title: MicroRNAs associated with ischemia-reperfusion injury and cardioprotection by ischemic pre- and postconditioning: protectomiRs.
abstract: We aimed to characterize early changes in microRNA expression in acute cardioprotection by ischemic pre- and postconditioning in rat hearts. Hearts isolated from male Wistar rats were subjected to 1) time-matched nonischemic perfusion, 2) ischemia-reperfusion (30 min of coronary occlusion and 120 min of reperfusion), 3) preconditioning (3 × 5 min of coronary occlusion) followed by ischemia-reperfusion, or 4) ischemia-reperfusion with postconditioning (6 × 10 s of global ischemia-reperfusion at the onset of reperfusion). Infarct size was significantly reduced by both interventions. Of 350 different microRNAs assessed by microarray analysis, 147-160 microRNAs showed detectable expression levels. Compared with microRNA alterations induced by ischemia-reperfusion versus time-matched nonischemic controls, five microRNAs were significantly affected by both pre- and postconditioning (microRNA-125b*, microRNA-139-3p, microRNA-320, microRNA-532-3p, and microRNA-188), four microRNAs were significantly affected by preconditioning (microRNA-487b, microRNA-139-5p, microRNA-192, and microRNA-212), and nine microRNAs were significantly affected by postconditioning (microRNA-1, microRNA let-7i, microRNA let-7e, microRNA let-7b, microRNA-181a, microRNA-208, microRNA-328, microRNA-335, and microRNA-503). Expression of randomly selected microRNAs was validated by quantitative real-time PCR. By a systematic comparison of the direction of microRNA expression changes in all groups, we identified microRNAs, specific mimics, or antagomiRs that may have pre- and postconditioning-like cardioprotective effects (protectomiRs). Transfection of selected protectomiRs (mimics of microRNA-139-5p, microRNA-125b*, microRNA let-7b, and inhibitor of microRNA-487b) into cardiac myocytes subjected to simulated ischemia-reperfusion showed a significant cytoprotective effect. This is the first demonstration that the ischemia-reperfusion-induced microRNA expression profile is significantly influenced by both pre- and postconditioning, which shows the involvement of microRNAs in cardioprotective signaling. Moreover, by analysis of microRNA expression patterns in cardioprotection by pre- and postconditioning, specific protectomiRs can be revealed as potential therapeutic tools for the treatment of ischemia-reperfusion injury.
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Zoltán V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary;
authors.forename: Agnes
authors.initials: A
authors.lastname: Zvara
authors.affiliation: Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary;
authors.forename: Nóra
authors.initials: N
authors.lastname: Faragó
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary;
authors.forename: Gabriella F
authors.initials: GF
authors.lastname: Kocsis
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary;
authors.forename: Márton
authors.initials: M
authors.lastname: Pipicz
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary;
authors.forename: Renáta
authors.initials: R
authors.lastname: Gáspár
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Bencsik
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Görbe
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Csonka
authors.affiliation: Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary;
authors.forename: László G
authors.initials: LG
authors.lastname: Puskás
authors.affiliation: Institue of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Csont
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary peter.ferdinandy@pharmahungary.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D057775:Ischemic Postconditioning; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D013997:Time Factors; D014162:Transfection
chemical_list: D035683:MicroRNAs
keywords: cardioprotection; miR; miRNA; microRNA; reperfusion injury