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目的研究肌浆网钙ATP酶2a(SERCA2a)转基因在非缺血性和缺血性心力衰竭中的治疗价值。方法构建含SERCA2acDNA的重组腺病毒和腺相关病毒载体,制备腹主动脉缩窄和心肌梗死心力衰竭两种心衰大鼠模型,分别采用经膈将病毒液(2×1011病毒颗粒)注入心包腔,和局部心肌注射方法导入病毒,术后10~30d经颈动脉插管至左心室进行血流动力学检测。结果重组腺相关病毒rAAV2-SERCA2a导入主动脉束扎心衰大鼠心包腔后10d、30d其血流动力学与对照治疗组(rAAV2-EGFP)组相比有明显改善,30d左室收缩压(LVSP)、左室内压最大上升速率(+dp/dt)、左室内压最大下降速率(-dp/dt)分别提高57%(94mmHgvs147mmHg)、110%(5350mmHg/svs11225mmHg/s)和99.8%(4198mmHg/svs8390mmHg/s),左室舒张末压(LVEDP)则降低60%(22mmHgvs9mmHg)。转导SERCA2a后,rAAV-SERCA2a导入组在30d时SERCA2a蛋白质表达明显高于心衰组和rAAV2-EGFP导入组,达到对照组大鼠水平。重组腺病毒rAV-SERCA2a导入心肌梗死心力衰竭心衰大鼠心肌后21d血流动力学明显优于rAAV2-EGFP导入组,LVSP、+dp/dt和-dp/dt分别提高28%(86mmHgvs110mmHg)、41%(4272mmHg/svs6026mmHg/s)和71%(2789mmHg/svs4756mmHg/s),LVEDP则降低70%(3.89mmHgvs-5.34mmHg),但未能纠正至对照组水平。结论重组腺相关病毒rAAV2-SERCA2a和腺病毒rAV-SERCA2a,介导SERCA2a在大鼠心肌过表达,可有效改善心衰大鼠模型血流动力学状况。
Objective To investigate the therapeutic value of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) transgene in non-ischemic and ischemic heart failure. Methods The recombinant adenovirus and adeno-associated virus vector containing SERCA2acDNA were constructed and used to prepare two kinds of heart failure rat models of abdominal aortic constriction and myocardial infarction. The virus solution (2 × 1011 virus particles) , And local myocardial injection method into the virus, 10 ~ 30d after the carotid artery catheterization to the left ventricular hemodynamics. Results The hemodynamics of recombinant adeno-associated virus rAAV2-SERCA2a was significantly improved at 10 days and 30 days after aortic banding heart failure compared with the control group (rAAV2-EGFP group). The left ventricular systolic pressure LVSP, + dp / dt, and -dp / dt increased 57% (94mmHg vs 147mmHg), 110% (5350mmHg / svs11225mmHg / s) and 99.8% (4198mmHg) / svs8390mmHg / s) and LVEDP decreased by 60% (22mmHg vs9mmHg). After transduction of SERCA2a, SERCA2a protein expression in rAAV-SERCA2a-induced group was significantly higher than that in HF group and rAAV2-EGFP-induced group at 30 days, reaching the level of control rats. The hemodynamics of recombinant adenovirus rAV-SERCA2a was significantly higher than that of rAAV2-EGFP on day 21 after myocardial infarction heart failure in rats with myocardial infarction. The LVSP, + dp / dt and -dp / dt were increased by 28% (86mmHgvs110mmHg) 41% (4272mmHg / svs6026mmHg / s) and 71% (2789mmHg / svs4756mmHg / s) while LVEDP decreased by 70% (3.89mmHgvs-5.34mmHg) but failed to correct to the control level. Conclusion Recombinant adeno-associated virus rAAV2-SERCA2a and adenovirus rAV-SERCA2a mediate SERCA2a overexpression in rat myocardium, which can effectively improve the hemodynamic status of rat model of heart failure.