Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats

Meryem Temiz-Resitoglu, Sefika Pinar Kucukkavruk, Demet Sinem Guden, Pelin Cecen, Ayse Nihal Sari, Bahar Tunctan, Aysegul Gorur, Lulufer Tamer-Gumus, Cuneyt Kemal Buharalioglu, Kafait Malik, Seyhan Sahan-Firat

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Abstract

Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-κB (NF-κB) p65, inhibitor κB (IκB)-α, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)−2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-α and activity of myeloperoxidase (MPO), which results in hypotension and inflammation. Injection of LPS (10 mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF, and TNF-α levels and MPO activity, and increased expressions and/or activities of rpS6, NF-κB p65, iNOS, and COX-2 and decreased expression of IκB-α in renal, cardiac, and vascular tissues. LPS also increased serum and tissue nitrite levels. Rapamycin (1 mg/kg, i.p.) given one h after injection of LPS reversed these effects of LPS. These data suggest that the activation of mTOR/IκB-α/NF-κB pathway associated with vasodilator and proinflammatory mediator formation contributes to LPS-induced hypotension and inflammation.

Original languageEnglish (US)
Pages (from-to)7-19
Number of pages13
JournalEuropean Journal of Pharmacology
Volume802
DOIs
StatePublished - Jan 1 2017

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Controlled Hypotension
Sirolimus
Lipopolysaccharides
Inflammation
Ribosomal Protein S6
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Hypotension
Peroxidase
Tumor Necrosis Factor-alpha
Toll-Like Receptor 4
Injections
Peroxynitrous Acid
Protein-Serine-Threonine Kinases
Metabolic Diseases
Epoprostenol
Nitrites
Vasodilator Agents
Blood Vessels
3'-(1-butylphosphoryl)adenosine

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Temiz-Resitoglu, M., Kucukkavruk, S. P., Guden, D. S., Cecen, P., Sari, A. N., Tunctan, B., ... Sahan-Firat, S. (2017). Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats. European Journal of Pharmacology, 802, 7-19. https://doi.org/10.1016/j.ejphar.2017.02.034

Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats. / Temiz-Resitoglu, Meryem; Kucukkavruk, Sefika Pinar; Guden, Demet Sinem; Cecen, Pelin; Sari, Ayse Nihal; Tunctan, Bahar; Gorur, Aysegul; Tamer-Gumus, Lulufer; Buharalioglu, Cuneyt Kemal; Malik, Kafait; Sahan-Firat, Seyhan.

In: European Journal of Pharmacology, Vol. 802, 01.01.2017, p. 7-19.

Research output: Contribution to journalArticle

Temiz-Resitoglu, M, Kucukkavruk, SP, Guden, DS, Cecen, P, Sari, AN, Tunctan, B, Gorur, A, Tamer-Gumus, L, Buharalioglu, CK, Malik, K & Sahan-Firat, S 2017, 'Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats', European Journal of Pharmacology, vol. 802, pp. 7-19. https://doi.org/10.1016/j.ejphar.2017.02.034
Temiz-Resitoglu, Meryem ; Kucukkavruk, Sefika Pinar ; Guden, Demet Sinem ; Cecen, Pelin ; Sari, Ayse Nihal ; Tunctan, Bahar ; Gorur, Aysegul ; Tamer-Gumus, Lulufer ; Buharalioglu, Cuneyt Kemal ; Malik, Kafait ; Sahan-Firat, Seyhan. / Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats. In: European Journal of Pharmacology. 2017 ; Vol. 802. pp. 7-19.
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AU - Cecen, Pelin

AU - Sari, Ayse Nihal

AU - Tunctan, Bahar

AU - Gorur, Aysegul

AU - Tamer-Gumus, Lulufer

AU - Buharalioglu, Cuneyt Kemal

AU - Malik, Kafait

AU - Sahan-Firat, Seyhan

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