5,14-HEDGE, a 20-HETE mimetic, reverses hypotension and improves survival in a rodent model of septic shock: contribution of soluble epoxide hydrolase, CYP2C23, MEK1/ERK1/2/IKKβ/IκB-α/NF-κB pathway, and proinflammatory cytokine formation.

Abstract

We have previously demonstrated that a stable synthetic analog of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), restores vascular reactivity, blood pressure, and heart rate in endotoxemic rats. The aim of this study was to determine whether decreased renal expression and activity of soluble epoxide hydrolase (sEH), MEK1, ERK1/2, IKKβ, IκB-α, and NF-κB as well as systemic and renal proinflammatory cytokine production associated with increased expression and activity of CYP2C23 contributes to the effect of 5,14-HEDGE to prevent hypotension, tachycardia, inflammation, and mortality in response to systemic administration of lipopolysaccharide (LPS). Blood pressure fell by 33 mmHg and heart rate rose by 57 beats/min in LPS (10 mg/kg, i.p.)-treated rats. Administration of LPS also increased mRNA and protein expression of sEH associated with a decrease in CYP2C23 mRNA and protein expression. Increased activity of sEH and p-MEK1, p-ERK1/2, p-IκB-α, NF-κB, and p-NF-κB protein levels as well as TNF-α and IL-8 production by LPS were also associated with a decreased activity of AA epoxygenases. These effects of LPS were prevented by 5,14-HEDGE (30 mg/kg, s.c.; 1 h after LPS). Treatment of endotoxemic mice with 5,14-HEDGE also raised the survival rate of animals from 84% to 98%. A competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, 20-HEDE (30 mg/kg, s.c.; 1 h after LPS) prevented the effects of 5,14-HEDGE on blood pressure, heart rate, expression and/or activity of sEH, CYP2C23, and ERK1/2 as well as TNF-α and IL-8 levels in rats treated with LPS. These results suggest that decreased expression and/or activity of sEH and MEK1/ERK1/2/IKKβ/IκB-α/NF-κB pathway as well as proinflammatory cytokine production associated with increased CYP2C23 expression and antiinflammatory mediator formation participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, inflammation, and mortality in the rodent model of septic shock.

• Authors: Bahar Tunctan, Belma Korkmaz, Ayse Nihal Sari, Meltem Kacan, Demet Unsal, Mehmet Sami Serin, C Kemal Buharalioglu, Seyhan Sahan-Firat, Tuba Cuez, Wolf-Hagen Schunck, John R Falck, Kafait U Malik
• Journal: Prostaglandins & other lipid mediators (Prostaglandins Other Lipid Mediat) 2013 Apr-May Vol. 102-103 Pg. 31-41 ISSN: 1098-8823 [Print] United States
• PMID: 23454652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Cyp2c23 protein, rat
• Hydroxyeicosatetraenoic Acids
• Lipopeptides
• N-(20-hydroxyeicosa-5,14-dienoyl)glycine
• NF-kappa B
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2J2
• Epoxide Hydrolases

Topics

• Animals
• Blood Pressure (drug effects)
• Cytochrome P-450 CYP2J2
• Cytochrome P-450 Enzyme System (biosynthesis)
• Disease Models, Animal
• Epoxide Hydrolases (biosynthesis)
• Gene Expression Regulation (drug effects)
• Heart Rate (drug effects)
• Humans
• Hydroxyeicosatetraenoic Acids (administration & dosage, chemical synthesis)
• Hypotension (drug therapy, pathology)
• Inflammation (drug therapy, metabolism, pathology)
• Lipopeptides (administration & dosage, chemical synthesis)
• MAP Kinase Signaling System
• Mice
• NF-kappa B (metabolism)
• Rats
• Shock, Septic (drug therapy, metabolism, pathology)
• Survival