Atherosclerosis 152 2000 43 – 50
Dietary fish oil reduces intercellular adhesion molecule 1 and scavenger receptor expression on murine macrophages
Elizabeth A. Miles , Fiona A. Wallace, Philip C. Calder
Institute of Human Nutrition, Uni6ersity of Southampton, Bassett Crescent East, Southampton SO
16 7
PX, UK Received 11 June 1999; received in revised form 11 October 1999; accepted 28 October 1999
Abstract
During atherogenesis, a pathological accumulation of lipids occurs within aortic intimal macrophages through uptake of oxidised low-density lipoprotein LDL via scavenger receptors. Here we investigate whether some of the anti-atherosclerotic
effects ascribed to dietary fish oil are mediated through effects on macrophage intercellular adhesion molecule 1 ICAM-1 and scavenger receptor expression. Mice were fed on a low fat diet containing 25 gkg corn oil or on high fat diets containing 200
gkg coconut oil, safflower oil or fish oil. Thioglycollate-elicited peritoneal macrophages were analysed for fatty acid composition by gas chromatography. Macrophage scavenger receptor A MSR-A type I + type II and ICAM-1 expression were measured by
flow cytometry and the levels of mRNA coding for MSR-A type I, MSR-A type II and ICAM-1 were measured by reverse-transcription polymerase chain reaction. Feeding mice diets enriched with different fats resulted in significant changes in
the fatty acid profile of macrophages, which reflected the fatty acid compositions of the diets. Macrophages from the fish oil fed mice had the lowest expression of ICAM-1 and MSR-A at the level of both mRNA and cell surface expression. The reduced
expression of ICAM-1 and MSR-A on macrophages from mice fed on a fish oil-rich diet supports our hypothesis that part of the protective effect of fish oil against atherosclerosis might be due to an altered macrophage phenotype and function ameliorating
macrophage-induced plaque formation. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Scavenger receptor; Intercellular adhesion molecule 1; Fish oil; Atherosclerosis; Murine peritoneal macrophage www.elsevier.comlocateatherosclerosis
1. Introduction
Two key initial events within the arterial wall during early atherogenesis are the recruitment and differentia-
tion of circulating monocytes, and the uptake of choles- terol by these tissue macrophages to become lipid-laden
foam cells. Intercellular adhesion molecule 1 ICAM-1 is involved in leukocyte-endothelial interactions and
extravasation of monocytes. ICAM-1 is strongly ex- pressed on macrophages within atherosclerotic plaques
where it has a role in leukocyte-leukocyte interactions [1,2]. Disruption of the ICAM-1 gene in C57Bl6 mice
fed on a high-fat diet results in reduced development of fatty streaks compared with mice with the wild type
ICAM-1 gene and thus protects against the atheroscle- rotic process [3]. Tissue macrophages within the aortic
intima take up cholesterol through binding and uptake of oxidised low-density lipoprotein LDL to become
the lipid-laden foam cells characteristic of early atherosclerotic lesions [4,5]. This oxidised LDL uptake
is mediated via macrophage scavenger receptors [6]. Macrophage scavenger receptor A MSR-A was the
first of the scavenger receptors to be characterised [7]. It has three splice variants, two of which are active as
oxidised LDL receptors type I and type II [7,8]. MSR-A expression is upregulated in animals fed high
cholesterol diets [9] and it has been demonstrated in human atherosclerotic lesions where it co-localizes with
oxidised LDL [10]. The expression of MSR-A type I and type II in human atherosclerotic lesions is restricted
to macrophage-derived foam cells with very little ex- pression by smooth muscle cells or aortic endothelium
Abbre6iations
:
Ac-LDL, acetylated low-density lipoprotein; CO, coconut oil; FO, fish oil; ICAM-1, intercellular adhesion molecule 1;
LDL, low-density lipoprotein; LF, low fat; MSR-A type I, macrophage
scavenger receptor
A type
I; MSR-A
type II,
macrophage scavenger receptor A type II; SO, safflower oil. Corresponding author. Tel.: + 44-1703-594-689; fax: + 44-1703-
595-489. E-mail address
:
eamsoton.ac.uk E.A. Miles. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 4 4 6 - 3
[11]. The role for MSR-A in plaque formation is indi- cated by studies showing that MSR-A knockout mice
fed on a high cholesterol diet have a significantly reduced development of atherosclerotic plaques [12,13].
Increased intake of oily fish or fish oils containing long chain n-3 polyunsaturated fatty acids confers pro-
tection against cardiovascular and ischaemic heart dis- ease in man [14,15]. Addition of fish oil to a diet high
in saturated fats reduced the development of atheroscle- rotic plaques in mice [16], while fish oil given orally to
Watanabe heritable hyperlipidaemic rabbits resulted in a significant reduction of aortic cholesterol content and
a lowered development of aortic atherosclerotic lesions [17].
We hypothesise that some of the anti-atherogenic effects demonstrated by dietary fish oils may be medi-
ated through effects on ICAM-1 and MSR-A expres- sion on macrophages. Therefore, in this study we
investigated the effects of diets containing 20 by weight of different oils fish oil, safflower oil, coconut
oil on surface and mRNA expression of the adhesion molecule ICAM-1 and two scavenger receptors MSR-
A types I and II by murine peritoneal macrophages, a convenient source of inflammatory macrophages.
2. Methods
