Abstract
TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.7 macrophages and Angiotensin II-infused apolipoprotein E-deficient mice were in vitro and in vivo models, respectively. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 on TLR4 functional activity in response to bacterial LPS (in vitro) and endogenous ligands of sterile inflammation (in vitro and in vivo). Following activation of TLR4, in vitro and in vivo data revealed that FP7 inhibited p38 MAPK and p65 NF-kB phosphorylation associated with down-regulation of a number of TLR4-dependent pro-inflammatory proteins. In addition to inhibition of LPS-induced TLR4 signalling, FP7 negatively regulated TLR4 activation in response to ligands of sterile inflammation (hydroperoxide-rich oxidised LDL, in vitro and Angiotensin II infusion, in vivo). These results demonstrate the ability of FP7 to negatively regulate in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling both in humans and mice, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of vascular inflammatory diseases.
Highlights
The worldwide incidence of cardiovascular diseases (CVD) has increased dramatically for the last few decades because of a variety of health, economic and social factors.[1]
Pharmacological intervention using TLR4 antagonists has been a challenging approach for the last two decades; these candidates failed in different stages of clinical trials and a generation of new TLR4 modulators is of great interest.[11,12]
In this study we showed that FP7 had the potential to inhibit haematopoietic and non-haematopoietic TLR4 signalling in response to distinct TLR4 ligands which are associated with the pathogenesis of CVD
Summary
The worldwide incidence of cardiovascular diseases (CVD) has increased dramatically for the last few decades because of a variety of health, economic and social factors.[1]. Role in all stages of CVD.[2] TLRs serve as PRRs within the immune system and recognise PAMPs and dangerassociated molecular patterns (DAMPs) ligands as inflammatory triggers. Among these receptors, TLR4 is known to be activated by the Gram-negative bacteria LPS. TLR4 is activated by endogenous DAMPs, known as ligands of sterile inflammation, such as heat-shock proteins,[3] fibronectins, small fragments of hyaluronan,[4] saturated fatty acids[5] and oxidised low-density lipoprotein (oxLDL).[6] TLR4 expression has been described both in haematopoietic and non-haematopoietic cells.[6] TLR4 has been documented to be implicated in the pathogenesis of inflammatory-related CVD. Recent studies have demonstrated that deletion of the TLR4 gene in haematopoietic and non-haematopoietic cells protected against CVD.[7,8,9,10] These findings strongly support the idea that regulation of TLR4 may be a novel target for therapeutic control of CVD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
