Abstract
Ischemic preconditioning (IPre) reduces ischemia/reperfusion (I/R) injury in the heart. The non-coding microRNA miR-125b-1-3p has been demonstrated to play a role in the mechanism of IPre. Hypercholesterolemia is known to attenuate the cardioprotective effect of preconditioning; nevertheless, the exact underlying mechanisms are not clear. Here we investigated, whether hypercholesterolemia influences the induction of miR-125b-1-3p by IPre. Male Wistar rats were fed with a rodent chow supplemented with 2% cholesterol and 0.25% sodium-cholate hydrate for 8 weeks to induce high blood cholesterol levels. The hearts of normo- and hypercholesterolemic animals were then isolated and perfused according to Langendorff, and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPre (3 × 5 min I/R cycles applied before index ischemia). IPre significantly reduced infarct size in the hearts of normocholesterolemic rats; however, IPre was ineffective in the hearts of hypercholesterolemic animals. Similarly, miR-125b-1-3p was upregulated by IPre in hearts of normocholesterolemic rats, while in the hearts of hypercholesterolemic animals IPre failed to increase miR-125b-1-3p significantly. Phosphorylation of cardiac Akt, ERK, and STAT3 was not significantly different in any of the groups at the end of reperfusion. Based on these results we propose here that hypercholesterolemia attenuates the upregulation of miR-125b-1-3p by IPre, which seems to be associated with the loss of cardioprotection.
Highlights
Myocardial infarction, characterized by restriction of blood flow to the myocardium, is a major cause of death worldwide [1,2]
We investigated the expression levels of miR-125b-1-3p in ex vivo perfused hearts, and we showed upregulation of miR-125b-1-3p by ischemic preconditioning (IPre) in normocholesterolemic hearts, suggesting that miR-125b-1-3p may play a role in IPre-induced cardioprotection
This finding is in accordance with our previous studies, when we identified miR-125b-1-3p as a protectomiR since both IPre and postconditioning induced miR-125b-1-3p expression in the setting of I/R [7]
Summary
Myocardial infarction, characterized by restriction of blood flow to the myocardium, is a major cause of death worldwide [1,2]. One of the most powerful strategies to trigger endogenous cardioprotective mechanisms in the myocardium is ischemic preconditioning (IPre), i.e., when short, repetitive cycles of ischemia/reperfusion (I/R) are applied before the sustained lethal ischemia [3]. Trigger molecules (e.g., adenosine, opioids, bradykinin, and nitric oxide) induced by preconditioning has been shown. ONrmoromchoochl oalnadnd HyHpyeprcehrcohl orel freerfetrotnoonromrom-oa-nadnhdyhpyeprcehrcohleosletesrteorloemlemia,iar,ersepsepceticvtievlyel.y. Int. J. Ischemic Preconditioning Failed to Affect the RISK and SAFE Pathways at the End of Reperfusion. SInTAhyTp3ewrcehroelensotetraoflfeemctiecdgbroyuIpPsrep.hosphorylation of Akt, ERK1/2, and STAT3 were not affected by IPre. FFiigguurree 44. DDeellaayyeedd pphhoosspphhoorryyllaattiioonnooffSSTTAATT33,, AAkktt,, aanndd EERRKK11//22 pprrootteeiinnssaasssseesssseeddbbyyWWeesstteerrnn bblloottss. VVeennttrriiccuullaarr ssaammpplleess wweerree hhaarrvveesstteedd aatt tthhee eenndd ooff rreeppeerrffuussiioonn ffrroomm nnoorrmmoo-- aanndd hhyyppeerrcchhoolleesstteerroolleemmiicc hheeaarrttss ssuubbjjeecctteeddttooisiscchheemmiaia/r/erepperefrufusisoinon(I(/RI/)Rw) withitohrowr iwthiothuotuistcihsecmheimc picrepcroencdointidointiionngi(nIgPr(eI)P.rDe)a.tDa aatrae aerxepreexspsreedssaesdmaesamn e±anSE±MS;EnM=; n5,=T5w, oT-wwoa-ywAaNy OAVNAO.VNAo.rNmoorcmhoolcahnodl aHnydpHerycpheorlcrheofel rretofenr otormnoo-rmanodahnydpehrychpoerlecshtoelreoslteemroiale,mreisap, ercetsipveeclyti.vely
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