Altered monocyte CD44 expression in peripheral arterial disease is corrected by fish oil supplementation
Introduction
Peripheral arterial disease (PAD) is an atherosclerotic disease. It affects up to 28% of the adult population and is associated with leg pain, impairment of mobility, and an increased risk of cardiovascular death [1]. It is now widely accepted that atherosclerosis is an inflammatory process [2]. Monocytes adhering to the wall of arteries play a key role in the initiation and progression of atheromatous lesions. Within the plaque monocytes take up cholesterol to form large foam cells, which perpetuate the inflammatory state by the release of cytokines, chemokines and growth factors [2].
CD44 is an adhesion molecule functionally associated with extravasation of cells. Its principal role is as a cell surface receptor for the intercellular matrix polymer hyaluronic acid (HA) [3]. CD44–HA interactions have been associated with leukocyte rolling on inflamed vascular endothelium [4] and are required for HA catabolism to smaller units which can promote inflammation [5].CD44 can be upregulated in response to inflammatory cytokines such as interleukin (IL)-1α and tumour necrosis factor (TNF)-α [6], [7], and increased CD44 expression has been associated with inflammation and autoimmune disease [8]. A study in apo E−/− mice demonstrated that CD44 is directly involved in monocyte recruitment and the progression of atherosclerosis [9]. Thus, CD44 expression on monocytes may be important in their recruitment to atherosclerotic plaques.
In addition to the basic CD44 structural exons, the human CD44 gene has nine exons termed variants 2–10. These exons are spliced from the mRNA and in theory can produce thousands of combinations, although only 20 or so variants have been detected [10]. The variant exons confer greater post-translational modification to the receptor and are thought to alter function. Different splice variants have been associated with different inflammatory diseases [11]. CD44 variant 3 (CD44v3) contains a binding site for heparin sulphate chains, which can in turn bind growth factors [3]. This has led to the belief that isoforms containing the CD44v3 exon may have relevance in inflammation. The association of specific CD44 variants with atherosclerosis is unknown.
Dietary supplementation with long chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs), found in oily fish and fish oils, has been shown to reduce inflammation in several settings [12] and a reduced number of macrophages were found in carotid atherosclerotic plaques from individuals supplemented with fish oil compared to controls [13]. The mechanisms underlying these observations have yet to be fully determined. Regulation of CD44 expression by fatty acids could play a role in reducing monocyte recruitment and differentiation in atherosclerotic plaques. The effect of fish oil supplementation on CD44 and CD44v3 expression has not been investigated to date.
Here we examine the hypothesis that CD44 and CD44v3 expression are upregulated on blood monocytes from individuals with the inflammatory condition PAD and that dietary fish oil will reduce CD44 and CD44v3 expression.
Section snippets
Study population
The experimental protocols involving PAD patients and healthy controls, including that for obtaining informed consent, were approved by the Southampton and South West Hampshire Research Ethics Committee.
Male patients with symptomatic PAD (stable claudication) and with ankle brachial pressure index (ABPI) <0.9 and male controls were recruited into the study. PAD patients were excluded if they had had intervention for the condition within the previous 3 months or if they showed critical leg
Characteristics of PAD patients and healthy controls
Ninety-seven PAD patients (age range 46–85 years) and 108 healthy controls (age range 45–83 years) were recruited into the study. The characteristics of the two groups are shown in Table 1. No difference was observed between PAD patients and controls in the total:HDL cholesterol ratio (4.16 ± 0.97 vs 4.62 ± 1.0) or in plasma triacylglycerol concentrations. Plasma C-reactive protein concentrations were higher in the PAD group compared to controls (4.6 ± 6.0 mg/l vs 2.3 ± 1.6 mg/l (p = 0.001)).
CD44 expression on monocytes – effects of PAD and fish oil
Blood monocytes
Discussion
This study shows that CD44 expression is upregulated on peripheral blood monocytes from PAD patients compared to healthy controls. This finding is in accordance with the findings of Krettek that atheromatous plaques expressed more CD44 by Western blot than control arterial samples [16] and also reports of increased CD44 expression on blood cells in other inflammatory conditions such as rheumatoid arthritis, ulcerative colitis and Crohn's disease [8], [17]. However, to our knowledge, this is the
Acknowledgements
The project was funded by a grant from the Biotechnology and Biological Sciences Research Council (BBSRC) UK. Fish oil capsules were supplied by Seven Seas, Hull, UK.
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