Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction

Acutetreatmentwithmetforminhasaprotectiveeffectinmyocardialinfarctionbysuppressionof
inflammatoryresponsesduetoactivationofAMP-activatedproteinkinase(AMPK).Inthepresentstudy,
the effectofchronicpre-treatmentwithmetforminoncardiacdysfunctionandtoll-likereceptor4
(TLR4) activitiesfollowingmyocardialinfarctionandtheirrelationwithAMPKwereassessed.Male
Wistar ratswererandomlyassignedtooneof5groups(n¼6): normalcontrolandgroupswereinjected
isoproterenolafterchronicpre-treatmentwith0,25,50,or100mg/kgofmetformintwicedailyfor14
days.Isoproterenol(100mg/kg)wasinjectedsubcutaneouslyonthe13thand14thdaystoinduceacute
myocardialinfarction.Isoproterenolalonedecreasedleftventricularsystolicpressureandmyocardial
contractility indexedasLV dp/dtmax and LV dp/dtmin. Theleftventriculardysfunctionwassignificantly
lowerinthegroupstreatedwith25and50mg/kgofmetformin.Metfrominmarkedlylowered
isoproterenol-inducedelevationinthelevelsofTLR4mRNA,myeloiddifferentiationprotein88
(MyD88), tumornecrosisfactor-alpha(TNF-α), andinterleukin6(IL-6)inthehearttissues.Similar
changes werealsoseenintheserumlevelsofTNF-α and IL-6.However,thelowerdosesof25and50mg/
kg weremoreeffectivethan100mg/kg.PhosphorylatedAMPKα (p-AMPK) inthemyocardiumwas
significantly elevatedby25mg/kgofmetformin,slightlyby50mg/kg,butnotby100mg/kg.Chronic
pre-treatmentwithmetforminreducespost-myocardialinfarctioncardiacdysfunctionandsuppresses
inflammatoryresponses,possiblythroughinhibitionofTLR4activities.Thismechanismcanbe
considered asatargettoprotectinfarctedmyocardium