Abstract
The acute phase protein serum amyloid A (SAA), a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF) in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction—a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC). HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1), WRW4; receptor for advanced glycation-endproducts (RAGE), (endogenous secretory RAGE; esRAGE) and toll-like receptors-2/4 (TLR2/4) (OxPapC), before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL), a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.
Highlights
The pathogenesis of atherosclerosis encompasses arterial wall inflammation, accumulation of native and oxidised lipids, plaque formation and thrombosis [1]
Due to the atherogenic potential of serum amyloid A (SAA)-mediated signalling on the vascular endothelium, we examined the effectiveness of inhibiting SAA activity in human carotid artery endothelial cells (HCtAEC) with various pharmacological inhibitors targeting formyl peptide receptor-like-1 (FPRL-1), receptor for advanced glycation-endproducts (RAGE) and toll-like receptors-2/4 (TLR2/4)
SAA induces the expression of pro-inflammatory and pro-thrombotic factors in peripheral blood mononuclear cells [22] and endothelial cells [24,39]
Summary
The pathogenesis of atherosclerosis encompasses arterial wall inflammation, accumulation of native and oxidised lipids, plaque formation and thrombosis [1]. Arterial endothelial dysfunction leads to loss of barrier function that promotes inflammatory cell uptake and lipid accumulation. The exact cause of endothelial dysfunction leading to loss of barrier function is not known but may be linked to upregulation of cellular adhesion molecules [4,5,6], altered production and bioactivity of endothelium-derived nitric oxide (NO) [7] and accumulation of reactive oxygen species through a mechanism of unregulated production and decreased ability to neutralise damaging oxidants [8]. The inflammatory cytokine tumour necrosis factor (TNF) promotes the expression of adhesion molecules on endothelial cells and induces tissue factor (TF), itself linked to the development of atherosclerotic plaque and subsequent thrombus formation [9,10,11]
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.
