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.

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).
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.
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.
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.
AuthorsA 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
JournalInflammation 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
PMID24915805 (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
  • 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)

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