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)

Proliferation of fibroblasts is vital for adequate wound healing but is probably also involved in different hyperproliferative disorders such as atherosclerosis and cancer. The regeneration of tissue usually starts with coagulation, involving release of mitogenic and inflammatory factors from activated platelets. This study focuses on the role of eicosanoids in the proliferative effects of platelets on human fibroblasts. We show that the phospholipase A (2) inhibitor 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), the combined cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) and the LOX inhibitor 5,8,11-eicosatriynoic acid (ETI) block the platelet-induced proliferation of serum starved subconfluent human fibroblasts. Anti-proliferative effects were also obtained by specific inhibition of 5-LOX with 5,6-dehydro arachidonic acid (5,6-dAA), whereas the 12-LOX inhibitor cinnamyl-3,4-dihydroxy- a -cyanocinnamate (CDC) did not affect the platelet-stimulated growth of fibroblasts. The expression of 5-LOX was analyzed by reverse-transcriptase-mediated PCR (RT-PCR), Western blotting and HPLC. 5-LOX message and protein was detected in fibroblasts but not in platelets. Incubation with platelets markedly increased, already after one hour, the expression of 5-LOX in the fibroblast culture. The increased 5-LOX activity was associated with an elevated level of the 5-LOX metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) reaching its maximum after 1 - 2 hours of co-incubation of fibroblasts and platelets. The 5-HETE production was reduced by the inhibitors DMDA, ETYA and ETI. In conclusion, this study suggests that platelet-stimulated proliferation of fibroblasts is mediated by an increased 5-LOX activity, which supports recent findings indicating a crucial role for this enzyme in proliferative disorders such as atherosclerosis.
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PMID:Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase. 1708 Feb 23

Arachidonate 5-lipoxygenase is an enzyme encoded by the ALOX5 gene, and plays an important role in the synthesis of leukotrienes. These are inflammatory mediators, and have been involved in atherosclerosis and other pathological processes that require proinflammatory activities. Human and animal studies have suggested a role for the ALOX5 gene in atherosclerosis, including a significant association between a promoter polymorphism and a carotid intimal-medial thickness in response to dietary fat. This polymorphism was three- to six-tandem repeats of a Sp1/Egr1 binding motif (GGGCGG)(n), and the number of repeats has been linked with the amount of gene expression. We hypothesized that this ALOX5 polymorphism could influence the risk for myocardial infarction (MI). First, we analysed the effect of the four alleles on gene expression by transfecting the HEK-293 cell line with luciferase reporter-constructs. We found that luciferase activities are dependent on the number of the Sp1/Egr1 repeats, with the three and six repeats having the lowest and highest values. We genotyped 312 male MI survivors, aged < 55 years, and 376 healthy controls matched with patients for sex, age, and ethnicity. Ninety-six per cent of the patients were smokers, compared to only 42% among the controls (P < 0.001; OR = 31.84). The 55 + 56 repeat genotypes were less frequent in patients (55 = 56%, 56 = 0.6%) compared to controls (55 = 60%, 56 = 3%). However, these were non-significantly different frequencies. In addition, no difference in MI-onset age and biochemical values was found between the allele and genotypes. In conclusion, we confirmed the effect of the ALOX5-promoter polymorphism on gene expression, but our data did not support a significant effect of this functional variation on MI risk.
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PMID:A functional Sp1/Egr1-tandem repeat polymorphism in the 5-lipoxygenase gene is not associated with myocardial infarction. 1737 38

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 are potent inflammatory mediators synthesized locally within the cardiovascular system through the 5-lipoxygenase pathway of arachidonic acid metabolism. The leukotrienes, consisting of dihydroxy leukotriene LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, act by targeting cell surface receptors expressed on inflammatory cells and on structural cells of vessel walls. LTB, induces leukocyte activation and chemotaxis via high- and low-affinity receptor subtypes (BLT1 and BLT2), respectively. Recently, BLT, receptors were found on human vascular smooth muscle cells, inducing their migration and proliferation. Cysteinyl leukotrienes are vasoconstrictors and induce endothelium-dependent vascular responses through the CysLT, and CysLT2 receptor subtypes. There is also pharmacological evidence for the existence of further CysLT receptor subtypes. Taken together, experimental and genetic studies suggest a major role of leukotrienes in atherosclerosis and in its ischemic complications such as acute coronary syndromes and stroke. Furthermore, the effects on vascular smooth muscle cells suggest a role in the vascular remodeling observed after coronary angioplasty, as well as in aortic aneurysm. Further experimental and clinical studies are needed to determine the potential of therapeutic strategies targeting the leukotriene pathway in cardiovascular disease.
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PMID:[Leukotrienes: potential therapeutic targets in cardiovascular diseases]. 1745 Jun 83

This review article focuses on two aspects regarding 5-lipoxygenase. First, mechanisms for activation of the enzyme. Second, the involvement of 5-lipoxygenase and leukotrienes in atherosclerosis.
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PMID:5-lipoxygenase: regulation and possible involvement in atherosclerosis. 1748 51

Inflammatory eicosanoids generated by the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism are now known to have at least 6 receptors: OXE, which recognizes 5-HETE and 5-oxo-ETE; a putative receptor recognizing a potent 5-oxo-ETE metabolite, FOG(7); the LTB(4) receptors, BLT1 and BLT2; the cysteinyl leukotriene receptors, CysLT(1) and CysLT(2), which recognize leukotrienes LTC(4), LTD(4), LTE(4) and LTF(4). The 5-LO pathway is activated in many diseases and invokes inflammatory responses not affected by glucocorticoids, but therapy with selective BLT1 or CysLT(1) antagonists in asthma has met with variable success. Studies show that 5-LO pathway eicosanoids are not primary mediators in all cases of asthma, but may be especially important in severe persistent asthma, aspirin- and exercise-induced asthma, allergic rhinitis, COPD, idiopathic pulmonary fibrosis, atherosclerosis, atopic dermatitis, acne and ischemia-related organ injury. These disorders appear to involve multiple 5-LO pathway eicosanoids and receptor subtypes, suggesting that inhibition of the pathway at the level of 5-LO may be necessary for maximal efficacy.
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PMID:Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. 1748 54

Leukotriene B(4) (LTB(4)) is an inflammatory mediator derived from the 5-lipoxygenase pathway of arachidonic acid metabolism and has recently implicated in the pathogenesis of atherosclerosis. There are two membrane bound receptors for LTB(4): BLT(1) and BLT(2), which represent the high and low affinity receptors, respectively. BLT receptors are expressed on leukocytes, and LTB(4) is a potent chemoattractant for neutrophils, eosinophils, and T lymphocytes. Recent studies have in addition shown that LTB(4) is an indirectly acting vasoconstrictor of isolated vascular preparations. In the guinea pig aorta, the LTB(4)-induced contractions were inhibited by endothelium-denudation. In addition, pre-treatment with the NO synthase inhibitor, L-NOARG, significantly enhanced the contractions induced by LTB(4). The contractile response induced by LTB(4) in the guinea pig aorta was abolished by the selective BLT(1) receptor antagonist U75302 and the expression of BLT(1) receptor mRNA in the guinea pig aorta was established by RT-PCR. Taken together, these results suggest that LTB(4) activates BLT(1) receptors on the endothelium of the guinea pig aorta, associated with the release of both contractile factors and NO.
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PMID:Endothelium-dependent vascular responses induced by leukotriene B4. 1748 57

Leukotriene B(4) is a proinflammatory lipid mediator generated by the enzymes 5-lipoxygenase and leukotriene A(4) hydrolase. Leukotriene B(4) signals primarily through its high-affinity G protein-coupled receptor, BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. In this study, we tested the hypothesis that BLT1 is necessary for abdominal aortic aneurysm (AAA) formation, a major complication of atherosclerotic vascular disease. Chow-fed Apoe(-/-) and Apoe(-/-)/Blt1(-/-) mice were treated with a 4-wk infusion of angiotensin II (1000 ng/min/kg) beginning at 20 wk of age, in a well-established murine AAA model. We found a reduced incidence of AAA formation as well as concordant reductions in the maximum suprarenal/infrarenal diameter and total suprarenal/infrarenal area in the angiotensin II-treated Apoe(-/-)/Blt1(-/-) mice as compared with the Apoe(-/-) controls. Diminished AAA formation in BLT1-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, we have shown that BLT1 contributes to the frequency and size of abdominal aortic aneurysms in mice and that BLT1 deletion in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. These findings extend the role of BLT1 to a critical complication of vascular disease and underscore its potential as a target for intervention in modulating multiple pathologies related to atherosclerosis.
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PMID:Inhibited aortic aneurysm formation in BLT1-deficient mice. 1757 92

Emerging evidence now indicates that the 5-lipoxygenase (5-LO) pathway play a role in the pathogenesis of atherosclerosis and restenosis. The expression of 5-LO by activated macrophages in symptomatic plaques leads to leukotriene B(4) (LTB(4)) accumulation and enhanced synthesis and release of matrix metalloproteinases (MMPs) that can promote plaque rupture. However, the role of 5-LO pathway in diabetic vascular disease has not been previously reported. Thus, the present study was designed to analyze the expression of 5-LO in carotid plaques of diabetic patients and to investigate the possible role of 5-LO pathway in the pathogenesis and progression of diabetic atherosclerosis. Atherosclerotic plaques from 60 patients undergoing carotid endarterectomy were divided into non-diabetic and diabetic group. Plaques were analyzed for 5-LO, MMP-2 and MMP-9 by immunohistochemical, Western blot, and densitometric analyses, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+macrophages, CD3+T-lymphocytes, and HLA-DR+inflammatory cells. LTB(4) were quantified by enzyme-linked immunosorbent assay. 5-LO showed abundant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage infiltrates in atherosclerotic intima. 5-LO expression was higher in diabetic compared with non-diabetic plaques and was associated with increased MMP-2 and MMP-9 expression. Follow-up analyze with zymography assay revealed MMP activity was elevated in diabetic compared with non-diabetic plaques. Notably, in contrast to non-diabetic plaques, LTB(4) levels were significantly increased in diabetic plaques by enzyme-linked immunosorbent assay. These results suggest that overexpression of 5-LO and LTB(4) in atherosclerotic plaques possibly promote MMP-induced plaque rupture in diabetes. Hence, anti-LTs may be useful, not only in reducing atherogenesis, but also in the prevention and treatment of acute atherothrombotic events in diabetic patients.
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PMID:Expanding expression of the 5-lipoxygenase/leukotriene B4 pathway in atherosclerotic lesions of diabetic patients promotes plaque instability. 1782 94

The 5-lipoxygenase (5-LO) pathway generates lipid mediators, i.e. the cysteinyl leukotrienes (cysLTs) LTC(4)/LTD(4) and LTB(4). CysLT receptors are expressed in endothelial cells (EC) and EC cysLT(2)-R activation induces diverse pro-inflammatory genes in vitro. We now report that LTD(4) promotes formation of an atherosclerosis-protective and anti-thrombotic eicosanoid by markedly up-regulating EC cyclooxygenase-2 (COX-2). CysLT-induced COX-2 transcripts were transiently up-regulated as determined by microarray and QRT-PCR analyses though COX-2 protein remained elevated for several hours. Prostacyclin formation, measured as its stable metabolite 6-keto-PGF(1alpha), was increased several fold in LTD(4)-stimulated ECs, and was inhibited by the COX-2-specific inhibitor, NS-398. COX-2 up-regulation was Ca(2+)-dependent and was partially blocked by cyclosporin A indicating that the 5-LO/COX-2 cross-talk involved signaling through a nuclear factor of activated T cells (NFAT) dependent pathway. Since prostacyclin is a major blood vessel-protective and anti-thrombotic eicosanoid, the EC cysLT(2)-R may limit its otherwise pro-inflammatory actions through a protective Ca(2+)/calcineurin/NFAT-dependent COX-2 feedback loop.
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PMID:5-Lipoxygenase/cyclooxygenase-2 cross-talk through cysteinyl leukotriene receptor 2 in endothelial cells. 1799 13


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