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: Experimental aneurysms -- Toll like receptor 4 -- Toll like receptor 4 antagonist IAXO-102 -- Vascular inflammation; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.08.010
• Languages: English
• ISSNs: 0021-9150

Abstract

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. Highlights: IAXO-102 has a marked inhibitory effect on both aneurysm rupture and development. IAXO-102 can modulate vascular inflammation by blocking non-hematopoietic TLR4 signalling. IAXO-102 is a potential new drug for pharmacological intervention of aneurysms. Further support for TLR4 as a potential target for aneurysm treatment.