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

The first drugs affecting the leukotriene-lipoxygenase pathway, which have been introduced in clinical application, inhibit effects of slow reacting substance of anaphylaxis (SRS-A). Although, a 5-lipoxygenase inhibitor was first used in clinical practice as an anti-asthma drug, cysteinyl-leukotriene type 1 receptor (cysLT(1)R) antagonists are preferred as anti-asthma and anti-rhinitis drugs because they are almost as effective as the 5-lipoxygenase inhibitors but have fewer side effects. The cloning of genes related to lipoxygenase-leukotriene metabolism prompted us to try to elucidate the role of leukotrienes in various inflammations. There are at least two types of cysLTRs known: cysLT(1)R and cysLT(2)R. CysLT(1)R plays an important role in the pathophysiology of asthma; however, the role of the cysLT(2)R remains unknown. The abundant distribution of cysLT(2)R in heart and brain tissues suggests that cysLTs play an important role in the pathophysiology of ischemic heart diseases or arrhythmias and through this receptor (cysLT(2)R), psychoneurological disorders. The use of a selective cysLT(2)R antagonist may clarify these questions. Since the 5-lipoxygenase pathway is abundantly expressed in atherosclerotic lesions, and 12/15-lipoxygenase is able to oxygenate polyunsaturated fatty acid esterified in the membranous phospholipids, 5-lipoxygenase or 12/15-lipoxygenase inhibitors may prevent progression of atherosclerosis. In addition, it has been reported that 15-lipoxygenase participates in suppression of prostate cancer. In conclusion, the leukotriene-lipoxygenase metabolism may be involved in the pathophysiology of acute inflammatory to chronic progressive disorders. We think that more drugs modifying leukotriene-lipoxygenase metabolism will be introduced into clinical practice in the future.
 ...
PMID:[Leukotriene-lipoxygenase pathway and drug discovery]. 1557 46

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.
 ...
PMID:5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders. 1558 13

Oxidative modification of low-density lipoprotein (LDL) is one of the critical steps for the development of atherosclerosis. Accumulating studies have indicated that 12/15-lipoxygenase highly expressed in macrophages plays an essential role in the oxidation of circulating LDL. It has been demonstrated that LDL needs to bind the LDL receptor-related protein (LRP), a cell-surface receptor, prior to its oxidation by 12/15-lipoxygenase expressed in macrophages. LRP is suggested to mediate the selective transfer of cholesteryl ester in LDL to the plasma membrane of macrophages without endocytosis and degradation of the LDL particle. At the same time, binding of LDL to LRP translocates the 12/15-lipoxygenase from the cytosol to the plasma membrane. It is also demonstrated that 5-lipoxygenase localized in macrophages generates leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues and contribute to lesion development. Therefore, the inhibition of these lipoxygenases may be effective in the prevention and treatment of the inflammatory diseases.
 ...
PMID:Essential roles of lipoxygenases in LDL oxidation and development of atherosclerosis. 1570 89

Cardiovascular disease is the leading cause of morbidity in Westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. AT supplementation decreases interleukin 1 and 6 release from human monocytes. Thus, the aim of this study was to examine the effect of AT on an important proinflammatory cytokine, tumor necrosis factor-alpha (TNF) release from human monocytes. AT supplementation (1200 IU/day for 3 months) significantly decreased TNF release from activated human monocytes. Mechanisms that were examined included its effect as a general antioxidant, its inhibitory effect on protein kinase C (PKC), and the cycloxygenase-lipoxygenase pathway. While AT decreased TNF release from activated monocytes, other antioxidants had no effect on TNF release. Specific PKC inhibitors had no effect on TNF release from activated monocytes. The inhibition of TNF release by AT in activated monocytes was reversed by leukotriene B(4) (LTB(4)), a major product of the 5-lipoxygenase (5-LO) pathway. Similar observations were seen with inhibitors of 5-lipoxygenase. Indomethacin, a COX inhibitor, in the presence and absence of AT failed to affect TNF activity. These findings suggest that AT decreases TNF release from activated human monocytes via inhibition of 5-lipoxygenase. Also, AT as well as a 5-LO inhibitor significantly decreased TNF mRNA. Furthermore, AT and the 5-LO inhibitor decreased NFkappab-binding activity. Thus, in activated human monocytes, AT appears to inhibit TNF mRNA and protein by inhibition of 5-LO.
 ...
PMID:Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. 1580 19

The enzyme 5-lipoxygenase (5-LO) initiates the synthesis of leukotrienes. For this reason, 5-LO activity is important for immune defense, whereas improper regulation contributes to pathogenesis, including chronic inflammation, asthma and atherosclerosis. Like all lipoxygenases, the 5-LO protein consists of two domains, a regulatory domain and a catalytic domain. Naturally, the regulatory domain determines catalytic activity and controls leukotriene synthesis. This domain shares features with classical C2 domains in that it has a beta-sandwich structure and binds calcium, nucleotides and phospholipids. However, important structural features place this domain in a distinct family, the PLATs (for Polycystin-1, Lipoxygenase, alpha-Toxin). In this review, we summarize our current understanding of the three dimensional organization of this important component of the 5-LO molecule. In addition, we point to findings from structural analyses of related proteins to suggest further details relating 5-LO structure to function.
 ...
PMID:Structural organization of the regulatory domain of human 5-lipoxygenase. 1585 49

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, alpha-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine-kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.
 ...
PMID:Vitamin E, oxidative stress, and inflammation. 1601 63

The metabolism of arachidonic acid can be catalysed by either one of two enzyme families: the cyclooxygenases or the lipoxygenases. The lipoxygenase enzymes are classed into several subcategories including 5-, 12- and 15-lipoxygenases. The 5-lipoxygenase pathway has been the major focus of study due to the pronounced pro-inflammatory role of leukotrienes and the approval of 5-lipoxygenase inhibitors and leukotriene receptor antagonists for the clinical treatment of asthma. Although less well characterized, the 12-lipoxygenase as well as the 15-lipoxygenase pathway may also play an important role in the progression of human diseases such as cancer, psoriasis and atherosclerosis. The present review article summarizes the findings from an extensive literature search on plants that have been assessed for 12- and 15-lipoxygenase inhibitory activity as well as for leukotriene receptor antagonistic properties. The results are presented in a tabular format, and a discussion about promising plant species and natural compounds as well as relevant in vitro assays are included in this article.
 ...
PMID:Lipoxygenase inhibitors from natural plant sources. Part 2: medicinal plants with inhibitory activity on arachidonate 12-lipoxygenase, 15-lipoxygenase and leukotriene receptor antagonists. 1604 64

Leukotrienes (LTs) are powerful inflammatory lipid mediators derived from the 5-lipoxygenase (5-LO) cascade of arachidonic acid. Recent clinical, population genetic, cell biological, and mouse studies indicate participation of the 5-LO pathway in atherogenesis and arterial wall remodeling. 5-LO is expressed by leukocytes including blood monocytes, tissue macrophages, dendritic cells, neutrophils, and mast cells. LTB4 and the cysteinyl LTs LTC4, LTD4, and LTE4, act through two BLT and two cysLT receptors that are differentially expressed on hematopoietic and arterial wall cells. The precise roles of LTs or the LT receptors in cardiovascular physiology remain largely to be explored. In this review, we will discuss what is currently known about the 5-LO atherosclerosis connection. We will attempt to propose strategies to further explore potential links between the 5-LO pathway and blood vessel physiology and disease progression.
 ...
PMID:The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. 1608 17

Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL- and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARalpha and PPARgamma agonists, such as thiazolidinediones and fibrates, and PPARdelta agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.
 ...
PMID:Macrophage differentiation to foam cells. 1617 64

The 5-lipoxygenase pathway has been strongly implicated in the pathogenesis of chronic inflammatory disorders, such as bronchial asthma and atherosclerosis. Cysteinyl leukotrienes (cysLTs), 5-lipoxygenase pathway products, are recognized now not only as important factors in asthmatic inflammation, but also as mediators of cell trafficking and innate immune responses. To study a role of cysLTs in inflammatory reactions we have characterized the gene structure of human cysteinyl leukotriene receptor type I (cysLT(1)R). The cysLT(1)R gene consists of 5 exons that are variably spliced and a single promoter region with multiple transcription start sites. Four different cysLT(1)R transcripts were identified. RT-PCR showed dominant and wide expression of the transcript I, containing exons 1, 4, and 5, with the strongest presence in blood leukocytes, spleen, thymus, lung, and heart. The expression of cysLT(1)R is functionally regulated at the transcriptional level by IL-4 through a STAT6 response element localized to the proximal cysLT(1)R promoter region. IL-4 stimulation increased cysLT(1)R mRNA (real-time PCR) and surface protein expression (flow cytometry) in a time-dependent fashion. CysLTs (LTD(4) and LTC(4)) induced an increased production of a potent monocyte chemoattractant CCL2 (MCP-1) in IL-4-primed THP-1 cells in a dose-dependent manner. This effect was effectively inhibited by the cysLT(1)R-selective antagonist MK571 in a dose-dependent manner and only partially by a nonselective cysLT(1)R/cysLT(2)R inhibitor BAY-u9773, implying a cysLT(1)R-mediated mechanism. Thus, cysLTs signaling through cysLT(1)R might contribute to inflammatory reactions by cooperating with IL-4 in enhanced CCL2 production in human monocytic cells.
 ...
PMID:Functional characterization of human cysteinyl leukotriene 1 receptor gene structure. 1621 Jun 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>