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目的比较肌浆网钙离子ATP酶2 a(SERCA2 a)基因治疗,骨髓干细胞(MSC)移植以及SERCA2 a基因修饰的细胞移植治疗慢性缺血性心力衰竭的效应,评价MSC作为治疗基因的细胞载体策略的可行性。方法制作心力衰竭大鼠模型并随机分为4组。SERCA2 a基因治疗组(组Ⅰ,7只),MSC细胞移植组(组Ⅱ,7只),基因修饰的细胞移植组(组Ⅲ,8只),腺病毒空载体对照组(组Ⅳ,7只)。检测各组SERCA2 a基因,蛋白表达及活性。超声心动图及有创血流动力学评价心脏功能。HE染色观察心室形态。结果组Ⅰ,组Ⅱ,组Ⅲ比对照组Ⅳ心功能和血流动力学明显改善。治疗后组Ⅱ(2.9 mm±0.2 mm)和组Ⅲ(3.0 mm±0.1 mm)大鼠室壁厚度增加,心室腔减小。治疗后14d组Ⅰ,组Ⅱ与组Ⅲ射血分数(EF)为26.6%±3.9%,20.6%±5.0%,25.6%±2.7%。短轴缩短率(FS)分别为13.3%±2.0%,10.1%±2.5%,12.1%±1.0%(P<0.05)。治疗后21 d组Ⅰ,组Ⅱ与组ⅢEF分别为19.7%±5.0%,21.4%±5.2%,26.6%±4.1%,FS分别为9.7%±2.5%,10.7%±2.6%,12.8%±2.2%(P<0.05)。组Ⅳ治疗后14 d EF无变化,治疗后21 d EF下降了6.6%±4.0%。组Ⅰ和组ⅢSERCA2 a基因,蛋白表达及酶活性均高于组Ⅱ和组Ⅳ(P<0.01)。结论MSC移植和SERCA2 a基因修饰的细胞移植组大鼠呈现稳定持续的心功能改善作用。MSC可以作为治疗基因的有效转移载体。
Objective To compare the effect of sarcoplasmic reticulum calcium ATPase 2 a (SERCA2 a) gene therapy, bone marrow stem cell (MSC) transplantation and SERCA2 a gene-modified cell transplantation in the treatment of chronic ischemic heart failure and evaluate the role of MSC as a cellular vector for therapeutic gene therapy The feasibility of the strategy. Methods The rat model of heart failure was established and randomly divided into 4 groups. SERCA2 a gene therapy group (group Ⅰ, 7), MSC cell transplantation group (group Ⅱ, 7), genetically modified cell transplantation group (group Ⅲ, 8), adenovirus empty vector control group only). The SERCA2 a gene, protein expression and activity of each group were detected. Echocardiography and invasive hemodynamic assessment of cardiac function. HE staining observed ventricular morphology. Results Group Ⅰ, Ⅱ, Ⅲ than the control group Ⅳ cardiac function and hemodynamic significantly improved. After treatment, the wall thickness of rats in group Ⅱ (2.9 mm ± 0.2 mm) and group Ⅲ (3.0 mm ± 0.1 mm) increased and the ventricular cavity decreased. After 14 days of treatment, the ejection fraction (EF) of group Ⅰ, group Ⅱ and group Ⅲ were 26.6% ± 3.9%, 20.6% ± 5.0% and 25.6% ± 2.7% respectively. The short axis shortening rates were 13.3% ± 2.0%, 10.1% ± 2.5% and 12.1% ± 1.0%, respectively (P <0.05). After 21 days of treatment, the IEFs in group I, group II and group III were 19.7% ± 5.0%, 21.4% ± 5.2%, 26.6% ± 4.1%, and FS were 9.7% ± 2.5%, 10.7% ± 2.6%, 12.8% ± 2.2% (P <0.05). There was no change in EF at 14 days after treatment in group IV, and EF was decreased by 6.6% ± 4.0% at 21 days after treatment. The gene and protein expression and activity of SERCA2 a in group Ⅰ and group Ⅲ were higher than those in group Ⅱ and Ⅳ (P <0.01). Conclusion The MSC transplantation and SERCA2 a gene-modified cell transplantation group showed stable and continuous improvement of cardiac function. MSC can serve as an effective transfer vector for therapeutic genes.