Preferential Incorporation of Administered Eicosapentaenoic Acid Into Thin-Cap Atherosclerotic Plaques

Abstract

Objective: n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have beneficial effects on atherosclerosis. Although specific salutary actions have been reported, the detailed distribution of n-3 polyunsaturated fatty acids in plaque and their relevance in disease progression are unclear. Our aim was to assess the pharmacodynamics of EPA and DHA and their metabolites in atherosclerotic plaques. Approach and Results: Apolipoprotein E-deficient (Apoe −/− ) mice were fed a Western diet supplemented with EPA (1%, w/w) or DHA (1%, w/w) for 3 weeks. Imaging mass spectrometry analyses were performed in the aortic root and arch of the Apoe −/− mice to evaluate the distribution of EPA, DHA, their metabolites and the lipids containing EPA or DHA in the plaques. Liquid chromatography-mass spectrometry and histological analysis were also performed. The intima-media thickness of atherosclerotic plaque decreased in plaques containing free EPA and EPAs attached with several lipids. EPA was distributed more densely in the thin-cap plaques than in the thick-cap plaques, while DHA was more evenly distributed. In the aortic root, the distribution of total EPA level and cholesteryl esters containing EPA followed a concentration gradient from the vascular endothelium to the media. In the aortic arch, free EPA and 12-hydroxy-EPA colocalized with M2 macrophage. Conclusions: Administered EPA tends to be incorporated from the vascular lumen side and preferentially taken into the thin-cap plaque.

The resolution of inflammation through omega-3 fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification

“…Studies in hyperlipidemic mice have supported that dietary omega-3 PUFA supplementation both alter systemic cholesterol levels towards a beneficial lipoprotein profile and are locally incorporated into cardiovascular tissues [29–31]. These findings hence raise the notion that EPA may serve as the substrate to increase the local production of omega-3 PUFA-derived metabolites, which potentially could act locally to resolve atherosclerotic inflammation.…”

“…These findings hence raise the notion that EPA may serve as the substrate to increase the local production of omega-3 PUFA-derived metabolites, which potentially could act locally to resolve atherosclerotic inflammation. Specifically, 12- and 18-HEPE increase after EPA supplementation in apolipoprotein E (apoE)-deficient mice [29, 31], of which 18-HEPE is the precursor for the proresolving mediator RvE1. Importantly, dietary-supplemented EPA appears to preferentially distribute to thin cap atherosclerotic plaques [29], indicating a particular therapeutic potential for plaque stabilization, which will be further discussed below.…”

Effects of Eicosapentaenoic Acid on Arterial Calcification

“…Additionally, EPA was preferentially incorporated into the thin-cap plaque rather than the thick-cap plaque and reduced atherosclerotic lesions in some mouse models. Atheroma formation in ApoE-deficient mice and LDL receptor-deficient mice and aortic aneurysm formation in osteoprotegerin-deficient/ApoE-deficient mice were prevented by orally administered EPA through anti-inflammatory effects [41][42][43][44].…”

Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites

“…In mice that lack apolipoprotein E (Apoe −/− ) fed a Western diet supplemented with EPA (1%, w/w) or DHA (1%, w/w) for 3 weeks, EPA treatment reduces plaque volume as compared to DHA. 48 Eicosapentaenoic acid and its metabolites, especially 12-hydroxyeicospentaenoic acid (12-HEPE), preferentially associate with thin-cap plaques and accumulation of anti-inflammatory M2 macrophages, while DHA associates with plaques of various sizes. In the aortic root, total EPA and 12-HEPE levels follow a concentration gradient from the vascular endothelium to the media.…”