title: Attenuation of Cardiac Dysfunction in Polymicrobial Sepsis by MicroRNA-146a Is Mediated via Targeting of IRAK1 and TRAF6 Expression.
abstract: Cardiac dysfunction is a major consequence of sepsis/septic shock and contributes to the high mortality of sepsis. Innate and inflammatory responses mediated by TLRs play a critical role in sepsis-induced cardiac dysfunction. MicroRNA-146 (miR-146) was first identified as a negative regulator in innate immune and inflammatory responses induced by LPS. This study examined whether miR-146a will have a protective effect on sepsis-induced cardiac dysfunction. Lentivirus-expressing miR-146a (LmiR-146a) or lentivirus-expressing scrambled miR (LmiR-control) was delivered into the myocardium via the right carotid artery. Seven days after transfection, mice were subjected to cecal ligation and puncture (CLP). Untransfected mice were also subjected to CLP-induced sepsis. Cardiac function was examined by echocardiography before and 6 h after CLP. In vitro studies showed that increased miR-146a levels suppress LPS-induced IκBα phosphorylation and inflammatory cytokine production in both H9C2 cardiomyocytes and J774 macrophages. In vivo transfection of LmiR-146a attenuated sepsis-induced cardiac dysfunction. The values for percent ejection fraction and percent fractional shortening in LmiR-146a-transfected CLP mice were significantly greater than in untransfected CLP control. LmiR-146a transfection prevented sepsis-induced NF-κB activity, suppressed IRAK and TRAF6 expression in the myocardium, and attenuated sepsis-induced inflammatory cytokine production in both plasma and peritoneal fluid. In addition, LmiR-146a transfection decreased sepsis-induced infiltration of neutrophils and macrophages into the myocardium. LmiR-146a can also transfect macrophages in the periphery. We conclude that miR-146a attenuates sepsis-induced cardiac dysfunction by preventing NF-κB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of IRAK and TRAF6 in both cardiomyocytes and inflammatory monocytic cells.
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: He
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Department of Biometry and Medical Computing, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
authors.forename: John H
authors.initials: JH
authors.lastname: Kalbfleisch
authors.affiliation: Animal Model Research Center, Nanjing University, Nanjing, 210093 China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Li@etsu.edu.
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D002339:Carotid Arteries; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000008:administration & dosage; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D018805:Sepsis / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse