Altered monocyte CD44 expression in peripheral arterial disease is corrected by fish oil supplementation

doi:10.1016/j.numecd.2008.06.011

Nutrition, Metabolism and Cardiovascular Diseases

Volume 19, Issue 4, May 2009, Pages 247-252

https://doi.org/10.1016/j.numecd.2008.06.011 Get rights and content

Abstract

Background and aims

CD44 and its splice variants can be expressed on all leukocytes, conferring adhesive properties and enhancing cellular recruitment to the endothelium during inflammation. CD44 expression is increased in inflammatory conditions such as rheumatoid arthritis and CD44 variant 3 (CD44v3) expression may be associated with inflammation. We have examined CD44 and CD44v3 expression on peripheral blood monocytes from patients with peripheral arterial disease (PAD) and healthy controls. We have also examined the effect of fish oil supplementation on these markers.

Methods and results

CD44 and CD44v3 were assessed at baseline and following dietary supplementation with fish oil for 12 weeks in both PAD and control groups. Monocytes from PAD patients had higher CD44 expression than those from controls (median intensity fluorescence (MIF): 480 ± 278 vs 336 ± 251 (mean ± SD); p < 0.001). Following 12 weeks dietary supplementation with fish oil, CD44 expression was reduced in PAD patients (MIF: 480 ± 278 vs 427 ± 262; p = 0.05) but not in controls (336 ± 251 vs 355 ± 280; ns). Monocyte CD44v3 expression was lower in cultured monocytes from PAD patients compared to those from controls (0.15 ± 0.15 vs 0.22 ± 0.14 OD units; p < 0.02). This was increased in the PAD group following fish oil supplementation (0.15 ± 0.14 to 0.27 ± 0.23 OD units; p < 0.001).

Conclusion

Monocyte CD44 and CD44v3 expression are altered in arterial disease but are returned towards levels seen in control subjects by dietary 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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View full text

Altered monocyte CD44 expression in peripheral arterial disease is corrected by fish oil supplementation

Abstract

Background and aims

Methods and results

Conclusion

Introduction

Section snippets

Study population

Characteristics of PAD patients and healthy controls

CD44 expression on monocytes – effects of PAD and fish oil

Discussion

Acknowledgements

Matrix Biol

Adv Immunol

Lancet

Am J Clin Nutr

Lancet

Am J Pathol

Am J Pathol

J Biol Chem

Matrix Biol

Curr Opin Struct Biol

Cell

Am J Clin Nutr

Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population

Int J Epidemiol

Atherosclerosis – An inflammatory disease

N Engl J Med

CD44 structure and function

Front Biosci