A brief elevation of serum amyloid A is sufficient to increase atherosclerosis

Joel C Thompson,Colton Jayne,Jennifer Thompson,Patricia G Wilson,Meghan H Yoder,Nancy Webb,Lisa R Tannock

doi:10.1194/jlr.m054015

Abstract

Serum amyloid A (SAA) has a number of proatherogenic effects including induction of vascular proteoglycans. Chronically elevated SAA was recently shown to increase atherosclerosis in mice. The purpose of this study was to determine whether a brief increase in SAA similarly increased atherosclerosis in a murine model. The recombination activating gene 1-deficient (rag1(-/-)) × apolipoprotein E-deficient (apoe(-/-)) and apoe(-/-) male mice were injected, multiple times or just once respectively, with an adenoviral vector encoding human SAA1 (ad-SAA); the injected mice and controls were maintained on chow for 12-16 weeks. Mice receiving multiple injections of ad-SAA, in which SAA elevation was sustained, had increased atherosclerosis compared with controls. Strikingly, mice receiving only a single injection of ad-SAA, in which SAA was only briefly elevated, also had increased atherosclerosis compared with controls. Using in vitro studies, we demonstrate that SAA treatment leads to increased LDL retention, and that prevention of transforming growth factor beta (TGF-β) signaling prevents SAA-induced increases in LDL retention and SAA-induced increases in vascular biglycan content. We propose that SAA increases atherosclerosis development via induction of TGF-β, increased vascular biglycan content, and increased LDL retention. These data suggest that even short-term inflammation with concomitant increase in SAA may increase the risk of developing CVD.

Highlights

Serum amyloid A (SAA) has a number of proatherogenic effects including induction of vascular proteoglycans
To determine whether SAA increased the binding of apoB-containing lipoproteins to vascular matrix, primary apolipoprotein E deficient (apoeϪ/Ϫ) vascular smooth muscle cell (VSMC) were incubated with vehicle or SAA for 24 h followed by incubation with Alexa-594-labeled LDL for 2 h
Cells treated with SAA or TGF-␤, known to stimulate proteoglycan synthesis, had increased LDL retention compared with vehicle-treated cells (P < 0.001; Fig. 1); the presence of sodium chlorate attenuated this effect, implying that the increased LDL binding was due to increased proteoglycan synthesis and/or sulfation

Summary

Introduction

Serum amyloid A (SAA) has a number of proatherogenic effects including induction of vascular proteoglycans. We propose that SAA increases atherosclerosis development via induction of TGF-␤, increased vascular biglycan content, and increased LDL retention. These data suggest that even short-term inflammation with concomitant increase in SAA may increase the risk of developing CVD.—Thompson, J. SAA has several characteristics that make it potentially atherogenic It can enhance monocyte recruitment by increasing expression of chemokine ligand 2 (CCL2) in a formyl peptide receptor-like dependent manner [7], directly stimulate foam cell formation by upregulating lectin-like oxidized LDL receptor 1 [8], stimulate chemotaxis of lymphocytes to subcutaneous sites of recombinant SAA injection [9], and facilitate the binding of HDL to vascular proteoglycans [10].

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