Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

15-lipoxygenase-1 (also known as 12/15-LO in mice) and 5-LO/5-LO-activating protein (FLAP) cascades play central roles in low-density lipoprotein oxidation and leukotriene biosynthesis, respectively. Several genetic and expression studies unraveling an association of the 5-LO/FLAP pathway to human cardiovascular disease have surfaced recently. Experimental studies in 12/15-LO knockout, 15-LO-1 transgenic, and 5-LO knockout mice on atherosclerotic backgrounds combined with gene expression data in human coronary artery disease have created compelling links that these pathways participate in the etiologic progression. However, a few conflicting studies and several unexplained mechanistic issues need to be resolved prior to assigning firm roles for LOs in cardiovascular disease. Development of novel pharmacologic tools to dissect the individual enzymes and receptors in the LO pathways should improve understanding of the individual components in the inflammatory aspects of atherosclerosis disease progression.
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PMID:Lipoxygenase pathways in atherogenesis. 1526 91

There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio-cerebro-vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio-cerebro-vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids.
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PMID:5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders. 1558 13

Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.
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PMID:Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. 1564 Sep 73

We first hypothesized in 2000 that a polymorphism of the human gene encoding the enzyme 5-lipoxygenase (5-LOX) might be associated with Alzheimer's disease. Only a little progress has been made in directly testing our proposal. However, additional important new data lead us to hypothesize that genetic variability not only in the 5-LOX gene, i.e., ALOX5, but also in polymorphism of the five-lipoxygenase activating protein (FLAP) gene, i.e., ALOX5AP, may be associated with Alzheimer's pathology. Studies in mice followed by several extensive clinical studies have identified ALOX5 and ALOX5AP polymorphisms as strong risk factors for atherosclerosis and cerebrovascular pathologies. New data point to a significant aggregation of vascular risk factors and risk of Alzheimer's disease. Preliminary findings in postmortem brain of Alzheimer's patients identified elevated 5-LOX immunostaining in this disease. We suggest that our hypothesis of a link between the ALOX5 and ALOX5AP gene polymorphisms and Alzheimer's disease could be tested in a clinical setting and in animal models, i.e., transgenic mice could be produced by crossing the available 5-LOX-deficient mice with the available transgenic mice models of Alzheimer's disease.
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PMID:5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease. 1627 51

Leukotrienes (LT) are a group of proinflammatory lipid mediators that are implicated in the pathogenesis and progression of atherosclerosis. Here we report that mRNA levels for the three key proteins in LTB4 biosynthesis, namely 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTA4 hydrolase (LTA4H), are significantly increased in human atherosclerotic plaque (n = 72) as compared with healthy controls (n = 6). Neither LTC4 synthase nor any of the LT receptors exhibits significantly increased mRNA levels. Immunohistochemical staining revealed abundant expression of 5-LO, FLAP, and LTA4H protein, colocalizing in macrophages of intimal lesions. Human lesion tissue converts arachidonic acid into significant amounts of LTB4, and a selective, tight-binding LTA4H inhibitor can block this activity. Furthermore, expression of 5-LO and LTA4H, but not FLAP, is increased in patients with recent or ongoing symptoms of plaque instability, and medication with warfarin correlates with increased levels of FLAP mRNA. In contrast to human plaques, levels of 5-LO mRNA are not significantly increased in plaque tissues from two atherosclerosis-prone mouse strains, and mouse plaques exhibit segregated cellular expression of LTA4H and 5-LO as well as strong increases of CysLT1 and CysLT2 mRNA. These discrepancies indicate that phenotypic changes in the synthesis and action of LT in specific mouse models of atherosclerosis should be cautiously translated into human pathology. The abundant expression of LTA4H and correlation with plaque instability identify LTA4H as a potential target for pharmacological intervention in treatment of human atherosclerosis.
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PMID:Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. 1669 24

Transforming growth factor-beta (TGF-beta) is a major antiinflammatory mediator in atherosclerosis. Transgenic ApoE(-/-) mice with a dominant-negative TGFbeta type II receptor (dnTGFbetaRII) on CD4(+) and CD8(+) T cells display aggravated atherosclerosis. The aim of the present study was to elucidate the mechanisms involved in this enhanced inflammatory response. Gene array analyses identified the 5-lipoxygenase-activating protein (FLAP) among the most upregulated genes in both the aorta and adipose tissue of dnTGFbetaRII transgenic ApoE(-/-) mice compared with their ApoE(-/-) littermates, a finding that was confirmed by real-time quantitative RT-PCR. Aortas from the former mice in addition produced increased amounts of the lipoxygenase product leukotriene B(4) after ex vivo stimulation. FLAP protein expression in both the aorta and adipose tissue was detected in macrophages, but not in T cells. Four weeks of treatment with the FLAP inhibitor MK-886 (10 mg/kg in 1% tylose delivered by osmotic pumps) significantly reduced atherosclerotic lesion size and T-cell content. Finally, FLAP mRNA levels were upregulated approximately 8-fold in adipose tissue derived from obese ob/ob mice. In conclusion, the results of the present study suggest a key role for mediators of the 5-lipoxygenase pathway in inflammatory reactions of atherosclerosis and metabolic disease.
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PMID:5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. 1737 35

Leukotrienes have physiological roles in innate immune responses and pathological roles in inflammatory diseases, such as asthma, allergic rhinitis and atherosclerosis. Anti-leukotriene therapy has proven benefits in the treatment of respiratory disease, either through the inhibition of leukotriene synthesis or the selective antagonism of leukotriene receptors. The first committed step in the synthesis of leukotrienes is the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LO), and the integral membrane protein 5-lipoxygenase-activating protein (FLAP) is an essential partner of 5-LO for this process. FLAP was molecularly identified via a photoaffinity probe and an affinity gel based on MK-886, a selective leukotriene inhibitor that has no activity against broken-cell preparations of 5-LO. Several FLAP inhibitors showed efficacy in early clinical trials in asthma but were not developed commercially for unpublished reasons. Recently, the FLAP (ALOX5AP) gene has been linked to risk for myocardial infarction, stroke and restenosis, reigniting pharmaceutical interest in this target. In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design.
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PMID:What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases. 1818 10

Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
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PMID:Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease. 1836 64

Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Dyslipidemia is one of the main risk factors leading to atherosclerosis. Moreover, there is evidence for a role of oxidation in linking lipids and inflammation to development and progression of atherosclerosis. Current therapeutic approaches with lipid-lowering agents, such as statins, fail to protect more than half of patients from cardiovascular events. Therefore, there is a need for additional and alternative treatment options. There are several novel molecules undergoing preclinical or clinical development for the treatment of dyslipidemia or against distinct pathways which contribute to the development of atherosclerosis. Novel squalene synthase inhibitors with significant cholesterol-lowering and antiatherosclerotic properties are under development. Targeting the production of apolipoprotein B-100 with an antisense oligonucleotide is another interesting approach for lowering low density lipoprotein(LDL)-cholesterol levels. Raising high density lipoprotein(HDL)-cholesterol levels or improving its antiatherosclerotic properties constitute additional attractive targets for protection against CVD. Such compounds include the cholesteryl ester transfer protein inhibitors, HDL-derived proteins, and mimetic peptides/lipids. Direct targeting of atherosclerosis remains a challenge. Molecules against oxidation and/or inflammation could be beneficial in reducing atherosclerosis. Other targets involved in distinct pathways of atherosclerosis include the lipoprotein-associated phospholipase A(2), 5-lipoxygenase-activating protein, acyl-CoA:cholesterol acyltransferase, chemokine receptors, and protein kinases. In conclusion, there are several promising novel therapeutic approaches for dyslipidemia and atherosclerosis under development which are expected to be of great benefit for patients at risk of CVD.
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PMID:Novel molecules targeting dyslipidemia and atherosclerosis. 1839 49

Alternatively activated (M2) macrophages regulate steady state-, cancer-, and inflammation-related tissue remodeling. They are induced by Th2-cytokines and glucocorticoids (GC). The responsiveness of mature macrophages to TGF-beta, a cytokine involved in inflammation, cancer, and atherosclerosis, is currently controversial. Recently, we demonstrated that IL-17 receptor B is up-regulated in human monocyte-derived macrophages differentiated in the presence of Th2 cytokines IL-4 and TGF-beta1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2(IL-4/GC)) but not M2(IL-4) responds to TGF-beta1 which induced a gene expression program comprising 111 genes including transcriptional/signaling regulators (ID3 and RGS1), immune modulators (ALOX5AP and IL-17 receptor B) and atherosclerosis-related genes (ALOX5AP, ORL1, APOC1, APOC2, and APOE). Analysis of molecular mechanism underlying GC/TGF-beta cooperation revealed that surface expression of TGF-betaRII was high in M2(GC) and M2(IL-4/GC), but absent from M2(IL-4), whereas the expression of TGF-betaRI/II mRNA, TGF-betaRII total protein, and surface expression of TGF-betaRIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-betaRII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-beta1-treated M2(IL-4/GC) was due to insufficient activity of negative feedback mechanism what can be explained by up-regulation of SIRT1, a negative regulator of Smad7, and the retention of TGF-betaRII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF-beta by GC-induced surface expression of TGF-betaRII activate in response to TGF-beta1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.
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PMID:Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II. 1845 74


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