The acute-phase protein serum amyloid A induces endothelial dysfunction that is inhibited by high-density lipoprotein

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 mu g/ml) decreased nitric oxide ((center dot)NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10 mu g/ml) stimulated a Ca(2+) influx linked to apocynin-sensitive superoxide radical anion (0) production. Gene expression for arginase-1, nuclear factor kappa B (NF-kappa B), 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 (center dot)NO bioavailability by stimulating O(2)(center dot-) 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, mu g/ml) before (not after) SAA treatment ameliorated the Ca2+ influx and O(2)(center dot-)-production; decreased TF, NF-kappa B, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating (center dot)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. (C) 2011 Elsevier Inc. All rights reserved.