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

• Published in: European 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
• Language: English
• Published: Netherlands Elsevier B.V 05.05.2017
• Subjects: 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; Lipopolysaccharide; mTOR; Inflammation; rpS6; Rat; Hypotension
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.02.034

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.