Effects of 5,14-HEDGE, a 20-HETE mimetic, on lipopolysaccharide-induced changes in MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway and circulating miR-150, miR-223, and miR-297 levels in a rat model of septic shock.

Abstract

OBJECTIVES:

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), which mimics the effects of endogenously produced 20-HETE, prevents vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The present study was performed to determine whether decreased renal and cardiovascular expression and activity of myeloid differentiation factor 88 (MyD88)/transforming growth factor-activated kinase 1 (TAK1)/inhibitor of κB (IκB) kinase β (IKKβ)/IκB-α/nuclear factor-κB (NF-κB) pathway and reduced circulating microRNA (miR)-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation 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 LPS challenge and blood, kidney, heart, thoracic aorta, and superior mesenteric artery were collected for measurement of the protein expression.

RESULTS:

LPS-induced fall in blood pressure and rise in heart rate were associated with increased MyD88 expression and phosphorylation of TAK1 and IκB-α in cytosolic fractions of the tissues. LPS also caused an increase in both unphosphorylated and phosphorylated NF-κB p65 proteins in the cytosolic and nuclear fractions as well as nuclear translocation of NF-κB p65. In addition, serum miR-150, miR-223, and miR-297 expression levels were increased in LPS-treated rats. These effects of LPS were prevented by 5,14-HEDGE.

CONCLUSIONS:

These results suggest that downregulation of MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway as well as decreased circulating miR-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation in the rat model of septic shock.

• Authors: A Nihal Sari, Belma Korkmaz, Mehmet Sami Serin, Meltem Kacan, Demet Unsal, C Kemal Buharalioglu, Seyhan Sahan Firat, Vijay L Manthati, John R Falck, Kafait U Malik, Bahar Tunctan
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 63 Issue 9 Pg. 741-56 (Sep 2014) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 24915805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxyeicosatetraenoic Acids
• I kappa B beta protein
• I-kappa B Proteins
• Lipopeptides
• Lipopolysaccharides
• MicroRNAs
• Myd88 protein, rat
• Myeloid Differentiation Factor 88
• N-(20-hydroxyeicosa-5,14-dienoyl)glycine
• Protective Agents
• Transcription Factor RelA
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• I-kappa B Kinase
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Aorta, Thoracic (drug effects, metabolism)
• Arterial Pressure (drug effects)
• Disease Models, Animal
• Heart Rate (drug effects)
• Hydroxyeicosatetraenoic Acids
• I-kappa B Kinase (metabolism)
• I-kappa B Proteins (metabolism)
• Kidney (drug effects, metabolism)
• Lipopeptides (pharmacology, therapeutic use)
• Lipopolysaccharides
• MAP Kinase Kinase Kinases (metabolism)
• Male
• Mesenteric Artery, Superior (drug effects, metabolism)
• MicroRNAs (blood)
• Myeloid Differentiation Factor 88 (metabolism)
• Myocardium (metabolism)
• Protective Agents (pharmacology, therapeutic use)
• Rats, Wistar
• Shock, Septic (blood, drug therapy, metabolism, physiopathology)
• Transcription Factor RelA (metabolism)