Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathy by reducing apoptosis and fibrosis
Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathy by reducing apoptosis and fibrosis
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DOI：
10.1093/cvr/cvu001
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发表时间：
2014-03-01
影响因子：
10.8
通讯作者：
Leong-Poi, Howard
中科院分区：
文献类型：
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作者：
Lee, Paul J. H.;Rudenko, Dmitriy;Leong-Poi, Howard
目的探讨超声介导的凋亡抑制蛋白Survivin基因治疗对阿霉素所致心力衰竭大鼠左心室收缩功能障碍及细胞凋亡的影响。Survivin转导后，在细胞培养上清液中检测到Survivin蛋白，证实了细胞外Survivin的分泌。在阿霉素刺激下，Survivin转导的细胞明显减少了凋亡；然而，与Survivin条件培养液孵育也显示了凋亡的减少，而空白条件培养液中没有这种情况。以Fischer大鼠为模型，建立阿霉素心肌病模型。在第3周，动物亚组接受超声介导的Survivin基因转移或空载体基因转移。对照组大鼠只接受阿霉素。对动物进行了聚合酶链式反应、免疫组织化学、超声心动图和侵入性血流动力学研究，直到第6周。与对照组和空白组相比，Survivin组超声心动图的LV%缩短率和压力-容量环的收缩功能更大。Survivin治疗组大鼠心肌细胞凋亡率和caspase活性在第4周明显低于空白对照组和空白对照组，第6周时间质纤维化明显减轻。结论Survivin基因治疗可以延缓阿霉素心肌病大鼠左室收缩功能障碍的发展。这种作用可以归因于减少心肌细胞的凋亡和防止适应性不良的左室重构，这既是通过直接的心肌细胞转基因，也可能是通过旁分泌机制。
Aims The aim of this study was to investigate anti-apoptotic gene therapy using ultrasound-mediated plasmid delivery of survivin, an inhibitor of apoptosis protein, to prevent apoptosis and to attenuate left ventricular (LV) systolic dysfunction in a model of heart failure induced by doxorubicin.Methods and results Effect of survivin transduction was investigated in vitro in rat cardiomyoblasts. After survivin transduction, survivin protein was detected in cell culture supernate confirming secretion of extracellular survivin. Under doxorubicin stimulation, survivin-transduced cells had significantly reduced apoptosis; however, incubation with survivin-conditioned media also showed reduced apoptosis that was absent with null-conditioned media. Doxorubicin-induced cardiomyopathy was established in Fischer rats. Subsets of animals underwent ultrasound-mediated survivin gene delivery or empty vector gene delivery at Week 3. Control rats received doxorubicin alone. Animals were studied using PCR, immunohistochemistry, echocardiography, and invasive haemodynamic studies out to Week 6. By Week 6, LV% fractional shortening by echocardiography and systolic function by pressure-volume loops were greater in survivin treated when compared with control-and empty-treated animals. There was reduced apoptosis by TUNEL and caspase activity in survivin-treated animals compared with control and empty treated at Week 4, with reduced interstitial fibrosis at Week 6.Conclusion Survivin gene therapy can attenuate the progression of LV systolic dysfunction in doxorubicin cardiomyopathy. This effect can be attributed to decreased myocyte apoptosis and prevention of maladaptive LV remodelling, by both direct myocyte transfection and potentially by paracrine mechanisms.