Expression of 5-lipoxygenase and leukotriene A ₄ hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability

Abstract

Atherosclerosis is an inflammatory disorder involving complex interactions between vascular wall cells and invading inflammatory cells (14). Genetically modified mouse models of atherosclerosis, based on two pivotal genes of lipid metabolism, i.e., apolipoprotein E (ApoE) and the low-density lipoprotein receptor (LDLR), have been crossed with mice deficient in a specific gene of the LT cascade, e.g., 5-LO and BLT 1 , to investigate the impact of the gene product on the atherosclerotic process (9,(15)(16)(17).In the present study we examined the expression of 5-LO, FLAP, LTA4H, LTC4S, and the receptors BLT 1 , BLT 2 , CysLT 1 , and CysLT 2 in human carotid plaques and aortic lesions from both ApoE (Ϫ͞Ϫ) and compound ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice. In contrast to the mouse models, we find that both 5-LO and LTA4H are expressed at increased levels and colocalize within human atherosclerotic lesions, with expression levels correlating with recent or ongoing symptoms of plaque instability. We also report that a selective inhibitor of LTA4H can block LTB 4 biosynthesis in plaque tissue, thus identifying LTA4H as a potential target for development of drugs for prevention and treatment of atherosclerosis and acute atherothrombotic events. Results Expression of 5LO, FLAP, LTA4H, and LTC4S mRNA in Human CarotidPlaque and Mouse Atherosclerotic Aorta. In the human carotid atherosclerotic lesions, the transcript levels of 5-LO, FLAP, and LTA4H were high, corresponding to a 7.5-fold (7.5 Ϯ 4.1, P Ͻ 0.001), 2.7-fold (2.7 Ϯ 1.3, P ϭ 0.003), and nearly 2-fold (1.9 Ϯ 1.0, P ϭ 0.03) increase relative to normal iliac arteries, respectively (Fig. 1A). In contrast, the levels of LTC4S mRNA were not significantly different from controls.In the ApoE (Ϫ͞Ϫ) mouse aorta, 5-LO and LTA4H mRNA levels were essentially unaltered, whereas FLAP and LTC4S mRNA showed a tendency to increase relative tissue from wild-type C57BL͞6J mice (Fig. 1B). In ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice, the expression pattern of the enzymes was essentially the same as in ApoE (Ϫ͞Ϫ) mice, except that LTA4H mRNA levels were significantly increased (1.7 Ϯ 0.3, P ϭ 0.01) (Fig. 1C). Expression of 5-LO, FLAP, and LTA4H Protein in Human and MouseAtherosclerotic Lesions. Staining of human carotid plaque demonstrated prominent expression of 5-LO, FLAP, and LTA4H in intimal lesion areas that also stained positively for human macrophage marker CD163 (Fig. 2). The distribution of 5-LO,

Leptin and mTOR: Partners in metabolism and inflammation

“…It has been shown that 5-LO is enhanced in the atherosclerotic plaque, and that both higher 5-LO expression and increased LTB 4 production or activity are associated with complications of these lesions. [91][92][93] Thus, leptin may contribute to atherogenesis by inducing the formation of lipidladen macrophages that have an increased capacity for synthesis of inflammatory mediators. Collectively, these data suggest a role key for mTOR and leptin in regulating the accumulation and metabolism of intracellular lipids in macrophages.…”

ALOX5AP gene variants and risk of coronary artery disease: an angiography-based study

“…4 Interestingly, ALOX5AP encodes the 5-lipoxygenase-activating protein (FLAP), which is an essential regulator of the biosynthesis of the leukotriene A4 (LTA4). 5,6 Indeed, the 5-lipoxygenase (5-LO)/leukotriene pathway has been independently implicated in the pathogenesis of atherosclerosis in humans 7,8 and mice 9 (reviewed by Zhao and Funk 10 ). While not successful in discovering causal variants in ALOX5AP, the original study by Helgadottir et al 4 identified a 4-SNP haplotype, named HapA, as a risk factor for MI and stroke in the Icelandic population.…”

Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice

“…5-Lipoxygenase (5-LO) 3 and its derivatives are highly expressed within human carotid, aortic, and coronary artery plaques (1)(2)(3). Furthermore, genetic studies have associated particular variants of 5-LO, its accessory protein 5-LO-activating protein, as well as the enzyme leukotriene A 4 (LTA 4 ) hydrolase with stroke and myocardial infarction in humans (4 -6).…”