Objectives: The toll-like receptors (TLRs), including TLR4, have been shown to play a crucial role in vascular inflammatory diseases, such as atherosclerosis and aneurysm. The main goal of this study was to determine the potential of IAXO-102 (Innaxon, Tewkesbury), a novel small molecule TLR4 antagonist, to modulate non-hematopoietic TLR4 proinflammatory signalling and inhibit experimental abdominal aortic aneurysm (AAA) development. Methods: Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our in vitro and in vivo models respectively. Western blotting, antibody array and ELISA approaches were used to explore the effect of IAXO-102 on TLR4 functional activity on two levels: modulation of TLR4-induced mitogen activated protein kinases (MAPK) and p65 NF-kB phosphorylation and expression of TLR4 dependent proinflammatory proteins. Results: Following activation of TLR4, in vitro/in vivo data revealed that IAXO-102 inhibited MAPK and p65 NF-kB phosphorylation associated with down regulation of the expression of TLR4 and TLR4 dependent proinflammatory proteins. Furthermore, IAXO-102 decreased Angiotensin II-induced aortic expansion, rupture and incidence of AAA. Conclusions: These results demonstrate the ability of IAXO-102 to negatively regulate TLR4 signalling and to inhibit experimental AAA development, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of AAA.

Huggins, C., Pearce, S., Peri, F., Neumann, F., Cockerill, G., Pirianov, G. (2015). A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development. ATHEROSCLEROSIS, 242(2), 563-570 [10.1016/j.atherosclerosis.2015.08.010].

A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development

PERI, FRANCESCO
;
2015

Abstract

Objectives: The toll-like receptors (TLRs), including TLR4, have been shown to play a crucial role in vascular inflammatory diseases, such as atherosclerosis and aneurysm. The main goal of this study was to determine the potential of IAXO-102 (Innaxon, Tewkesbury), a novel small molecule TLR4 antagonist, to modulate non-hematopoietic TLR4 proinflammatory signalling and inhibit experimental abdominal aortic aneurysm (AAA) development. Methods: Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our in vitro and in vivo models respectively. Western blotting, antibody array and ELISA approaches were used to explore the effect of IAXO-102 on TLR4 functional activity on two levels: modulation of TLR4-induced mitogen activated protein kinases (MAPK) and p65 NF-kB phosphorylation and expression of TLR4 dependent proinflammatory proteins. Results: Following activation of TLR4, in vitro/in vivo data revealed that IAXO-102 inhibited MAPK and p65 NF-kB phosphorylation associated with down regulation of the expression of TLR4 and TLR4 dependent proinflammatory proteins. Furthermore, IAXO-102 decreased Angiotensin II-induced aortic expansion, rupture and incidence of AAA. Conclusions: These results demonstrate the ability of IAXO-102 to negatively regulate TLR4 signalling and to inhibit experimental AAA development, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of AAA.
Articolo in rivista - Articolo scientifico
Experimental aneurysms; Toll like receptor 4; Toll like receptor 4 antagonist IAXO-102; Vascular inflammation;
Experimental aneurysms; Toll like receptor 4; Toll like receptor 4 antagonist IAXO-102; Vascular inflammation; Amino Sugars; Animals; Aorta; Aortic Aneurysm, Abdominal; Apolipoproteins E; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glycolipids; Human Umbilical Vein Endothelial Cells; Humans; Incidence; Inflammation; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Cardiology and Cardiovascular Medicine
English
563
570
8
Huggins, C., Pearce, S., Peri, F., Neumann, F., Cockerill, G., Pirianov, G. (2015). A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development. ATHEROSCLEROSIS, 242(2), 563-570 [10.1016/j.atherosclerosis.2015.08.010].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/152462
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