Potential role of the lipoxygenase derived lipid mediators in atherosclerosis: leukotrienes, lipoxins and resolvins

Abstract

Atherogenesis is an inflammatory process with leukocytes infiltrating the arterial intima. The lipoxygenase pathways play a role in leukocyte recruitment through the generation of two classes of arachidonic acid lipid mediators, the leukotrienes and the lipoxins, and one class of omega-3 fatty acid metabolites, the resolvins. There is evidence from animal studies and human genetic studies that the leukotrienes and the enzymes necessary for their generation play a role in atherosclerosis, and possibly even in the development of the vulnerable plaque. Less is known about the effect of the anti-inflammatory lipid mediators in atherosclerosis, the lipoxins and the resolvins. Studies modulating the activity of an enzyme necessary for the production of these lipid mediators, 12/15-lipoxygenase, showed discrepant results in several animal models. Also, human genetic studies have not clearly dissected the effect of the enzyme on atherosclerosis. However, stable forms of the lipoxins and the resolvins protect animals from inflammatory diseases. Whether blocking the leukotrienes or applying anti-inflammatory lipoxins and resolvins will be effective in attenuating human atherosclerosis needs to be demonstrated in future studies. In this review, the biosynthesis of these lipid mediators, their biological effects and the evidence for their possible role in atherosclerosis are discussed with an emphasis on human disease.

Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

“…Isoprostanes are a class of prostaglandin-like products formed via free-radical-mediated oxidation of arachidonic acid, esterified in membrane phospholipids. All these lipid mediators are consistently observed in atherosclerotic lesions where, together with the oxLDL-derived oxidized lipids, they contribute to the inflammatory responses and to plaque progression [228][229][230][231][232].…”

“…Leukotrienes (LTs) are generated from arachidonic acid by the 5-, 12-, and 15-LO pathways [232]. Several studies have suggested the existence of a potential link between the LT signaling cascade and the progression of atherosclerosis.…”

Papel dos ácidos graxos ômega 3 na resolução dos processos inflamatórios

“…Os produtos resultantes destas vias enzimáticas vão depender de quais são os tipos celulares que estão funcionando como alvos. 17,46 Os AGP ω3 são precursores de mediadores que incluem as resolvinas da série E (E1 ou RvE1: ácido 5S, 12R,18R-trihidroxi-6Z, 8E, 10E, 14Z, 16E eicosapentanóico / E2 ou RvE2: ácido 5S, 18 diidroxieiconadóide) que derivam dos EPA. Também são precursores das resolvinas da série D (D1 ou RvD1: ácido 7S, 8R, 17S-trihidroxi-4Z, 9E, 11E, 13Z, 15E, 19Z docosapentanóico / D2 ou RvD2: ácido 7S, 16R, 17S-trihidroxi-docosa-4Z, 8E, 10Z, 12E, 14E, 19Z hexaenóico) e suas formas epiméricas desencadeadas por Aspirina® derivadas de DHA, e as protectinas (PT)/ neuroprotectinas (NPD), também derivadas de DHA (Figura 2).…”

“…Além disso, sabe-se que mediadores derivados destes ω3 estão envolvidos na produção de resolvinas e protectinas, importantes na resolução da inflamação. 2,17 Os primeiros mediadores derivados do AA que foram descritos foram as LX, que exibem efeitos pró-inflamatórios e têm papel importante na resolução.…”

No evidence for the involvement of the lipoxin A4 receptor (FPR2/ALX) gene in the susceptibility to coronary artery disease

“…Expression of the FPR2/ALX has been observed in several human chronic infl ammatory diseases, such as dermatitis, rheumatoid arthritis, and severe asthma, however, the role of the FPR2/ALX in atherosclerosis has not been investigated (3) .…”