Inhibition of NLRP3 inflammasome contributes to protective effect of 5,14-HEDGE against lipopolysaccharide-induced septic shock

Bahar Tunctan, Sefika Pinar Kucukkavruk, Meryem Temiz-Resitoglu, Demet Sinem Guden, Ayse Nihal Sari, Seyhan Sahan-Firat, Mahesh Paudyal, J R Falck, Kafait Ullah Malik

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Background and Objective: Nucleotide binding domain and leucine-rich repeat protein 3 (NLRP3) is reported to be involved in the pathogenesis of numerous inflammatory diseases including Alzheimer disease, Parkinson disease, Prion disease and type 2 diabetes mellitus. Previous studies have 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, inflammation and mortality in a rodent model of septic shock. This study was aimed to assess effect of 5,14-HEDGE on the changes in NLRP3/apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)/pro-caspase-1 inflammasome in lipopolysaccharide (LPS)-induced septic shock in rats. Methodology: Rats were injected with saline (4 mL kg-1) or LPS (10 mg kg-1) at time 0. Blood pressure and heart rate were measured using a tail-cuff device. 5,14-HEDGE (30 mg kg-1) was administered to rats 1 h after injection of saline or LPS. The rats were sacrificed 4 h after saline or LPS injection and kidney, heart, thoracic aorta and superior mesenteric artery were isolated for measurement of caspase-1/11 p20, NLRP3, ASC and β-actin proteins as well as interleukin-1β (IL-1β) levels. Data were analysed by one-way ANOVA followed by Student-Newman-Keuls test for multiple comparisons, Kruskal-Wallis test followed by Dunns test for multiple comparisons and Student's test or Mann-Whitney U tests when appropriate. Results: Blood pressure decreased by 33 mmHg and heart rate increased by 63 bpm in the LPS-treated rats. In the LPS-treated rats, tissue protein expression of caspase-1/11 p20, NLRP3 and ASC in addition to IL-1β levels were increased. The 5,14-HEDGE prevented the LPS-induced changes. Conclusion: These findings suggest that inhibition of renal, cardiac and vascular formation/activity of NLRP3/ASC/pro-caspase-1 inflammasome involves in the protective effect of 5,14-HEDGE on LPS-induced septic shock in rats.

Original languageEnglish (US)
Pages (from-to)654-666
Number of pages13
JournalInternational Journal of Pharmacology
Volume13
Issue number6
DOIs
StatePublished - Jan 1 2017

Keywords

  • 14-HEDGE
  • 20-HETE
  • 5
  • Blood pressure
  • Heart rate
  • IL-1β
  • Inflammation
  • Lipopolysaccharide
  • NLRP3 inflammasome

ASJC Scopus subject areas

  • Pharmacology

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    Tunctan, B., Kucukkavruk, S. P., Temiz-Resitoglu, M., Guden, D. S., Sari, A. N., Sahan-Firat, S., Paudyal, M., Falck, J. R., & Malik, K. U. (2017). Inhibition of NLRP3 inflammasome contributes to protective effect of 5,14-HEDGE against lipopolysaccharide-induced septic shock. International Journal of Pharmacology, 13(6), 654-666. https://doi.org/10.3923/ijp.2017.654.666