Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators

Abstract

Atherosclerosis is now recognized as an inflammatory disease involving the vascular wall. Recent results indicate that acute inflammation does not simply passively resolve as previously assumed but is actively terminated by a homeostatic process that is governed by specific lipid-derived mediators initiated by lipoxygenases. Experiments with animals and humans support a proinflammatory role for the 5-lipoxygenase system. In contrast, results from animal experiments show a range of responses with the 12/15-lipoxygenase pathways in atherosclerosis. To date, the only two clinical epidemiology human studies both support an antiatherogenic role for 12/15-lipoxygenase downstream actions. We tested the hypothesis that atherosclerosis results from a failure in the resolution of local inflammation by analyzing apolipoprotein E-deficient mice with 1) global leukocyte 12/15-lipoxygenase deficiency, 2) normal enzyme expression, or 3) macrophage-specific 12/15-lipoxygenase overexpression. Results from these indicate that 12/15-lipoxygenase expression protects mice against atherosclerosis via its role in the local biosynthesis of lipid mediators, including lipoxin A(4), resolvin D1, and protectin D1. These mediators exert potent agonist actions on macrophages and vascular endothelial cells that can control the magnitude of the local inflammatory response. Taken together, these findings suggest that a failure of local endogenous resolution mechanisms may underlie the unremitting inflammation that fuels atherosclerosis.

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

“…Because RvD1 did not activate PPAR signaling within its bioactive concentration range, it was reasonable to determine whether the recognition sites were present on the surfaces of phagocytes, which was in line with the finding that RvD1 actions were PTX sensitive, pointing to the family of GPCRs. [ 3 H]-RvD1 prepared by total organic synthesis was used to identify high-affinity cell-surface recognition sites for RvD1 on human leukocytes, giving a K d of ∼0.2 nM (∼75 pg/mL), which is within the range of its levels measured in murine cells and tissues, i.e., >75-300 pg (13,22), and bioactions. Of interest, LXA 4 partially displaced [ 3 H]-RvD1 specific binding to human PMNs.…”

“…We next determined whether human leukocytes display specific RvD1-binding sites. To this end, tritium-labeled resolvin D1 ([ 3 H]-RvD1) was prepared by catalytic hydrogenation of synthetic [13,14]-acetylenic RvD1 methyl ester (Fig. S4).…”

“…Following catalytic hydrogenation with tritium, 3 Hlabeled RvD1 coeluted with authentic RvD1 methyl ester beneath a single HPLC peak and gave the characteristic UV absorbance maximum at 301 nm with shoulders at 280 and 315 nm (8,12). Next, [ 3 H]-RvD1 methyl ester was subjected to saponification to obtain the corresponding carboxylic acid, [13,14]-[ 3 H]-RvD1, which was isolated immediately before each binding experiment (n = 8). Representative saturation curves and Scatchard analysis are shown in Fig.…”

“…RvD1 limits PMN infiltration at nanogram levels in murine peritonitis and blocks transendothelial migration of human PMNs (8,12) as well as enhances phagocytosis by human macrophages (MΦ) (13). Recently, RvD1 was found to directly act at a single-cell level in microfluidic chambers to stop human PMN migration to interleukin-8 (14).…”

Chemerin/ChemR23 signaling axis is involved in the endothelial protection by KATP channel opener iptakalim

“…ChemR23, when activated by RvE1, induces the phosphorylation of the ribosomal protein S6 of the PI3K-Akt pathway, which may contribute to the resolution of vascular inflammation and ADP-dependent platelet activation in pathological cardiovascular events [16,17] . The chemerin/ ChemR23 axis may become weaker in pathological conditions, which may not only impair endothelial function, but may also accelerate cardiovascular inflammation [18] . We demonstrated that the expression of the chemerin/ChemR23 axis fluctuates with endothelial function.…”