Epigenetic Upregulation of Endogenous VEGF-A Reduces Myocardial Infarct Size in Mice

“Epigenetherapy” alters epigenetic status of the targeted chromatin and modifies expression of the endogenous therapeutic gene. In this study we used lentiviral in vivo delivery of small hairpin RNA (shRNA) into hearts in a murine infarction model. shRNA complementary to the promoter of vascular endothelial growth factor (VEGF-A) was able to upregulate endogenous VEGF-A expression. Histological and multiphoton microscope analysis confirmed the therapeutic effect in the transduced hearts. Magnetic resonance imaging (MRI) showed in vivo that the infarct size was significantly reduced in the treatment group 14 days after the epigenetherapy. Importantly, we show that promoter-targeted shRNA upregulates all isoforms of endogenous VEGF-A and that an intact hairpin structure is required for the shRNA activity. In conclusion, regulation of gene expression at the promoter level is a promising new treatment strategy for myocardial infarction and also potentially useful for the upregulation of other endogenous genes.表观遗传疗法（epigenetherapy）通过改变靶染色质的表观遗传状态，调控内源性治疗基因的表达。本研究采用慢病毒活体递送小发夹RNA（small hairpin RNA, shRNA）至小鼠梗死模型的心脏中。靶向血管内皮生长因子（vascular endothelial growth factor, VEGF-A）启动子的shRNA可有效上调内源性VEGF-A的表达。组织学与多光子显微镜分析证实了转导心脏的治疗效果。磁共振成像（Magnetic resonance imaging, MRI）在体检测显示，表观遗传疗法干预14天后，治疗组小鼠的梗死面积显著缩小。值得注意的是，本研究证实，靶向启动子的shRNA可上调内源性VEGF-A的所有亚型，且shRNA的活性依赖于完整的发夹结构。综上，在启动子层面调控基因表达是一种极具潜力的心肌梗死新型治疗策略，同时也有望用于其他内源性基因的上调表达。