title: Contribution of PPARα/β/γ, AP-1, importin-α3, and RXRα to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against hypotension, tachycardia, and inflammation in a rat model of septic shock.
abstract: OBJECTIVE
  We have previously demonstrated that downregulation of the MyD88/TAK1-dependent signaling pathway associated with increased CYP4A1 expression and 20-HETE formation participates in the protective effect of N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), a 20-HETE mimetic, against vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The aim of this study was to determine whether increased renal and cardiovascular expression of PPARα/β/γ and RXRα associated with decreased expression and/or activity of AP-1 and importin-α3 participates in the protective effect of 5,14-HEDGE 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 saline or LPS administration and the kidney, heart, thoracic aorta, and superior mesenteric artery were collected for measurement of protein expression.
  
  
  RESULTS
  Blood pressure fell by 33 mmHg and heart rate rose by 72 beats/min at 4 h after LPS administration. In LPS-treated rats, tissue protein expressions of cytosolic/nuclear PPARα/β/γ and nuclear RXRα, in addition to nuclear translocation of PPARα/β/γ proteins, were decreased, while cytosolic/nuclear AP-1 subunit c-jun/phosphorylated c-jun and importin-α3 protein expression as well as their nuclear translocation were increased. The LPS-induced changes were prevented by 5,14-HEDGE.
  
  
  CONCLUSIONS
  The results suggest that an increase in the expression of PPARα/β/γ and RXRα as well as a decrease in AP-1 and importin-α3 expression/activity participates in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation during endotoxemia and thus have a beneficial effect in septic shock treatment.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: Sefika Pinar
authors.initials: SP
authors.lastname: Senol
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: Meryem
authors.initials: M
authors.lastname: Temiz
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: Demet Sinem
authors.initials: DS
authors.lastname: Guden
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: Pelin
authors.initials: P
authors.lastname: Cecen
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: Ayse Nihal
authors.initials: AN
authors.lastname: Sari
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey.
authors.forename: Seyhan
authors.initials: S
authors.lastname: Sahan-Firat
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Rambabu
authors.initials: R
authors.lastname: Dakarapu
authors.affiliation: Department of Pharmacology, College of Medicine, Center for Health Sciences, University of Tennessee, Memphis, TN, USA.
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169, Mersin, Turkey. btunctan@gmail.com.
authors.forename: Bahar
authors.initials: B
authors.lastname: Tunctan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006893:Hydroxyeicosatetraenoic Acids; D007022:Hypotension / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D017208:Rats, Wistar; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism*; D013610:Tachycardia / Q000188:drug therapy / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D006893:Hydroxyeicosatetraenoic Acids; D055666:Lipopeptides; D008070:Lipopolysaccharides; C533498:N-(20-hydroxyeicosa-5,14-dienoyl)glycine; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D047490:Retinoid X Receptor alpha; D018808:Transcription Factor AP-1; D028901:alpha Karyopherins; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid
keywords: AP-1; Endotoxin; Importin-α3; PPARα/β/γ; RXRα; Septic shock