Angiopoietin-1 gene therapy for acute myocardial infarction

在急性心肌梗死（AMI）中，预后和死亡率与梗死面积及梗死后心力衰竭的进展密切相关。血管生成基因治疗为AMI的治疗提供了新的途径。血管生成素-1 （Ang1）是血管成熟的关键血管生成因子，并与血管内皮生长因子（VEGF）诱导的血管生成形成互补。我们假设Angl基因治疗AMI可能促进血管生成与内源性VEGF协同作用。为了评估Angi对AMI的治疗效果，我们采用大鼠AMI模型，并将腺病毒Angi基因转移到心脏。在腺病毒Angi基因治疗的梗死心脏中，毛细血管密度显著增加，梗死面积减小。此外，Angl组心脏性能显著提高。心肌梗死急性期腺病毒给药可减轻心肌梗死急性期心功能障碍，对心肌梗死急性期心功能障碍加重无不良影响。然而，腺病毒载体的不良反应可能是临床上应用Angl基因治疗AIVII时需要关注的问题。为此，我们评估了裸质粒注射和仙台病毒载体（SeVV）作为腺病毒载体的替代基因递送方法。在我们的研究结果中，以裸CA启动子为基础的质粒注射和SeVV介导的转基因表达在心脏中是非常有效的。与腺病毒Angi基因治疗类似，使用SeVV或裸质粒注射将Angi基因传递给梗死心脏可明显促进心肌血管生成，减少梗死面积，从而防止重构。特别是，SeVV介导的Angi基因治疗显示缺血事件的早期恢复（3天内）。经Angl基因修饰的骨髓间充质干细胞（MSC）移植比基因治疗或单独移植更能有效地恢复缺血。编码血管生成素-1基因的裸质粒或仙台病毒载体是治疗急性心肌梗死安全有效的选择。少

In acute myocardial infarction (AMI), prognosis and the mortality rate are closely related to the infarct size, and the progression of post-infarction cardiac failure. Angiogenic gene-therapy has presented a new approach for the treatment of AMI. Angiopoietin-1 (Ang1) is a critical angiogenic factor for vascular maturation and enhances vascular endothelial growth factor (VEGF)-induced angiogenesis in a complementary manner. We hypothesized that gene-therapy of Angl for AMI might promote angiogenesis cooperatively with intrinsic VEGF.To evaluate the therapeutic effects of Angi in AMI, we employed a rat AMI model, and adenoviral Angi gene transfer to the heart. A significant increase in capillary density, and reduction in infarct size were noted in the infarct hearts with adenoviral Angi gene treatment. Furthermore, Angl group showed significantly higher cardiac performance. The adenoviral delivery Angi during the acute phase of myocardial infarction would be feasible to attenuate the pr … More ogression of cardiac dysfunction in the rat model without unfavorable effects. However, adverse effects of adenoviral vector might be concern for clinical use of Angl gene therapy for AIVII. For this purpose, we evaluated naked plasmid injection and Sendai virus vector (SeVV) as an alternative gene delivery method of adenoviral vector. In our results, transgene expression mediated by naked CA promoter-based plasmid injection and SeVV were shown to be quite efficient in the heart. Similarly with adenoviral Angl gene therapy, Angi gene delivery for infarct heart utilizing SeVV or naked plasmid injection clearly promoted myocardial angiogenesis and reduced the infarct size resulting in the prevention of remodeling. Especially, SeVV'mediated Angi gene therapy demonstrated early recovery (within 3 days) of ischemic event. Furthermore transplantation of bone marrow mesenchymal stem cells (MSC) modified with Angl gene was more efficient for the recovery of ischemia in comparison with gene therapy or MSCs transplantation alone.Naked plasmid or Sendai virus vector encoding angiopoietin-1 gene would be safe and useful therapeutic option for acute myocardial infarction. Less