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)

The development of atherosclerosis is accelerated in individuals with type 2 diabetes. Adhesion of monocytes to the vascular endothelium is a key initial step in atherogenesis. We have previously shown that monocyte adhesion to human aortic endothelial cells (HAECs) cultured long-term in high-glucose medium (25 mmol/L, 2 passages) is increased compared with cells grown in normal glucose (5 mmol/L). One potential mechanism for increased monocyte adhesion to HAECs under hyperglycemic conditions is via the 12-lipoxygenase (12-LO) pathway. In this study, we demonstrated in HAECs that the major LO metabolite of arachidonic acid was the 12-LO product, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which was increased severalfold in HAECs cultured under high-glucose conditions. Furthermore, treatment of HAECs with 12(S)-HETE induced monocyte, but not neutrophil, adhesion an average of 3-fold (range of 1.5- to 5-fold) compared with untreated cells (75+/-5 versus 26+/-1 monocytes per field, respectively, P<0.001). Expression of the adhesion molecules vascular cell adhesion molecule-1, E-selectin, and intercellular adhesion molecule-1 was not significantly increased. However, both glucose and 12(S)-HETE induced a 60% increase in HAEC surface expression of connecting segment-1 (ie, CS-1) fibronectin, a ligand for very late-acting antigen-4 (VLA-4). The antibodies used to block monocyte integrin VLA-4 and leukocyte function-related antigen-1, a monocytic counterreceptor for intercellular adhesion molecule-1, inhibited the ability of both 12-LO products and high glucose to induce monocyte adhesion. These results definitively demonstrate for the first time in HAECs that the 12-LO pathway can induce monocyte-endothelial cell interaction and that the effects of glucose may be mediated, at least in part, through this pathway. Thus, these results suggest that the 12-LO pathway may play a role in the increased susceptibility of diabetics to atherosclerosis.
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PMID:Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. 1055 3

In summary, we suggest that hyperglycemia causes upregulation of 12-lipoxygenase activity. The increased production of 12-LO products, 12(S) and 15(S)-HETE, activates monocyte integrins which result in enhanced adhesion of monocytes to endothelium. The binding of monocytes to endothelium is a key early event in development of atherosclerosis. Upregulation of this process by vascular cells exposed to chronic elevations in glucose may be one explanation for the accelerated atherosclerosis observed in patients with Type 2 diabetes.
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PMID:12-Lipoxygenase products increase monocyte:endothelial interactions. 1066 68

The 12-lipoxygenase (LO) enzyme has been implicated in playing a role in pancreatic beta cell inflammatory damage and atherosclerosis. 12-LO reacts with fatty acids to form hydroperoxides which may alter cellular growth. In this study we investigated the direct effect of mouse leukocyte type 12-LO cDNA overexpression on apoptosis in Chinese hamster ovary fibroblast cells that also stably overexpress the angiotensin II type 1a receptor. CHO-AT1a cells expressing background levels of 12-LO exhibited clear increases in growth in response to angiotensin II. In contrast, the new 12-LO transfected cells (CHO-AT1a/ML12-LO cells) displayed reduced basal and angiotensin Il-induced growth compared to CHO-AT1a cells. Furthermore, serum-deprivation resulted in a significantly greater number of non-viable cells in clones having the greatest magnitude of 12-LO overexpression. These results suggested that reduction of the proliferation rate of CHO-AT1a/ML12-LO cells was due to an increasing rate of cell death. To determine whether the increase in cell death was due to apoptosis, we evaluated nuclear DNA fragmentation, cell morphologic changes, and activation of caspase-3. Cells overexpressing 12-LO cDNA displayed all these changes characteristic of apoptosis. In addition the 12-LO product, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), directly induced apoptosis in CHO-AT1a cells. These results demonstrate for the first time that 12-LO activation can lead to apoptosis in fibroblasts, suggesting a role of 12-LO in leading to inflammatory mediated cellular damage.
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PMID:Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts. 1116 74

Arachidonate 12-lipoxygenase introduces a molecular oxygen at carbon 12 of arachidonic acid to generate a 12-hydroperoxy derivative. The enzymes generate 12-hydroperoxy derivatives with either S- or R-configurations. There are three isoforms of 12S-lipoxygenases named after the cells where they were first identified; platelet, leukocyte and epidermis. The leukocyte-type enzyme is widely distributed among cells, but the tissue distribution varies substantially from species to species. The platelet and epidermal enzymes are present in only a relatively limited number of cell types. Although the structures and enzymatic properties of the three isoforms of 12S-lipoxygenases have been elucidated, the physiological roles of the 12S-lipoxygenases are not yet fully understood. There are important roles for the enzymes and their products in several biological systems including those involved in atherosclerosis and neurotransmission.
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PMID:Arachidonate 12-lipoxygenases. 1243 22

The oxidation of low-density lipoprotein (LDL) is an important event in the development of atherosclerosis. In the present study, the antioxidant properties of two novel 2-biphenylmorpholine compounds (EP2306 and EP2302) were studied. Both compounds inhibited dose-dependently the in vitro oxidation of LDL induced by copper ions. EP2306 and EP2302 increased significantly the lag phase of the oxidation reaction at 0.1 and 10 microM, respectively, whereas they reduced the rate of the reaction at 1 and 10 microM, respectively. This inhibitory effect was not due to a free radical scavenging or copper-chelating activity of EP2300 compounds. Moreover, EP2306 and EP2302 inhibited 12-lipoxygenase activity dose-dependently with IC50 values of 454 and 318 microM, respectively, but had no effect on 15-lipoxygenase activity. In hyperlipidaemic rabbits treated with EP2306 for 4 weeks, there was a decrease in thiobarbituric acid-reactive substance (TBARS) levels and a significant increase in total peroxyl radical-trapping potential (TRAP) levels as compared to control animals. The present data suggest that EP2300 compounds are effective inhibitors of copper-mediated LDL oxidation in vitro. Moreover, EP2306 acts as an antioxidant in hyperlipidaemic rabbits, a property which could be beneficial in reducing atherosclerosis.
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PMID:Antioxidant properties of two novel 2-biphenylmorpholine compounds (EP2306 and EP2302) in vitro and in vivo. 1555 55

Platelet 12-lipoxygenase is believed to play a role in cancer and other pathological conditions, such as psoriasis, atherosclerosis and arthritis. The inhibition of 12-LOX is a potential therapeutic approach in the treatment of tumor metastasis. The extracts of Euclea racemosa Murr. ssp. schimperi (A. DC.) F. White (Ebenaceae) obtained by maceration and naphthoquinones isolated from the dichloromethane extract have been investigated for their 12(S)-HETE inhibitory activity using human platelets. At 100 microg/ml, the dichloromethane extract inhibited the formation of 12(S)-HETE by 88.7% and compounds 7-methyljuglone (2), isodiospyrin (3), neodiospyrin (4) and mamegakinone (5), isolated from this extract, exhibited significant activities with IC(50) values ranging from 4 to 58 microg/ml (22.2-155.7 microM). Of these the most abundant compound, 7-methyljuglone displayed a potent inhibitory activity with an IC(50) value of 4.18 microg/ml (22.2 microM), which was comparable to the positive control baicalein with an IC(50) value of 5 microg/ml (18.5 microM). In contrast, 4(S)-shinanolone (1), the reduced form of compound 2, did not show any significant inhibitory activity even at a concentration of 60 microg/ml.
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PMID:In vitro 12(S)-HETE inhibitory activities of naphthoquinones isolated from the root bark of Euclea racemosa ssp. schimperi. 1601 77

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.
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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

Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the beta-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, beta-oxa-23:4n-6, unlike natural PUFAs, lacked ability to stimulate oxygen radical production in neutrophils but caused marked inhibition of agonist-induced upregulation of leukocyte adhesion to cultured human umbilical vein endothelial cells (HUVEC) and E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression. In addition, beta-oxa-23:4n-6 inhibited acute and chronic inflammatory responses in mice as well as the upregulation of adhesion molecule expression in arterial endothelium. This action of beta-oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas beta-oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the IkappaB kinase/nuclear factor kappaB pathway was selectively inhibited. These novel PUFAs could form the basis for a potential new class of pharmaceuticals for treating inflammatory diseases, including atherosclerosis.
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PMID:A novel beta-oxa polyunsaturated fatty acid downregulates the activation of the IkappaB kinase/nuclear factor kappaB pathway, inhibits expression of endothelial cell adhesion molecules, and depresses inflammation. 1676 65

Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae. Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry. Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l;(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae. It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.
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PMID:Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors. 1745 68

Major reproductive events such as menstruation, ovulation, implantation, and cervical ripening are characterized by an increased number of invading leukocytes in the tissues. Sex steroid hormones, particularly estrogens, play an important role in these dynamic changes in the female reproductive tract. Estrogens have also been implicated in the pathogenesis of many common pathological conditions associated with leukocyte infiltration and immunological dysfunction, such as auto-immune diseases and atherosclerosis. Although the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, have been found in different leukocyte populations in tissues and in peripheral blood, there is still very little known about functional activity and importance of ERs in blood cells. To elucidate the different roles for ERalpha and ERbeta in peripheral blood leukocytes, we used microarray gene expression profiling of rat peripheral blood leukocytes subjected to in vivo treatment with estradiol (E2), the selective ERalpha agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), and the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). We report the identification of genes that were commonly regulated by E2, PPT, and DPN, and genes that were regulated either by the ERalpha or ERbeta agonist. Further confirmatory analyses of the selected regulated genes 12-lipoxygenase, fibulin-1, furin, and calgranulin B are also presented. These results were then compared with those from the uterine tissue of the same animals. Our study demonstrates that peripheral blood leukocytes are responsive to estrogens. E2 and selective ERalpha and ERbeta agonists regulate a number of genes that may contribute to inflammation and remodeling of the extracellular matrix.
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PMID:Studies on estrogen receptor (ER) alpha and beta responses on gene regulation in peripheral blood leukocytes in vivo using selective ER agonists. 1759 25


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