Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock
•5,14-HEDGE, a 20-HETE mimetic, reversed hypotension and tachycardia in endotoxemic rats.•5,14-HEDGE prevented LPS-induced increase in expression/activity of iNOS/sGC/PKG pathway, COX-2, and NOX2.•LPS-induced decrease in CYP4A1 expression and 20-HETE production was prevented by 5,14-HEDGE.•5,14-HEDG...
Gespeichert in:
Veröffentlicht in: | Nitric oxide 2013-09, Vol.33, p.18-41 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | •5,14-HEDGE, a 20-HETE mimetic, reversed hypotension and tachycardia in endotoxemic rats.•5,14-HEDGE prevented LPS-induced increase in expression/activity of iNOS/sGC/PKG pathway, COX-2, and NOX2.•LPS-induced decrease in CYP4A1 expression and 20-HETE production was prevented by 5,14-HEDGE.•5,14-HEDGE prevented LPS-induced increase in peroxynitrite formation.•Stable 20-HETE mimetics may have a therapeutic value in the treatment of septic shock.
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), prevents vascular hyporeactivity, hypotension, tachycardia, and inflammation in rats treated with lipopolysaccharide (LPS) and mortality in endotoxemic mice. These changes were attributed to decreased production of inducible nitric oxide (NO) synthase (iNOS)-derived NO, cyclooxygenase (COX)-2-derived vasodilator prostanoids, and proinflammatory mediators associated with increased cyctochrome P450 (CYP) 4A1-derived 20-HETE and CYP2C23-dependent antiinflammatory mediator formation. The aim of this study was to determine whether decreased expression and activity of iNOS, soluble guanylyl cyclase (sGC), protein kinase G (PKG), COX-2, gp91phox (NOX2; a superoxide generating NOX enzyme), and peroxynitrite production associated with increased expression of COX-1 and CYP4A1 and 20-HETE formation in renal and cardiovascular tissues of rats contributes to the effect of 5,14-HEDGE to prevent vasodilation, hypotension, tachycardia, and inflammation in response to systemic administration of LPS. Mean arterial pressure fell by 28mmHg and heart rate rose by 47beats/min in LPS (10mg/kg, i.p.)-treated rats. Administration of LPS also increased mRNA and protein expression of iNOS and COX-2 associated with a decrease in COX-1 and CYP4A1 mRNA and protein expression. Increased NOS activity, iNOS-heat shock protein 90 complex formation (an index for iNOS activity), protein expression of phosphorylated vasodilator stimulated phosphoprotein (an index for PKG activity), gp91phox, p47phox (NOXO2; organizer subunit of gp91phox), and nitrotyrosine (an index for peroxynitrite production) as well as cGMP (an index for sGC activity), 6-keto-PGF1α (a stable metabolite PGI2) and PGE2 levels (indexes for COX activity), and nitrotyrosine levels by LPS were also associated with decreased CYP hydroxylase activity as measured by 20-HETE formation from arachidonic acid in renal microsomes |
---|---|
ISSN: | 1089-8603 1089-8611 |
DOI: | 10.1016/j.niox.2013.05.001 |