Long-chain n-3 fatty acids enter advanced atherosclerotic plaques and are associated with decreased inflammation and decreased inflammatory gene expression.

Cawood, A.L., Ding, R., Napper, F.L., Young, R., Williams, J., Ward, M., Gudmundsen, O., Payne, S., Vic, H., Shearman, C.P., Ye, S., Gallagher, P.J., Grimble, R.F. and Calder, P.C. (2007) Long-chain n-3 fatty acids enter advanced atherosclerotic plaques and are associated with decreased inflammation and decreased inflammatory gene expression. Proceedings of the Nutrition Society, 66, 1A-13A. (doi:10.1017/S0029665107005733).

Abstract

Instability of atherosclerotic plaques is due to macrophage inflammatory activity and can result in rupture of the plaque (Plutzky, 1999). We previously showed that long-chain n-3 fatty acids enter advanced atherosclerotic plaques and alter their morphology to one indicative of greater stability (Thies et al. 2003). Whether these fatty acids decrease inflammatory activity within advanced plaques is not known. The objectives of the present study were to confirm that long-chain n-3 fatty acids enter advanced atherosclerotic plaques and to examine the effect on plaque inflammation and on the expression of selected inflammatory genes. Patients (n 121) awaiting carotid endarterectomy were randomly assigned to n-3 fatty acid ethyl esters (Omacor; Pronova Biocare AS, Lysaker, Norway) or olive oil as placebo (both 2 g/d) until surgery (7–109 d; median 21 d). Carotid-plaque phospholipid-fatty acid composition was determined by GC. Plaques were subject to histological examination, which identified the extent of inflammation and instability. Levels of mRNA encoding several matrix metalloproteinases (MMP), the inflammatory cytokine IL-6 and intercellular adhesion molecule (ICAM)-1 were determined by real-time RT–PCR using 36B4 as the housekeeping gene. The n-3 fatty acid EPA was significantly higher in plaque phospholipids from patients in the Omacor group (0.83 (SE 0.05) v. 0.43 (SE 0.05); P<0.0001). Plaque phospholipid-EPA content was significantly negatively correlated with plaque inflammation (P=0.011), plaque instability (P=0.021) and average plaque histology score, a composite end point that includes several histological features (P=0.043). Plaques from patients in the Omacor group expressed significantly lower levels of mRNA for MMP7, MMP9, MMP12, IL-6 and ICAM-1 (all P<0.05), but there was no difference in expression of mRNA for MMP3, MMP8 or MMP13. The present study confirms that long-chain n-3 fatty acids are incorporated into advanced atherosclerotic plaques over a short time period. Incorporation of EPA into advanced atherosclerotic plaques is associated with decreased expression of some of the MMP involved in inducing plaque instability and is associated with decreased plaque inflammation and instability. Incorporation of EPA into advanced atherosclerotic plaques is also associated with decreased expression of IL-6 and ICAM-1, indicating that these fatty acids exert anti-inflammatory actions within advanced plaques. These effects may result in increased plaque stability and so may play a role in decreasing cardiovascular events (see Calder, 2004).

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Contributors

Author: P.C. Calder

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