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.
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Aoyagi T, Kusakari Y, Xiao CY, Inouye BT, Takahashi M, Scherrer-Crosbie M, Rosenzweig A, Hara K, Matsui T (2012) Cardiac mTOR protects the heart against ischemia–reperfusion injury. Am J Physiol Heart Circ Physiol 303:H75–H85. doi:10.1152/ajpheart.00241.2012
Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S (2009) MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324:1710–1713. doi:10.1126/science.1174381
Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G, Ashraf M, Weintraub N, Ma G, Tang Y (2013) Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun 431:566–571. doi:10.1016/j.bbrc.2013.01.015
Chen X, Liang H, Zhang J, Zen K, Zhang CY (2012) Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell 3:28–37. doi:10.1007/s13238-012-2003-z
Davidson SM, Selvaraj P, He D, Boi-Doku C, Yellon RL, Vicencio JM, Yellon DM (2013) Remote ischaemic preconditioning involves signalling through the SDF-1alpha/CXCR4 signalling axis. Basic Res Cardiol 108:377. doi:10.1007/s00395-013-0377-6
Davies WR, Brown AJ, Watson W, McCormick LM, West NE, Dutka DP, Hoole SP (2013) Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv 6:246–251. doi:10.1161/CIRCINTERVENTIONS.112.000184
Diehl P, Fricke A, Sander L, Stamm J, Bassler N, Htun N, Ziemann M, Helbing T, El-Osta A, Jowett JB, Peter K (2012) Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 93:633–644. doi:10.1093/cvr/cvs007
Donato M, Buchholz B, Rodriguez M, Perez V, Inserte J, Garcia-Dorado D, Gelpi RJ (2013) Role of the parasympathetic nervous system in cardioprotection by remote hindlimb ischaemic preconditioning. Exp Physiol 98:425–434. doi:10.1113/expphysiol.2012.066217
Dore LC, Amigo JD, Dos Santos CO, Zhang Z, Gai X, Tobias JW, Yu D, Klein AM, Dorman C, Wu W, Hardison RC, Paw BH, Weiss MJ (2008) A GATA-1-regulated microRNA locus essential for erythropoiesis. Proc Natl Acad Sci USA 105:3333–3338. doi:10.1073/pnas.0712312105
Duan X, Ji B, Wang X, Liu J, Zheng Z, Long C, Tang Y, Hu S (2012) Expression of microRNA-1 and microRNA-21 in different protocols of ischemic conditioning in an isolated rat heart model. Cardiology 122:36–43. doi:10.1159/000338149
Fu YF, Du TT, Dong M, Zhu KY, Jing CB, Zhang Y, Wang L, Fan HB, Chen Y, Jin Y, Yue GP, Chen SJ, Chen Z, Huang QH, Jing Q, Deng M, Liu TX (2009) Mir-144 selectively regulates embryonic alpha-hemoglobin synthesis during primitive erythropoiesis. Blood 113:1340–1349. doi:10.1182/blood-2008-08-174854
Giricz Z, Varga ZV, Baranyai T, Sipos P, Paloczi K, Kittel A, Buzas E, Ferdinandy P (2014) Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol 68:75–78. doi:10.1016/j.yjmcc.2014.01.004
Gyorgy B, Paloczi K, Kovacs A, Barabas E, Beko G, Varnai K, Pallinger E, Szabo-Taylor K, Szabo TG, Kiss AA, Falus A, Buzas EI (2014) Improved circulating microparticle analysis in acid-citrate dextrose (ACD) anticoagulant tube. Thromb Res 133:285–292. doi:10.1016/j.thromres.2013.11.010
Han Z, Cao J, Song D, Tian L, Chen K, Wang Y, Gao L, Yin Z, Fan Y, Wang C (2014) Autophagy is involved in the cardioprotection effect of remote limb ischemic postconditioning on myocardial ischemia/reperfusion injury in normal mice, but not diabetic mice. PLoS ONE 9:e86838. doi:10.1371/journal.pone.0086838
Hausenloy DJ, Tsang A, Yellon DM (2005) The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 15:69–75. pii: S1050-1738(05)00025-3
Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175. doi:10.1016/S0140-6736(12)60916-7
Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res 110:111–115. doi:10.1161/CIRCRESAHA.113.302942
Hock J, Meister G (2008) The Argonaute protein family. Genome Biol 9:210. doi:10.1186/gb-2008-9-2-210
Iwaya T, Yokobori T, Nishida N, Kogo R, Sudo T, Tanaka F, Shibata K, Sawada G, Takahashi Y, Ishibashi M, Wakabayashi G, Mori M, Mimori K (2012) Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. Carcinogenesis 33:2391–2397. doi:10.1093/carcin/bgs288
Jensen RV, Stottrup NB, Kristiansen SB, Botker HE (2012) Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. Basic Res Cardiol 107:285. doi:10.1007/s00395-012-0285-1
Katsuura S, Kuwano Y, Yamagishi N, Kurokawa K, Kajita K, Akaike Y, Nishida K, Masuda K, Tanahashi T, Rokutan K (2012) MicroRNAs miR-144/144* and miR-16 in peripheral blood are potential biomarkers for naturalistic stress in healthy Japanese medical students. Neurosci Lett 516:79–84. doi:10.1016/j.neulet.2012.03.062
Kharbanda RK, Li J, Konstantinov IE, Cheung MM, White PA, Frndova H, Stokoe J, Cox P, Vogel M, Van Arsdell G, MacAllister R, Redington AN (2006) Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study. Heart 92:1506–1511. doi:10.1136/hrt.2004.042366
Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R (2001) Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia–reperfusion in humans in vivo. Circulation 103:1624–1630. doi:10.1161/01.CIR.103.12.1624
Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, Downey GP, Liu PP, Cukerman E, Coles JG, Redington AN (2004) The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 19:143–150. doi:10.1152/physiolgenomics.00046
Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, Cukerman E, Dawood F, Cheung MM, Shimizu M, Liu PP, Redington AN (2005) The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg 130:1326–1332. doi:10.1016/j.jtcvs.2005.03.050
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854
Li J, Xuan W, Yan R, Tropak MB, Jean-St-Michel E, Liang W, Gladstone R, Backx PH, Kharbanda RK, Redington AN (2011) Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of beta-catenin. Clin Sci (Lond) 120:451–462. doi:10.1042/CS20100466
Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655. doi:10.1007/s00395-010-0099-y
Martinez-Lopez N, Athonvarangkul D, Mishall P, Sahu S, Singh R (2013) Autophagy proteins regulate ERK phosphorylation. Nat Commun 4:2799. doi:10.1038/ncomms3799
Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, Jia J, Hua Y, Wang X, Ding Y, Lo EH, Ji X (2012) Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 79:1853–1861. doi:10.1212/WNL.0b013e318271f76a
Ovcharenko D, Kelnar K, Johnson C, Leng N, Brown D (2007) Genome-scale microRNA and small interfering RNA screens identify small RNA modulators of TRAIL-induced apoptosis pathway. Cancer Res 67:10782–10788. doi:10.1158/0008-5472.CAN-07-1484
Przyklenk K (2013) ‘Going out on a limb’: SDF-1alpha/CXCR4 signaling as a mechanism of remote ischemic preconditioning? Basic Res Cardiol 108:382. doi:10.1007/s00395-013-0382-9
Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Dai X, Manlhiot C, Li J, Redington AN (2012) Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol 107:241–245. doi:10.1007/s00395-011-0241-5
Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan J, Redington AN (2009) Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond) 117:191–200. doi:10.1042/CS20080523
Slagsvold KH, Rognmo O, Hoydal M, Wisloff U, Wahba A (2014) Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery. Circ Res 114:851–859. doi:10.1161/CIRCRESAHA.114.302751
Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Botker HE (2014) Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 35:168–175. doi:10.1093/eurheartj/eht369
Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, Redington A (2010) Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol 299:H1598–H1603. doi:10.1152/ajpheart.00396.2010
Surendra H, Diaz RJ, Harvey K, Tropak M, Callahan J, Hinek A, Hossain T, Redington A, Wilson GJ (2013) Interaction of delta and kappa opioid receptors with adenosine A receptors mediates cardioprotection by remote ischemic preconditioning. J Mol Cell Cardiol 60C:142–150. doi:10.1016/j.yjmcc.2013.04.010
Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhauser M, Peters J, Jakob H, Heusch G (2013) Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 382:597–604. doi:10.1016/S0140-6736(13)61450-6
Varga ZV, Zvara A, Farago N, Kocsis GF, Pipicz M, Gaspar R, Bencsik P, Gorbe A, Csonka C, Puskas LG, Thum T, Csont T, Ferdinandy P (2014) MicroRNAs associated with ischemia/reperfusion injury and cardioprotection by ischemic pre- and postconditioning: ProtectomiRs. Am J Physiol Heart Circ Physiol. pii: ajpheart.00812.2013
Wang JL, Hu Y, Kong X, Wang ZH, Chen HY, Xu J, Fang JY (2013) Candidate microRNA biomarkers in human gastric cancer: a systematic review and validation study. PLoS ONE 8:e73683. doi:10.1371/journal.pone.007368
Wang X, Zhu H, Zhang X, Liu Y, Chen J, Medvedovic M, Li H, Weiss MJ, Ren X, Fan GC (2012) Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1. Cardiovasc Res 94:379–390. doi:10.1093/cvr/cvs096
Wei M, Xin P, Li S, Tao J, Li Y, Li J, Liu M, Zhu W, Redington AN (2011) Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res 108:1220–1225. doi:10.1161/CIRCRESAHA.110.236190
Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–862
Xiao B, Wang Y, Li W, Baker M, Guo J, Corbet K, Tsalik EL, Li QJ, Palmer SM, Wood CW, Li Z, Chao NJ, He YW (2013) Plasma microRNA signature as a non-invasive biomarker for acute graft-versus-host disease. Blood 122:3365. doi:10.1182/blood-2013-06-510586
Yu D, dos Santos CO, Zhao G, Jiang J, Amigo JD, Khandros E, Dore LC, Yao Y, D’Souza J, Zhang Z, Ghaffari S, Choi J, Friend S, Tong W, Orange JS, Paw BH, Weiss MJ (2010) miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta. Genes Dev 24:1620–1633. doi:10.1101/gad.1942110
Zhang SZ, Wang NF, Xu J, Gao Q, Lin GH, Bruce IC, Xia Q (2006) Kappa-opioid receptors mediate cardioprotection by remote preconditioning. Anesthesiology 105:550–556
Zhang X, Wang X, Zhu H, Zhu C, Wang Y, Pu WT, Jegga AG, Fan GC (2010) Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte death. J Mol Cell Cardiol 49:841–850. doi:10.1016/j.yjmcc.2010.08.007
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This work was supported by grants from Foundation Leducq and The Canadian Institutes of Health Research.
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ANR has applied for a patent in regard to the properties of miR-144.
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To this original contribution an invited editorial is available at doi:10.1007/s00395-014-0429-6.
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Li, J., Rohailla, S., Gelber, N. et al. MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res Cardiol 109, 423 (2014). https://doi.org/10.1007/s00395-014-0423-z
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DOI: https://doi.org/10.1007/s00395-014-0423-z