title: Erythropoietin attenuates cardiac dysfunction in experimental sepsis in mice via activation of the β-common receptor.
abstract: There is limited evidence that the tissue-protective effects of erythropoietin are mediated by a heterocomplex of the erythropoietin receptor and the β-common receptor ('tissue-protective receptor'), which is pharmacologically distinct from the 'classical' erythropoietin receptor homodimer that is responsible for erythropoiesis. However, the role of the β-common receptor and/or erythropoietin in sepsis-induced cardiac dysfunction (a well known, serious complication of sepsis) is unknown. Here we report for the first time that the β-common receptor is essential for the improvements in the impaired systolic contractility afforded by erythropoietin in experimental sepsis. Cardiac function was assessed in vivo (echocardiography) and ex vivo (Langendorff-perfused heart) in wild-type and β-common receptor knockout mice, that were subjected to lipopolysaccharide (9 mg/kg body weight; young mice) for 16-18 hours or cecal ligation and puncture (aged mice) for 24 hours. Mice received erythropoietin (1000 IU/kg body weight) 1 hour after lipopolysaccharide or cecal ligation and puncture. Erythropoietin reduced the impaired systolic contractility (in vivo and ex vivo) caused by endotoxemia or sepsis in young as well as old wild-type mice in a β-common-receptor-dependent fashion. Activation by erythropoietin of the β-common receptor also resulted in the activation of well-known survival pathways (Akt and endothelial nitric oxide synthase) and inhibition of pro-inflammatory pathways (glycogen synthase kinase-3β, nuclear factor-κB and interleukin-1β). All the above pleiotropic effects of erythropoietin were lost in β-common receptor knockout mice. Erythropoietin attenuates the impaired systolic contractility associated with sepsis by activation of the β-common receptor, which, in turn, results in activation of survival pathways and inhibition of inflammation.
authors.affiliation: Centre for Translational Medicine and Therapeutics, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, The William Harvey Research Institute, EC1M 6BQ, London, UK. a.i.a.khan@qmul.ac.uk
authors.forename: Areeg I
authors.initials: AI
authors.lastname: Khan
authors.forename: Sina M
authors.initials: SM
authors.lastname: Coldewey
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Muhammed M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
authors.forename: Amar
authors.initials: A
authors.lastname: Kapoor
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D002432:Cecum / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism*; D019446:Endotoxemia / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D004921:Erythropoietin / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006334:Heart Function Tests; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011677:Punctures; D018805:Sepsis / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D053648:Cytokine Receptor Common beta Subunit; D053583:Interleukin-1beta; D051996:Transcription Factor RelA; D004921:Erythropoietin; D052250:Nitric Oxide Synthase Type III; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3