A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development. Issue 2 (October 2015)

• Record Type: Journal Article
• Authors: Huggins, Christopher; Pearce, Stuart; Peri, Francesco; Neumann, Frank; Cockerill, Gillian; Pirianov, Grisha
• Is Part Of: Atherosclerosis. Volume 242:Issue 2(2015)
• Page Start: 563
• Page End: 570
• Publication Date: 2015-10
• Subjects: Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.08.010
• Languages: English
• ISSNs: 0021-9150

Abstract

<abstract xml:lang="en" abstract-type="author" id="abs0010"> <title id="sectitle0010">Abstract</title> <sec> <title id="sectitle0015">Objectives</title> <p id="abspara0010">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.</p> </sec> <sec> <title id="sectitle0020">Methods</title> <p id="abspara0015">Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p> </sec> <sec> <title id="sectitle0025">Results</title> <p id="abspara0020">Following activation of TLR4, <italic>in vitro/in vivo</italic> 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.</p> </sec> <sec> <title id="sectitle0030">Conclusions</title> <p id="abspara0025">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.</p> </sec> </abstract>