Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine and St. Luke's Episcopal Hospital, Houston, TX 77030, USA. amerched@bcm.edu
Aksam J
AJ
Merched
Kerry
K
Ko
Katherine H
KH
Gotlinger
Charles N
CN
Serhan
Lawrence
L
Chan
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000502:physiology; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis; D044045:Lipoxins / Q000096:biosynthesis* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D014657:Vasculitis / Q000150:complications* / Q000378:metabolism
C475064:12-15-lipoxygenase; D001057:Apolipoproteins E; D007378:Interleukins; D044045:Lipoxins; C040527:lipoxin A4; C487679:protectin D1; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase