The acute-phase protein serum amyloid A induces endothelial dysfunction that is inhibited by high-density lipoprotein |
| |
Authors: | Witting Paul K Song Changjie Hsu Kenneth Hua Susan Parry Sarah N Aran Roshanak Geczy Carolyn Freedman Saul Benedict |
| |
Institution: | a Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW 2006 Australiab ANZAC Research Institute, Concord Hospital, University of Sydney, NSW 2139 Australiac Center for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052 Australia |
| |
Abstract: | The acute-phase protein serum amyloid A (SAA) is elevated during inflammation and may be deposited in atheroma where it promotes atherosclerosis. We investigated the proatherogenic effects of SAA on the vascular endothelium and their regulation by high-density lipoprotein (HDL). Exposure of human aortic endothelial cells (HAEC) to SAA (0.25-25 μg/ml) decreased nitric oxide (•NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10 μg/ml) stimulated a Ca2+ influx linked to apocynin-sensitive superoxide radical anion (O2•−) production. Gene expression for arginase-1, nuclear factor κB (NF-κB), interleukin-8, and tissue factor (TF) increased within 4 h of SAA stimulation. Enzymatically active Arg-1/2 was detected in HAEC cultured with SAA for 24 h. Therefore, in addition to modulating •NO bioavailability by stimulating O2•− production in the endothelium, SAA modulated vascular l-Arg bioavailability. SAA also diminished relaxation of preconstricted aortic rings induced by acetylcholine, and added superoxide dismutase restored the vascular response. Preincubation of HAEC with HDL (100 or 200, but not 50, μg/ml) before (not after) SAA treatment ameliorated the Ca2+ influx and O2•− production; decreased TF, NF-κB, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating •NO and l-Arg bioavailability, and HDL pretreatment may be protective. The relative HDL to SAA concentrations may regulate the proatherogenic properties of SAA on the vascular endothelium. |
| |
Keywords: | ACh acetylcholine l-Arg" target="_blank">l-Arg l-arginine" target="_blank">l-arginine Arg-1/2 arginase-1/2 cGMP guanosine 3&prime 5&prime -cyclic monophosphate DPI diphenyliodonium EC endothelial cell HAEC human aortic endothelial cell HPSS Hepes-buffered physiological salt solution MCP-1 monocyte chemotactic protein-1 &bull" target="_blank">&bull NO nitric oxide ODQ 1H-(1 2 4)-oxadiazolo-(4 3-a)-quinoxalin-1-one O2&bull &minus superoxide anion radical PBMC peripheral blood mononuclear cells PEG-SOD polyethylene glycol superoxide dismutase conjugate sGC soluble guanylyl cyclase SNP S-nitrosopenicillamine SAA serum amyloid A TF tissue factor |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|