Angiopoietin-1 gene therapy for acute myocardial infarction

在急性心肌梗死(AMI)中，预后和病死率与梗塞面积、梗塞后心力衰竭的进展密切相关。血管生成基因治疗为急性心肌梗死的治疗提供了一条新途径。血管生成素-1(Angiopoietin-1，Ang1)是一种促进血管成熟的重要血管生成因子，它以互补的方式促进血管内皮生长因子(VEGF)诱导的血管生成。我们推测，血管紧张素转换酶基因治疗急性心肌梗死可能与内源性血管内皮生长因子协同促进血管生成。为了评价血管紧张素转换酶对急性心肌梗死的治疗效果，我们采用大鼠急性心肌梗死模型，并将血管紧张素转换酶基因转入心脏。在用腺病毒Angi基因治疗的心肌梗死患者中，毛细血管密度显著增加，梗塞面积显著缩小。此外，Angl组的心功能显著高于对照组。心肌梗死急性期注射血管紧张素腺病毒可减弱pR-…在大鼠模型中，心功能不全有更多的进展，没有不利的影响。然而，腺病毒载体的不良反应可能是临床应用Ang1基因治疗AIVII的一个值得关注的问题。为此，我们评价了裸质粒注射和仙台病毒载体(SeVV)作为腺病毒载体的一种可选的基因输送方法。在我们的结果中，裸露的CA启动子载体注射和SeVV介导的转基因表达在心脏中被证明是非常有效的。与腺病毒Ang1基因治疗类似，利用SeVV或裸质粒注射对梗塞心脏进行Angi基因治疗，明显促进心肌血管生成，缩小心肌梗死面积，从而防止重构。特别是，SeVV‘介导的Angi基因治疗显示缺血事件早期(3天内)恢复。此外，与基因治疗或单独移植MSCs相比，经Ang1基因修饰的骨髓间充质干细胞(MSC)移植对缺血的恢复更有效。携带Angiopoietin-1基因的裸质粒或仙台病毒载体将是安全有效的急性心肌梗死治疗选择。较少

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