title: Effects of 5,14-HEDGE, a 20-HETE mimetic, on lipopolysaccharide-induced changes in MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway and circulating miR-150, miR-223, and miR-297 levels in a rat model of septic shock.
abstract: OBJECTIVE
  We have previously demonstrated that a stable synthetic analog of 20-hydroxyeicosatetraenoic acid (20-HETE), N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), which mimics the effects of endogenously produced 20-HETE, prevents vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The present study was performed to determine whether decreased renal and cardiovascular expression and activity of myeloid differentiation factor 88 (MyD88)/transforming growth factor-activated kinase 1 (TAK1)/inhibitor of κB (IκB) kinase β (IKKβ)/IκB-α/nuclear factor-κB (NF-κB) pathway and reduced circulating microRNA (miR)-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation in response to systemic administration of lipopolysaccharide (LPS).
  
  
  METHODS
  Conscious male Wistar rats received saline (4 ml/kg) or LPS (10 mg/kg) at time 0. Blood pressure and heart rate were measured using a tail-cuff device. Separate groups of LPS-treated rats were given 5,14-HEDGE (30 mg/kg) 1 h after injection of saline or LPS. The rats were killed 4 h after LPS challenge and blood, kidney, heart, thoracic aorta, and superior mesenteric artery were collected for measurement of the protein expression.
  
  
  RESULTS
  LPS-induced fall in blood pressure and rise in heart rate were associated with increased MyD88 expression and phosphorylation of TAK1 and IκB-α in cytosolic fractions of the tissues. LPS also caused an increase in both unphosphorylated and phosphorylated NF-κB p65 proteins in the cytosolic and nuclear fractions as well as nuclear translocation of NF-κB p65. In addition, serum miR-150, miR-223, and miR-297 expression levels were increased in LPS-treated rats. These effects of LPS were prevented by 5,14-HEDGE.
  
  
  CONCLUSIONS
  These results suggest that downregulation of MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway as well as decreased circulating miR-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation in the rat model of septic shock.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: A Nihal
authors.initials: AN
authors.lastname: Sari
authors.forename: Belma
authors.initials: B
authors.lastname: Korkmaz
authors.forename: Mehmet Sami
authors.initials: MS
authors.lastname: Serin
authors.forename: Meltem
authors.initials: M
authors.lastname: Kacan
authors.forename: Demet
authors.initials: D
authors.lastname: Unsal
authors.forename: C Kemal
authors.initials: CK
authors.lastname: Buharalioglu
authors.forename: Seyhan
authors.initials: S
authors.lastname: Sahan Firat
authors.forename: Vijay L
authors.initials: VL
authors.lastname: Manthati
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
authors.forename: Bahar
authors.initials: B
authors.lastname: Tunctan
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D062186:Arterial Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000097:blood; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017208:Rats, Wistar; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051996:Transcription Factor RelA / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D055666:Lipopeptides; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D020011:Protective Agents; D051996:Transcription Factor RelA; D000099151:MAP Kinase Kinase Kinase 7; C083487:I kappa B beta protein; C507781:Myd88 protein, rat; C533498:N-(20-hydroxyeicosa-5,14-dienoyl)glycine; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid