[Bone marrow stem cells-based SERCA2a gene therapy for heart failure after acute myocardium infarction]

ArticleinZhonghua yi xue za zhi 86(12):826-31 · April 2006with10 Reads
Source: PubMed
Abstract
Explore the possibility of MSC to be used to target delivery of therapeutic gene and evaluate the therapeutic effects among gene therapy, MSC transplantation and MSC-based gene therapy. MSC were infected with an adenoviral expression vector carrying SERCA2a. SD female rats were used to make animal model with heart failure after AMI and divided into 4 groups randomly. Group I (n = 7) received SERCA2a gene therapy, group II (n = 7) received MSC transplantation, group III (n = 8) received MSC infected with SERCA2a gene transplantation, and group IV (n = 7) received empty adenoviral vector. Cardiac function was evaluated by echocardiography and physiological recorder. SERCA2a gene and protein expression were evaluated by RT-PCR and Western blot respectively. Compared to group IV, EF and FS of group I, group II and group III were elevated significantly on 14 days after therapy (EF: 67.7 +/- 3.9, 62.6 +/- 4.0, 67.9 +/- 3.7 versus 45.0 +/- 2.2; FS: 33.9 +/- 1.9, 31.1 +/- 2.0, 33.9 +/- 1.9 versus 22.5 +/- 1.1, P < 0.05). While the elevation values of EF and FS began to reduce in group I 14 days after, it continued to increase in both group II and group III. Absolute value of LVEDP at 21 days after treatment was increased in group I, group II and group III compared to group IV (5.3 mm Hg +/- 1.2 mm Hg, 6.0 +/- 1.3 mm Hg, 6.2 mm Hg +/- 1.2 mm Hg versus 1.5 mm Hg +/- 0.2 mm Hg, P < 0.05), as well as absolute value of DP/dtmin (4756 mm Hg/s +/- 270 mm Hg/s, 5028 mm Hg/s +/- 253 mm Hg/s, 5283 mm Hg/s +/- 363 mm Hg/s versus 3201 mm Hg/s +/- 211 mm Hg/s, P < 0.05). DP/dtmax at 21 days after treatment increased in group I, group II and group III compared to group IV (6026 mm Hg/s +/- 281 mm Hg/s, 6278 mm Hg/s +/- 319 mm Hg/s, 7057 mm Hg/s +/- 389 mm Hg/s versus 5293 mm Hg/s +/- 360 mm Hg/s, P < 0.05). SERCA2a expressions and enzyme activity were significantly stronger in group I and group III than in group II and group IV. It showed that all MSC transplantation, SERCA2a gene therapy and MSC-based gene therapy could enhance cardiac function. The recovered heart function continued to improve in MSC transplantation group and MSC-based gene therapy group up to 21 days, however slowed down in single gene therapy group in 21 days. Such therapeutic tendency of MSC-based gene therapy was stronger than that of MSC transplantation. Thus, MSC proved an effective platform for the targeted delivery of therapeutic gene.
  • [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Myocardial cells have limited reproductive activity. Following acute myocardial infarction, cell transplantation is a popular method of regeneration myocardium. Survival of bone marrow mesenchymal stem cells (BMSCs) is affected by myocardial microenvironment. Endothelial progenitor cells (EPCs) participate in angiogenesis, and can provide microenvironment for BMSCs. OBJECTIVE: To investigate the effect of Salvianolic acid B preconditioned EPCs combined with BMSCs on cardiac function and gene expression in rat models of acute myocardial infarction. DESIGN, TIME AND SETTING: The randomized controlled animal study was performed at the Tianjin University of Traditional Chinese Medicine from January 2007 to March 2008. MATERIALS: A total of 45 clean male Wistar rats were provided by the Experimental Animal Center, Institute of Radiological Medicine, Chinese Academy of Medical Sciences. Salvianolic acid B (Tianshili, Tianjin, China), lot number 20060601 was used in this study. METHODS: Two and one rats were separately obtained. EPCs and BMSCs in vitro were isolated and purified by density-gradient centrifugation and adherence method. Remaining 42 rats were randomly assigned into 4 groups: sham operation group (n=9), model group (n=11), BMSCs group (n=12), and cotransplantation group (n=10). Rats in the sham operation group received chest open and braid, without deligation of the left coronary artery. In other three groups, the left coronary artery was ligated to establish myocardial infarction models. Following 15 minutes of coronary artery deligation, the chest was opened. Rats in the cotransplantation group were treated with 250 μ L (1×1010/L) BMSCs suspension + 8 mg/L Salvianolic acid B-treated EPC suspension 250 μ L (1×108/L) in five points of the myocardium surrounding the deligation region. Rats in the BMSCs group received 500 μ L BMSCs suspension. Rats in the model group were injected with an equal volume of cell medium. MAIN OUTCOME MEASURES: Left ventricular function was measured by ultrasonocardiograph. Expression of Nkx2.5 and GATA-4 was detected by Real-time PCR. RESULTS: Compared with the model group, left ventricular structure had the tendency to improve in the BMSCs group 4 weeks following cell transplantation (P > 0.05). Left ventricular end diastolic dimension, left ventricular end-systolic dimension, interventricular septum thickness at end diastole and interventricular septum thickness at end systole were significantly improved (P < 0.05), and ejection fraction and cardiac output were significantly improved (P < 0.05) in the cotransplantation group. Compared with the model group, Nkx2.5 and GATA-4 mRNA expression significantly increased in the BMSCs and cotransplantation group 4 weeks following transplantation. The increase in Nkx2.5 mRNA was significantly lower in the cotransplantation group than in the BMSCs group (P < 0.05). CONCLUSION: EPCs preconditioned with Salvianolic acid B combined with BMSCs transplantation improved the expression of NKx2.5 and GATA-4, promoted cardiac function of acute myocardial infarction rat models.
    Article · Jun 2009
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