title: Synthetic chemically modified mrna-based delivery of cytoprotective factor promotes early cardiomyocyte survival post-acute myocardial infarction.
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.
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork , Cork, Ireland.
authors.forename: Chien-Ling
authors.initials: CL
authors.lastname: Huang
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Leblond
authors.forename: Elizebeth C
authors.initials: EC
authors.lastname: Turner
authors.forename: Arun Hs
authors.initials: AH
authors.lastname: Kumar
authors.forename: Kenneth
authors.initials: K
authors.lastname: Martin
authors.forename: Derek
authors.initials: D
authors.lastname: Whelan
authors.forename: Donnchadh M
authors.initials: DM
authors.lastname: O'Sullivan
authors.forename: Noel M
authors.initials: NM
authors.lastname: Caplice
mesh_terms: D000818:Animals; D001702:Biopharmaceutics; D002460:Cell Line; D002470:Cell Survival; D019610:Cytoprotection / Q000235:genetics; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000235:genetics*; D014162:Transfection
chemical_list: D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I; D011094:Polyethyleneimine
keywords: cytoprotective; insulin-like growth factor-1; modified mRNA; myocardial infarction