Role Of Dynamin-related Protein 1 Activation In Sepsis-induced Conversion Of Cardiomyocytes Into A Proinflammatory Phenotype

Background: Sepsis is a systemic inflammatory response syndrome(SIRS) caused by a severe local infection, and further develops to multiple organ dysfunction syndrome(MODS). It is one of the major causes of death in clinical setting. One of the reasons of the myocardial dysfunction in sepsis is the cardiomyocytes converted to proinflammatory phenotype. Dynamin-related protein 1(Drp1) is a regulator of mitochondrial fission.. However, little is known to date that whether inhibition of Drp1 could prevent the conversion of cardiomyocytes into a proinflammatory phenotype in sepsis.Objective: To determine whether Drp1 plays a role in sepsis-induced conversion of cardiomyocytes into a proinflammatory phenotype.Method: In vivo: Rat model of sepsis was induced by intraperitoneal(i.p.) injection of fecal material(180 mg/m L) at a dose of 3 g/kg body weight. Rat received normal saline(NS) served as control(sham). Some rats were pretreated with Mdivi-1(25 mg/kg, i.p.) 1h before induction of sepsis.. Six hours after the induction of sepsis, rat plasma was isolated and hearts were harvested for myocardial myeloperoxidase(MPO) and neutrophil infiltration assay. In vitro: Isolated rat cardiomyocytes were challenged with either septic plasma(from septic rat), or sham plasma(from sham rat), Drp1 activation was evaluated with inhibitory Drp1 S637(serine 637) phosphorylation and mitochondria translocation. Proinflammatory phenotype of cardiomyocytes was determined by measuring chemokine(LIX and KC) expression.Results: Rats with sepsis incurred increased myocardial MPO activity and myocardial polymorphonuclear neutrophil(PMN) accumulation as compared to control animals(P<0.05). Treatment of the septic rat with Mdivi-1(25 mg/kg) attenuated the sepsis-induced increase in myocardial MPO activity(P<0.05)and myocardial PMN accumulation(P<0.05). Challenge of cardiomyocytes with septic plasma activated Drp1 and promoted Drp1 mitochondria translocation(P<0.05), and resulted in conversion of cardiomyocytes into a proinflammatory phenotype as indicated by increase in LIX and KC expression(P<0.05). Mdivi-1(10 μmol/L) pretreatment prevented the increase in LIX and KC production in cardiomyocytes with septic plasma(P<0.05)and the dephosphoration of Drp1 at S637(P<0.05) and the Drp1 translocation to mitochondria(P<0.05).Conclution: The activation of Drp1 plays a pivotal role in conversion of cardiomyocytes into proinflammatory phenotype in sepsis.