfarction zone increased in PBS group,but seems to no significance. The expression of TGFβ also increased in PBS group.While smad2 seems to no change.There were no significant difference of left ventricular geometry by echo examination and the expression of VEGF among 4 groups by western blot six months after acute myocardial infarction.
Conclusion
Both MSC and ACEI could reduce the expression of TGFβ,therefore,reduce the fibrosis in infarction area.
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