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

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 se...

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Published inEuropean journal of pharmacology Vol. 802; pp. 7 - 19
Main Authors 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 U., Sahan-Firat, Seyhan
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 05.05.2017
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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 (10mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF1α, 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 (1mg/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.
AbstractList 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 (10mg/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 (1mg/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.
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 (10mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF1α, 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 (1mg/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.
Author Buharalioglu, Cuneyt Kemal
Malik, Kafait U.
Guden, Demet Sinem
Temiz-Resitoglu, Meryem
Cecen, Pelin
Tunctan, Bahar
Sari, Ayse Nihal
Gorur, Aysegul
Sahan-Firat, Seyhan
Kucukkavruk, Sefika Pinar
Tamer-Gumus, Lulufer
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  email: seyhansahan06@gmail.com
  organization: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28228357$$D View this record in MEDLINE/PubMed
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Keywords Lipopolysaccharide
mTOR
Inflammation
rpS6
Rat
Hypotension
Language English
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Snippet Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic...
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SubjectTerms 6-Ketoprostaglandin F1 alpha - metabolism
Animals
Arterial Pressure - drug effects
Cyclooxygenase 2 - metabolism
Epoprostenol - biosynthesis
Gene Expression Regulation, Enzymologic - drug effects
Heart Rate - drug effects
Hypotension
Hypotension - chemically induced
Hypotension - metabolism
Hypotension - pathology
Hypotension - physiopathology
I-kappa B Proteins - metabolism
Inflammation
Inflammation - chemically induced
Inflammation - pathology
Lipopolysaccharide
Lipopolysaccharides - pharmacology
Male
mTOR
Nitric Oxide - biosynthesis
Nitric Oxide Synthase Type II - metabolism
Peroxidase - metabolism
Peroxynitrous Acid - biosynthesis
Rat
Rats
Rats, Wistar
Ribosomal Protein S6 - metabolism
rpS6
Signal Transduction - drug effects
TOR Serine-Threonine Kinases - metabolism
Transcription Factor RelA - metabolism
Tumor Necrosis Factor-alpha - biosynthesis
Tyrosine - analogs & derivatives
Tyrosine - metabolism
Title Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats
URI https://dx.doi.org/10.1016/j.ejphar.2017.02.034
https://www.ncbi.nlm.nih.gov/pubmed/28228357
Volume 802
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