title: MicroRNA-144 is a circulating effector of remote ischemic preconditioning.
abstract: Remote ischemic preconditioning (rIPC) induced by cycles of transient limb ischemia and reperfusion is a powerful cardioprotective strategy with additional pleiotropic effects. However, our understanding of its underlying mediators and mechanisms remains incomplete. We examined the role of miR-144 in the cardioprotection induced by rIPC. Microarray studies first established that rIPC increases, and IR injury decreases miR-144 levels in mouse myocardium, the latter being rescued by both rIPC and intravenous administration of miR-144. Going along with this systemic treatment with miR-144 increased P-Akt, P-GSK3β and P-p44/42 MAPK, decreased p-mTOR level and induced autophagy signaling, and induced early and delayed cardioprotection with improved functional recovery and reduction in infarct size similar to that achieved by rIPC. Conversely, systemic administration of a specific antisense oligonucleotide reduced myocardial levels of miR-144 and abrogated cardioprotection by rIPC. We then showed that rIPC increases plasma miR-144 levels in mice and humans, but there was no change in plasma microparticle (50-400 nM) numbers or their miR-144 content. However, there was an almost fourfold increase in miR-144 precursor in the exosome pellet, and a significant increase in miR-144 levels in exosome-poor serum which, in turn, was associated with increased levels of the miR carriage protein Argonaute-2. Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC. Future studies should assess the potential for plasma miR-144 as a biomarker of the effectiveness of rIPC induced by limb ischemia, and whether miR-144 itself may represent a novel therapy to reduce clinical ischemia-reperfusion injury.
authors: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X 8, Canada.
authors: Jing
authors: J
authors: Li
authors: Sagar
authors: S
authors: Rohailla
authors: Nitai
authors: N
authors: Gelber
authors: James
authors: J
authors: Rutka
authors: Nesrin
authors: N
authors: Sabah
authors: Rachel A
authors: RA
authors: Gladstone
authors: Can
authors: C
authors: Wei
authors: Pingzhao
authors: P
authors: Hu
authors: Rajesh K
authors: RK
authors: Kharbanda
authors: Andrew N
authors: AN
authors: Redington
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006801:Humans; D047468:Immunoprecipitation; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C554293:MIRN144 microRNA, human; C551064:MIRN144 microRNA, mouse; D035683:MicroRNAs