title: Cardioprotective effect of metformin in lipopolysaccharide-induced sepsis via suppression of toll-like receptor 4 (TLR4) in heart.
abstract: Sepsis-induced myocardial dysfunction is a serious organ complication. In the present study, we investigated the effect of metformin on myocardial dysfunction and TLR4 activity in LPS-induced sepsis. Male Wistar rats were randomly divided into 3 groups (n=6): control received normal saline (0.5ml), LPS group received lipopolysaccharide (0.5mg/kg; i.p), and metformin treated group received LPS (0.5mg/kg)+metformin (100mg/kg; i.p). 9h later the hemodynamic parameters were recorded, blood samples were collected, and the hearts were removed and weighted. The concentration of TNF-α, content of MYD88, the phosphorylation of AMPK, and the rate of TLR4 expression in the heart were assessed. In the animals treated with metformin, the preservation of left ventricular function was associated with the reduction of myeloperoxidase activity (31%, P<0.01) in the heart and decrease of TNF-α level both in the serum and heart tissue (20%, P<0.01 and 42%, P<0.05, respectively). It was found that the level of phosphorylated AMPK in heart was significantly upregulated by 43% (P<0.001) in the metformin group while the content of TLRs adapter protein of MyD88 was reduced by 45% (P<0.05). This was associated with a remarkable decrease in the expression of myocardial TLR4. Furthermore, in a mice model of sepsis, coadministration of compound C (20mg/kg) as an AMPK inhibitor reversed the suppressive effects of metformin on TLR4 expression and MYD88 protein level. These results suggest that metformin exhibits cardioprotective effects in sepsis by suppression of TLR4 activity, at least in part through pathways involving AMPK activation.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Haleh
authors.initials: H
authors.lastname: Vaez
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Rameshrad
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Moslem
authors.initials: M
authors.lastname: Najafi
authors.affiliation: Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Jaleh
authors.initials: J
authors.lastname: Barar
authors.affiliation: Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Barzegari
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: garjania@tbzmed.ac.ir.
authors.forename: Alireza
authors.initials: A
authors.lastname: Garjani
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018805:Sepsis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D002316:Cardiotonic Agents; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Heart; Lipopolysaccharide; Metformin; Sepsis; Toll-like receptor 4