Synthetic Chemically Modified mRNA-Based Delivery of Cytoprotective Factor Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction
Synthetic Chemically Modified mRNA-Based Delivery of Cytoprotective Factor Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction
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DOI：
10.1021/mp5006239
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发表时间：
2015-03-01
影响因子：
4.9
通讯作者：
Caplice, Noel M.
中科院分区：
文献类型：
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作者：
Huang, Chien-Ling;Leblond, Anne-Laure;Caplice, Noel M.
为了延长缺氧和心肌梗死（MI）后经历细胞凋亡的心肌细胞的细胞保护的时间窗，使用合成的化学修饰的mRNA（modRNA）来驱动胰岛素样生长因子-1（IGF 1）在MI的体内鼠模型中的风险区域内的递送。用基于聚乙烯亚胺的纳米颗粒递送IGF 1 modRNA，增强分泌的和细胞相关的IGF 1，促进心肌细胞存活并在缺氧诱导的细胞凋亡条件下消除细胞凋亡。modRNA-IGF 1的翻译足以诱导下游Akt和Erk磷酸化水平的增加。IGF 1特异性miRNA-1和-133的表达下调，但miR-145的表达没有下调。作为概念的证明，心肌内递送modRNA-IGF 1而非对照modRNA-GFP显著降低了MI后24小时梗塞边界区内TUNEL阳性细胞的水平，增强了Akt磷酸化，并降低了半胱天冬酶-9活性。这些发现证明了由合成modRNA递送驱动的瞬时IGF 1的延长细胞保护作用的潜力。
To extend the temporal window for cytoprotection in cardiomyocytes undergoing apoptosis after hypoxia and myocardial infarction (MI), a synthetic chemically modified mRNA (modRNA) was used to drive delivery of insulin-like growth factor-1 (IGF1) within the area at risk in an in vivo murine model of MI. Delivery of IGF1 modRNA, with a polyethylenimine-based nanoparticle, augmented secreted and cell-associated IGF1, promoting cardiomyocyte survival and abrogating cell apoptosis under hypoxia-induced apoptosis conditions. Translation of modRNA-IGF1 was sufficient to induce downstream increases in the levels of Akt and Erk phosphorylation. Downregulation of IGF1 specific miRNA-1 and -133 but not miR-145 expression was also confirmed. As a proof of concept, intramyocardial delivery of modRNA-IGF1 but not control modRNA-GFP significantly decreased the level of TUNEL positive cells, augmented Akt phosphorylation, and decreased caspase-9 activity within the infarct border zone 24 h post-MI. These findings demonstrate the potential for an extended cytoprotective effect of transient IGF1 driven by synthetic modRNA delivery.