Synthetic chemically modified mrna-based delivery of cytoprotective factor promotes early cardiomyocyte survival post-acute myocardial infarction.
Mol Pharm
; 12(3): 991-6, 2015 Mar 02.
Article
en En
| MEDLINE
| ID: mdl-25588055
ABSTRACT
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
ARN Mensajero
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Miocitos Cardíacos
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Infarto del Miocardio
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Mol Pharm
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Año:
2015
Tipo del documento:
Article