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

Sefika Pinar Senol, Meryem Temiz, Demet Sinem Guden, Pelin Cecen, Ayse Nihal Sari, Seyhan Sahan-Firat, J R Falck, Rambabu Dakarapu, Kafait U. Malik, Bahar Tunctan

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Objectives: 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.

Original languageEnglish (US)
Pages (from-to)1-21
Number of pages21
JournalInflammation Research
DOIs
StateAccepted/In press - Feb 13 2016

Keywords

  • AP-1
  • Endotoxin
  • Importin-α3
  • PPARα/β/γ
  • RXRα
  • Septic shock

ASJC Scopus subject areas

  • Pharmacology
  • Immunology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this