Peer-Reviewed Journal Details
Mandatory Fields
Huang, CL;Leblond, AL;Turner, EC;Kumar, AH;Martin, K;Whelan, D;O'Sullivan, DM;Caplice, NM
2015
March
Molecular Pharmaceutics
Synthetic Chemically Modified mRNA-Based Delivery of Cytoprotective Factor Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction
Validated
WOS: 31 ()
Optional Fields
POSTMYOCARDIAL INFARCTION IN-VITRO HEART CELLS EXPRESSION THERAPY MICE
12
991
996
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.
WASHINGTON
1543-8384
10.1021/mp5006239
Grant Details