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. 2011;4(1):12-24.
doi: 10.1159/000326890. Epub 2011 Apr 7.

Nutrigenetic disruption of inflammation-resolution homeostasis and atherogenesis

Aksam J Merched  1 , Charles N Serhan, Lawrence Chan
Affiliations

Nutrigenetic disruption of inflammation-resolution homeostasis and atherogenesis

Aksam J Merched et al. J Nutrigenet Nutrigenomics. 2011.

Abstract

Background/aim: Pro-resolving and anti-inflammatory mediator products of murine 12/15-lipoxygenase (LOX) exhibit potent actions on vascular inflammation and protect against the progression of atherosclerosis. The present study was designed to determine whether augmenting dietary lipids modulates the body's endogenous anti-inflammatory pro-resolving mechanisms and promotes atherosclerosis.

Methods/results: We investigated the biometabolic consequences of variations in lipid mediator biosynthesis using genetic knockout and overexpression models of 12/15-LOX mice fed the commonly used 'Western diet'. Unexpectedly, this high-fat diet annulled the protective actions of 12/15-LOX, and the combination of a Western diet and 12/15-LOX overexpression paradoxically promoted inflammation leading to production of diet-related and 12/15-LOX-dependent blood mediators that differentially activated endothelial cells via expression of ICAM-1. Hyperlipidemia not only affected the biosynthesis of lipoxin A4, a key pro-resolving mediator, but also disrupted the protective pro-resolving function of 12/15-LOX products, and the enzyme pathway no longer protected against atherosclerosis in vivo.

Conclusion: We uncovered a novel mechanism whereby a high-fat diet as well as hyperlipidemia disrupt the homeostasis of inflammation resolution. These findings underscore the importance of dietary essential PUFAs and LOX-derived lipid mediators in combination with lipid-lowering agents in the prevention and treatment of atherosclerotic cardiovascular diseases.

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Figures

Fig. 1
Fig. 1
Western diet slows down atherosclerosis in 12/15-LOX global deficiency. a Morphometric analysis of en face aortic lesions in apoE−/−/ 12/15LOX−/− mice compared with apoE−/− littermate controls (+/+) in female mice fed a Western-type diet after 10 weeks (n = 23 knock-out and 7 wild-type; left panel) or 14 weeks (n = 6 knock-out and 4 wild-type; right panel). b Plasma levels of cholesterol and triglycerides. ∗ p < 0.05 (t test).
Fig. 2
Fig. 2
Effect of Western diet on atherosclerosis in mice with leukocyte-specific 12/15-LOX deficiency. a Scheme of protocol for BMT. b En face aortic lesion showed 12/15-LOX−/− apoE−/− mice (−/−) that received BMT from either 12/15-LOX−/− apoE−/− (−/−) or 12/15-LOX+/+ apoE−/− (+/+) donors. Bone marrow recipients were fed a Western diet for 15 weeks after BMT (n = 5 knock-out and 5 wild-type, for females and males, respectively). c Plasma levels of cholesterol and triglycerides.
Fig. 3
Fig. 3
Western diet annuls the protection against atherosclerosis in 15-LOX transgenic mice with apoE−/− background. a Morphometric analysis of cross-sectional aortic sinuslesions in apoE−/−/15-LOXtg+/0 (tg) mice compared with apoE−/− littermate controls (+/+) after 10 weeks on a Western diet. b En face lesion area of the remaining part of the aortas. Results are mean ± SD (n = 6 wild-type and 6 tg). c Plasma levels of cholesterol and triglycerides.
Fig. 4
Fig. 4
Plasma from apoE−/− mice with or without 12/15-LOX gene deletion differentially regulates TNF-α-stimulated expression of ICAM-1 and VCAM-1 in HUVEC cells. Blood samples were collected from 5–6 mice of each group maintained under a regular low-fat chow diet (a) or a Western diet (b), incubated with cultured HUVEC cells and assessed for the expression of adhesion molecules on the surface of these endothelial cells as described in the Methods section. All analyses were performed in duplicate or triplicate. ∗ p < 0.005 (t test). Bar = SEM.
Fig. 5
Fig. 5
Actions of 12/15-LOX and LXA4 on macrophage gene expression and phagocytic function. a Thioglycolate-elicited macrophages were used to examine gene expression by quantitative RT-PCR. Open bars represent relative transcript level in 12/15-LOX-deficient macrophages, shaded bars that of wild-type macrophages. Each measurement was on RNA isolated from macrophages from 3–6 mice from each genotype. b CCL5 gene expression in macrophages treated with LXA4 analog for 1 h. ∗ p < 0.05 vs. baseline response. c Relative expression of IL-12p40 transcript in macrophages treated with 50 nM of LXA4 or its stable analog ATLa (n = 3 for each set). d Adherent macrophages were cultured overnight, washed with RPMI, and then incubated for 3 h with 10 μg/ml BODIPY FL-labeled acetylated LDL (Molecular Probes) in RPMI containing 2.5% lipoprotein-deficient serum in the presence of 50 nM of LXA4 or vehicle. The fluorescent (green in the online version) signal correlates with intracellular lipid as a result of acLDL taken up by cells. Results are mean ± SEM (n = 3). ∗∗ p < 0.05, ∗ p < 0.01, ∗∗∗ p < 0.001, using t test.
Fig. 6
Fig. 6
Impact of lipid conditions on LXA4 plasma levels and macrophage phagocytic activity. a Circulating LXA4 levels of apoE−/−/15-LOXtg+/0 (tg) and apoE−/− mice (+/+) fed a regular chow diet (n = 7 and 5) or a Western diet (WD, n = 4 and 4). ∗ p < 0.05, using Mann-Whitney rank sum test. b Plasma cytokine levels in transgenic mice (light gray bars) versus control (dark gray bars) under conditions of Western diet feeding. ∗ p < 0.05, ∗∗ p < 0.01, using Mann-Whitney rank sum test. c Macrophages (MPH) were treated with 50 nM of LXA4 (or vehicle) and co-incubated with fluorescent microspheres (for 70 min) in regular culture medium (RPMI with 10% FBS). High-lipid conditions are created by supplementing the media by additional 0.5 mg/dl of LDL to the phagocytosis medium; ∗∗ p < 0.01 (n = 4 for each set).
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References

    1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–1695. - PubMed
    1. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874. - PubMed
    1. Chiang N, Arita M, Serhan CN. Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins Leukot Essent Fatty Acids. 2005;73:163–177. - PubMed
    1. Serhan CN. Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochim Biophys Acta. 1994;1212:1–25. - PubMed
    1. Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution. Prostaglandins Other Lipid Mediat. 2002;68–69:433–455. - PubMed

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