title: Serum amyloid A receptor blockade and incorporation into high-density lipoprotein modulates its pro-inflammatory and pro-thrombotic activities on vascular endothelial cells.
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.
authors.affiliation: Discipline of Pathology, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. belal.chami@sydney.edu.au.
authors.forename: Belal
authors.initials: B
authors.lastname: Chami
authors.affiliation: Discipline of Pathology, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. nicola.gbarrie@gmail.com.
authors.forename: Nicola
authors.initials: N
authors.lastname: Barrie
authors.affiliation: Discipline of Pathology, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. xcai4874@uni.sydney.edu.au.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Cai
authors.affiliation: Discipline of Pathology, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. xiaosuo.wang@sydney.edu.au.
authors.forename: Xiaosuo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Transplantation Immunobiology Group, Central Clinical School, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. moumita.paul@sydney.edu.au.
authors.forename: Moumita
authors.initials: M
authors.lastname: Paul
authors.affiliation: Transplantation Immunobiology Group, Central Clinical School, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Morton-Chandra
authors.affiliation: Transplantation Immunobiology Group, Central Clinical School, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. alexandra.sharland@sydney.edu.au.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sharland
authors.affiliation: Discipline of Pathology, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. martindennis@optusnet.com.au.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Dennis
authors.affiliation: Sydney Medical School, the University of Sydney, ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, NSW 2139, Australia. ben.freedman@sydney.edu.au.
authors.forename: Saul B
authors.initials: SB
authors.lastname: Freedman
authors.affiliation: Discipline of Pathology, Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia. paul.witting@sydney.edu.au.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008075:Lipoproteins, HDL / Q000302:isolation & purification / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000737:chemistry / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D000685:Serum Amyloid A Protein / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; C105101:FPR2 protein, human; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D010455:Peptides; D010713:Phosphatidylcholines; D000067759:Receptor for Advanced Glycation End Products; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D013925:Thromboplastin
keywords: atherosclerosis; high-density lipoprotein; inflammation; serum amyloid A