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,

In the present study, we found sustained inflammation due to NF-kappaB activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-kappaB. We also suggest that HOXA9 might be involved in the regulation of NF-kappaB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation.

on behalf of the BiKE and ASAP study groups Background-Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown. Methods and Results-To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (PϽ0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent. Conclusions-This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting. (Circ Cardiovasc Genet. 2010;3:365-373.)

IDO-mediated Trp metabolism regulates vascular inflammation and plaque formation in hypercholesterolaemic Apoe(-/-) mice. Our data establish that this pathway plays a major role in the pathological process of atherogenesis.