title: Activation of JAK-STAT and nitric oxide signaling as a mechanism for donor heart dysfunction.
abstract: BACKGROUND
  Donor heart dysfunction (DHD) precluding procurement for transplantation occurs in up to 25% of brain-dead (BD) donors. The molecular mechanisms of DHD remain unclear. We investigated the potential role of myocardial interleukin (IL)-6 signaling through the JAK2-STAT3 pathway, which can lead to the generation of nitric oxide (NO) and decreased cardiac myocyte contractility.
  
  
  METHODS
  Hearts were procured using standard technique with University of Wisconsin (UW) solution from 14 donors with a left ventricular (LV) ejection fraction of <35% (DHD). Ten hearts with normal function (NF) after BD served as controls. LV IL-6 was quantitated by enzyme-linked immunoassay (ELISA) and JAK2-STAT3 signaling was assessed by expression of phosphorylated STAT3. Inducible NO synthase (iNOS) and caspase-3 were measured by activity assays.
  
  
  RESULTS
  Myocardial IL-6 expression was 8-fold greater in the DHD group vs NF controls. Phosphorylated STAT3 expression was 5-fold higher in DHD than in NF, indicating increased JAK2-STAT3 signaling. LV activity of iNOS was 2.5-fold greater in DHD than in NF. LV expression of the pro-apoptotic gene Bnip3 and caspase-3 activity were 3-fold greater in the DHD group than in the NF group.
  
  
  CONCLUSIONS
  Myocardial IL-6 expression is significantly higher in the setting of DHD compared with hearts procured with normal function. This may lead to increased JAK2-STAT3 signaling and upregulation of iNOS, which has been shown to decrease cardiac myocyte contractility. Increased NO production may also lead to increased apoptosis through upregulation of Bnip3 gene expression. Increased iNOS signaling may be an important mechanism of DHD and represents a novel therapeutic target to improve cardiac function after BD.
authors.affiliation: Department of Surgery, Section of Cardiothoracic Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Bulcao
authors.forename: Karen M
authors.initials: KM
authors.lastname: D'Souza
authors.forename: Ricky
authors.initials: R
authors.lastname: Malhotra
authors.forename: Michelle
authors.initials: M
authors.lastname: Staron
authors.forename: Jody Y
authors.initials: JY
authors.lastname: Duffy
authors.forename: Prakash K
authors.initials: PK
authors.lastname: Pandalai
authors.forename: Valluvan
authors.initials: V
authors.lastname: Jeevanandam
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Akhter
mesh_terms: D000328:Adult; D001926:Brain Death; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D006321:Heart / Q000503:physiopathology*; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014019:Tissue Donors
chemical_list: C090121:BNIP3 protein, human; D015850:Interleukin-6; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3