From Asthma to Atherosclerosis — 5-Lipoxygenase, Leukotrienes, and Inflammation
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《新英格兰医药杂志》
Eicosanoids are lipid mediators of inflammation; they include a variety of compounds (prostaglandins, thromboxanes, leukotrienes, hydroxy- and epoxy-fatty acids, lipoxins, and isoprostanes) that are derived from the ubiquitous 20-carbon atom arachidonate (20 in Greek is "eicosa") and a few similar polyunsaturated fatty acids. These fatty acids are esterified in the phospholipids of biologic membranes and then released in response to a variety of stimuli to become substrates for metabolizing enzymes. More than 20 years ago, Samuelsson and coworkers identified leukotrienes as a class of eicosanoids that are derived through the action of 5-lipoxygenase. This enzyme, which is selectively expressed in bone marrow–derived cells such as neutrophils, monocytes, macrophages, dendritic cells, and mast cells, catalyzes the transformation of arachidonic acid into leukotriene A4. Leukotriene A4, in turn, is either converted by enzymatic hydrolysis into leukotriene B4 or conjugated with glutathione to form leukotriene C4 (see Figure). Leukotriene C4 and its metabolites leukotrienes D4 and E4 are together referred to as cysteinyl leukotrienes. Leukotriene B4 is a potent chemoattractant for neutrophils, macrophages, and other inflammatory cells and induces chemokinesis and adhesion of these cells to the vascular endothelium. In contrast, cysteinyl leukotrienes increase vascular permeability and contract smooth-muscle cells, causing bronchoconstriction and vasoconstriction.
Figure. Main Putative Roles of 5-Lipoxygenase in Atherosclerosis.
Early development of lesions is caused by invasion of the intima by monocytes, followed by the transformation of monocyte-derived macrophages into foam cells through the uptake of minimally modified or oxidized low-density lipoproteins (LDL). Leukotrienes may contribute to atherosclerosis by promoting nonspecific leukocyte chemotaxis (leukotriene B4) and by increasing vascular permeability (cysteinyl leukotrienes C4, D4, and E4). The activation and gene expression of 5-lipoxygenase, the enzyme responsible for the initiation of the leukotriene biosynthetic pathway from arachidonic acid, can be increased by various cytokines in inflammatory conditions. Resident macrophages perpetuate a vicious circle of local inflammation by releasing inflammatory cytokines, matrix-degrading metalloproteinases (contributing to plaque rupture), and tissue factor (increasing plaque thrombogenicity), as well as by producing more leukotrienes.
Leukotrienes have been identified as mediators of a variety of inflammatory and allergic conditions, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and allergic rhinitis, but their most relevant pathophysiological implication so far has been a link to bronchial asthma. Blockers of the cysteinyl leukotriene receptor CysLT1 or of 5-lipoxygenase are now being marketed worldwide as effective antiasthmatic medications.
Despite the fact that antileukotriene drugs have proved to be effective in most patients with many types of asthma, their efficacy varies considerably among patients. It has been suggested that genetic variations in 5-lipoxygenase contribute to the variable response to antileukotriene drugs. The transcription rate of the gene encoding 5-lipoxygenase (located on chromosome 10) is controlled by its promoter, and particularly by a region, termed the core promoter, that contains a sequence of GC-rich tandem repeats, which are binding sites for two transcription factors, Sp-1 and Egr-1. Genetic variants in the core promoter region may change the binding of these transcription factors and the rate of 5-lipoxygenase transcriptional activation under inflammatory conditions. Indeed, a family of mutations in the GC-rich region, consisting of the deletion of one such binding site, the deletion of two of them, or the addition of one, was associated with altered (reduced) transcription of the 5-lipoxygenase gene, as compared with the common allele. It was then found that asthma in carriers of these genetic variants had a diminished response to treatment with antileukotriene drugs, indicating a pharmacogenetic effect of the promoter sequences on responses to treatment.
Originally confined to asthma, the implications of these findings have recently been extended unexpectedly to atherosclerosis. In a search for candidate genes that might contribute to the susceptibility to atherosclerosis in two widely used mouse models of atherosclerosis, the apolipoprotein E–/– mouse and the low-density lipoprotein (LDL)–receptor–/– mouse, a locus on mouse chromosome 6 was found to confer almost total resistance to atherogenesis. The 5-lipoxygenase gene at this locus in the mouse turned out to account for the entirety of this effect, since even LDL-receptor–/– mice that were missing only one of the two allelic copies of the 5-lipoxygenase gene had a dramatic decrease (by a factor of about 26) in the extent and severity of lesions. Also, the transplantation of bone marrow (supplying circulating blood cells) from 5-lipoxygenase–/– mice in LDL-receptor–/– mice conferred substantial protection from atherosclerosis, suggesting that 5-lipoxygenase from white cells (most likely monocyte–macrophages) was necessary for atherogenesis.
5-Lipoxygenase may make an important contribution to atherosclerosis because its leukotriene products, which are produced primarily by monocyte–macrophages or dendritic cells in the arterial intima, foster the chemoattraction of monocytes, T-cells, or other types of circulating cells within the vessel wall, increase vascular permeability, or both (see Figure). These mechanisms may create a vicious circle in which inflammatory cells, by producing these lipid mediators, cause local vascular inflammation, perpetuating the recruitment of inflammatory cells and the production of mediators. 5-Lipoxygenase might also contribute by oxidizing LDL or producing natural ligands for nuclear receptors, such as peroxisome-proliferator–activated receptor (PPAR).
Could it be that genetic variants of the 5-lipoxygenase promoter, which have previously been found to be associated with variable sensitivity to antiasthmatic medications, also influence atherosclerosis? In this issue of the Journal, Dwyer and coworkers (pages 29–37) report that this is apparently the case. Variant genotypes of the 5-lipoxygenase gene were found in 6 percent of the 470 healthy, middle-aged women and men in their cohort. Carotid intima–media thickness, used as a marker of the atherosclerotic burden, was significantly increased, by 80 μm, in the group with variant alleles, as compared with carriers of the common allele. The direction of the change in intima–media thickness in the group with variant alleles is contrary to what one would have expected on the basis of previous in vitro findings and is consistent with increased, rather than decreased, activity of the 5-lipoxygenase promoter associated with the mutant alleles. This issue clearly warrants further investigation through measurements of 5-lipoxygenase expression and of leukotrienes in these genetic variants; the interaction with recently identified mutations in other genes related to leukotriene production, such as that encoding 5-lipoxygenase–activating protein, should also be evaluated.
Dwyer et al. also report on a diet–gene interaction. Dietary arachidonic acid intake significantly enhanced the proatherogenic effect of the 5-lipoxygenase gene variants, whereas intake of n–3 polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acids) blunted this effect. Since eicosapentaenoic and docosahexaenoic acids may reduce the formation of leukotrienes by competing with arachidonic acid as substrates for 5-lipoxygenase and also generate the weaker leukotrienes of the 5 series (leukotrienes with five double bonds, in contrast to the leukotrienes derived from arachidonic acid, which have four), these findings suggest that the antiatherogenic effects of eicosapentaenoic and docosahexaenoic acid derived from fish might be more prominent in (or perhaps limited to) persons with genotypes favoring increased 5-lipoxygenase activity.
Overall, these findings contribute to the untangling of the intricate connections between inflammation and atherosclerosis in humans and might actually provide the first proof of a causal link between the two. In addition to indicating potential new targets for therapy in a multifaceted and multifactorial process such as atherosclerosis, they illustrate the complexity of the interactions between nutrients and our genes.
Source Information
From the Division of Cardiology and the Center of Excellence on Aging, Gabriele d'Annunzio University, Chieti (R.D.C.); and the Laboratory for Thrombosis and Vascular Research, Institute of Clinical Physiology, National Research Council, Pisa (R.D.C., A.Z.) — both in Italy.(Raffaele De Caterina, M.D)
Figure. Main Putative Roles of 5-Lipoxygenase in Atherosclerosis.
Early development of lesions is caused by invasion of the intima by monocytes, followed by the transformation of monocyte-derived macrophages into foam cells through the uptake of minimally modified or oxidized low-density lipoproteins (LDL). Leukotrienes may contribute to atherosclerosis by promoting nonspecific leukocyte chemotaxis (leukotriene B4) and by increasing vascular permeability (cysteinyl leukotrienes C4, D4, and E4). The activation and gene expression of 5-lipoxygenase, the enzyme responsible for the initiation of the leukotriene biosynthetic pathway from arachidonic acid, can be increased by various cytokines in inflammatory conditions. Resident macrophages perpetuate a vicious circle of local inflammation by releasing inflammatory cytokines, matrix-degrading metalloproteinases (contributing to plaque rupture), and tissue factor (increasing plaque thrombogenicity), as well as by producing more leukotrienes.
Leukotrienes have been identified as mediators of a variety of inflammatory and allergic conditions, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and allergic rhinitis, but their most relevant pathophysiological implication so far has been a link to bronchial asthma. Blockers of the cysteinyl leukotriene receptor CysLT1 or of 5-lipoxygenase are now being marketed worldwide as effective antiasthmatic medications.
Despite the fact that antileukotriene drugs have proved to be effective in most patients with many types of asthma, their efficacy varies considerably among patients. It has been suggested that genetic variations in 5-lipoxygenase contribute to the variable response to antileukotriene drugs. The transcription rate of the gene encoding 5-lipoxygenase (located on chromosome 10) is controlled by its promoter, and particularly by a region, termed the core promoter, that contains a sequence of GC-rich tandem repeats, which are binding sites for two transcription factors, Sp-1 and Egr-1. Genetic variants in the core promoter region may change the binding of these transcription factors and the rate of 5-lipoxygenase transcriptional activation under inflammatory conditions. Indeed, a family of mutations in the GC-rich region, consisting of the deletion of one such binding site, the deletion of two of them, or the addition of one, was associated with altered (reduced) transcription of the 5-lipoxygenase gene, as compared with the common allele. It was then found that asthma in carriers of these genetic variants had a diminished response to treatment with antileukotriene drugs, indicating a pharmacogenetic effect of the promoter sequences on responses to treatment.
Originally confined to asthma, the implications of these findings have recently been extended unexpectedly to atherosclerosis. In a search for candidate genes that might contribute to the susceptibility to atherosclerosis in two widely used mouse models of atherosclerosis, the apolipoprotein E–/– mouse and the low-density lipoprotein (LDL)–receptor–/– mouse, a locus on mouse chromosome 6 was found to confer almost total resistance to atherogenesis. The 5-lipoxygenase gene at this locus in the mouse turned out to account for the entirety of this effect, since even LDL-receptor–/– mice that were missing only one of the two allelic copies of the 5-lipoxygenase gene had a dramatic decrease (by a factor of about 26) in the extent and severity of lesions. Also, the transplantation of bone marrow (supplying circulating blood cells) from 5-lipoxygenase–/– mice in LDL-receptor–/– mice conferred substantial protection from atherosclerosis, suggesting that 5-lipoxygenase from white cells (most likely monocyte–macrophages) was necessary for atherogenesis.
5-Lipoxygenase may make an important contribution to atherosclerosis because its leukotriene products, which are produced primarily by monocyte–macrophages or dendritic cells in the arterial intima, foster the chemoattraction of monocytes, T-cells, or other types of circulating cells within the vessel wall, increase vascular permeability, or both (see Figure). These mechanisms may create a vicious circle in which inflammatory cells, by producing these lipid mediators, cause local vascular inflammation, perpetuating the recruitment of inflammatory cells and the production of mediators. 5-Lipoxygenase might also contribute by oxidizing LDL or producing natural ligands for nuclear receptors, such as peroxisome-proliferator–activated receptor (PPAR).
Could it be that genetic variants of the 5-lipoxygenase promoter, which have previously been found to be associated with variable sensitivity to antiasthmatic medications, also influence atherosclerosis? In this issue of the Journal, Dwyer and coworkers (pages 29–37) report that this is apparently the case. Variant genotypes of the 5-lipoxygenase gene were found in 6 percent of the 470 healthy, middle-aged women and men in their cohort. Carotid intima–media thickness, used as a marker of the atherosclerotic burden, was significantly increased, by 80 μm, in the group with variant alleles, as compared with carriers of the common allele. The direction of the change in intima–media thickness in the group with variant alleles is contrary to what one would have expected on the basis of previous in vitro findings and is consistent with increased, rather than decreased, activity of the 5-lipoxygenase promoter associated with the mutant alleles. This issue clearly warrants further investigation through measurements of 5-lipoxygenase expression and of leukotrienes in these genetic variants; the interaction with recently identified mutations in other genes related to leukotriene production, such as that encoding 5-lipoxygenase–activating protein, should also be evaluated.
Dwyer et al. also report on a diet–gene interaction. Dietary arachidonic acid intake significantly enhanced the proatherogenic effect of the 5-lipoxygenase gene variants, whereas intake of n–3 polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acids) blunted this effect. Since eicosapentaenoic and docosahexaenoic acids may reduce the formation of leukotrienes by competing with arachidonic acid as substrates for 5-lipoxygenase and also generate the weaker leukotrienes of the 5 series (leukotrienes with five double bonds, in contrast to the leukotrienes derived from arachidonic acid, which have four), these findings suggest that the antiatherogenic effects of eicosapentaenoic and docosahexaenoic acid derived from fish might be more prominent in (or perhaps limited to) persons with genotypes favoring increased 5-lipoxygenase activity.
Overall, these findings contribute to the untangling of the intricate connections between inflammation and atherosclerosis in humans and might actually provide the first proof of a causal link between the two. In addition to indicating potential new targets for therapy in a multifaceted and multifactorial process such as atherosclerosis, they illustrate the complexity of the interactions between nutrients and our genes.
Source Information
From the Division of Cardiology and the Center of Excellence on Aging, Gabriele d'Annunzio University, Chieti (R.D.C.); and the Laboratory for Thrombosis and Vascular Research, Institute of Clinical Physiology, National Research Council, Pisa (R.D.C., A.Z.) — both in Italy.(Raffaele De Caterina, M.D)