Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis

Abstract

Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocytetype 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.arachidonic acid cascade ͉ coronary heart disease

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

“…Furthermore, 5-LO was localized to macrophages, dendritic cells, foam cells, mast cells and neutrophilic granulocytes, and the number of cells expressing 5-LO was markedly greater in advanced lesions 18 . The leukocytes positive for 5-LO accumulated at distinct sites that are most prone to rupture 29 , such as the shoulder regions below the fibrous cap of the atherosclerotic lesion 18 . A 5-LO promoter variant is associated with abnormal carotid artery intima-media thickness and heightened inflammatory biomarkers 30 .…”

“…The role of the 5-LO pathway in the pathogenesis of atherosclerosis has recently received attention. A study of postmortem pathologic specimens showed an increase in the expression of members of the 5-LO pathway, including 5-LO and FLAP, in atherosclerotic lesions at various stages of development in the aorta, coronary arteries and carotid arteries 18 . Furthermore, 5-LO was localized to macrophages, dendritic cells, foam cells, mast cells and neutrophilic granulocytes, and the number of cells expressing 5-LO was markedly greater in advanced lesions 18 .…”

“…A study of postmortem pathologic specimens showed an increase in the expression of members of the 5-LO pathway, including 5-LO and FLAP, in atherosclerotic lesions at various stages of development in the aorta, coronary arteries and carotid arteries 18 . Furthermore, 5-LO was localized to macrophages, dendritic cells, foam cells, mast cells and neutrophilic granulocytes, and the number of cells expressing 5-LO was markedly greater in advanced lesions 18 . The leukocytes positive for 5-LO accumulated at distinct sites that are most prone to rupture 29 , such as the shoulder regions below the fibrous cap of the atherosclerotic lesion 18 .…”

“…FLAP, together with 5-lipoxygenase (5-LO), is a regulator of the leukotriene biosynthetic pathway that has recently been implicated in the pathogenesis of atherosclerosis [16][17][18] . Therefore, ALOX5AP was a good candidate for the gene underlying the association with myocardial infarction.…”

“…Through suggestive linkage to a locus on chromosome 13q12-13, we identified the gene (ALOX5AP) encoding FLAP and found that a four-SNP haplotype in the gene confers a nearly two times greater risk of myocardial infarction and stroke. FLAP is a regulator 15 of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model 16 and in human studies 17,18 . Males had the strongest association to the at-risk haplotype, and male carriers of the at-risk haplotype also had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction.…”