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

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 PPAR alpha/beta/gamma and RXR alpha associated with decreased expression and/or activity of AP-1 and importin-alpha 3 participates in the protective effect of 5,14-HEDGE in response to systemic administration of lipopolysaccharide (LPS). 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. 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 PPAR alpha/beta/gamma and nuclear RXR alpha, in addition to nuclear translocation of PPAR alpha/beta/gamma proteins, were decreased, while cytosolic/nuclear AP-1 subunit c-jun/phosphorylated c-jun and importin-alpha 3 protein expression as well as their nuclear translocation were increased. The LPS-induced changes were prevented by 5,14-HEDGE. The results suggest that an increase in the expression of PPAR alpha/beta/gamma and RXR alpha as well as a decrease in AP-1 and importin-alpha 3 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.