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)

12/15-Lipoxygenase (LOX) activity is elevated in vascular diseases associated with impaired nitric oxide (( small middle dot)NO) bioactivity, such as hypertension and atherosclerosis. In this study, primary porcine monocytes expressing 12/15-LOX, rat A10 smooth muscle cells transfected with murine 12/15-LOX, and purified porcine 12/15-LOX all consumed *NO in the presence of lipid substrate. Suppression of LOX diene conjugation by *NO was also found, although the lipid product profile was unchanged. *NO consumption by porcine monocytes was inhibited by the LOX inhibitor, eicosatetraynoic acid. Rates of arachidonate (AA)- or linoleate (LA)-dependent *NO depletion by porcine monocytes (2.68 +/- 0.03 nmol x min(-1) x 10(6) cells(-1) and 1.5 +/- 0.25 nmol x min(-1) x 10(6) cells(-1), respectively) were several-fold greater than rates of *NO generation by cytokine-activated macrophages (0.1-0.2 nmol x min(-1) x 10(6) cells(-1)) and LA-dependent *NO consumption by primary porcine monocytes inhibited *NO activation of soluble guanylate cyclase. These data indicate that catalytic *NO consumption by 12/15-LOX modulates monocyte *NO signaling and suggest that LOXs may contribute to vascular dysfunction not only by the bioactivity of their lipid products, but also by serving as catalytic sinks for *NO in the vasculature.
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PMID:Catalytic consumption of nitric oxide by 12/15- lipoxygenase: inhibition of monocyte soluble guanylate cyclase activation. 1142 23

Cytokines or hydroperoxides upregulate cell adhesion molecules (CAM) in early stages of atherosclerosis. VCAM-1 expression was therefore investigated in rabbit aortic smooth muscle cells (SMC) stably transfected either with phospholipid hydroperoxide glutathione peroxidase (PHGPx; SMCPHGPx) as a hydroperoxide-reducing enzyme or with 15-lipoxygenase (15-LOX; SMCLOX) as a hydroperoxide-producing enzyme. Transfected cells showed up to 3-fold enhanced PHGPx and a marked LOX activity, respectively, that was absent in controls. Intracellular hydroperoxides were 6-fold higher in SMCLOX than in SMC or SMCPHGPx. Intracellular protein thiols were decreased by 50 and 90% in SMCPHGPx and SMCLOX, respectively. Glutathione mixed disulfides were tentatively increased from SMC via SMCPHGPx to SMCLOX, accordingly. Thiol reduction with tris(2-carboxyethyl)phosphine completely restored protein thiols in SMCPHGPx, whereas in SMCLOX only 60% of control values were recovered. Basal VCAM-1 mRNA levels were decreased by 50% in SMCPHGPx and 75% in SMCLOX. VCAM-1-inducibility was abrogated in SMCLOX but not in SMCPHGPx. Accordingly, NFkappaB-driven reporter gene activation by IL-1 was unaffected in SMCPHGPx but abolished in SMCLOX. The data confirm that PHGPx overexpression dampens CAM expression either by lowering stimulatory hydroperoxides or by using hydroperoxides for protein modification. But hydroperoxides, when constitutively overproduced as in SMCLOX, inhibit CAM expression and render cells refractory to IL-1 stimulation likely due to oxidation of protein thiols of the signaling system.
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PMID:Inhibition of basal and interleukin-1-induced VCAM-1 expression by phospholipid hydroperoxide glutathione peroxidase and 15-lipoxygenase in rabbit aortic smooth muscle cells. 1474 25

BHUx is a polyherbal formulation consisting of water-soluble fractions of five medicinal plants (Commiphora mukul, Terminalia arjuna, Boswellia serrata, Semecarpus anacardium and Strychnos nux vomica). The present study was undertaken to evaluate its antioxidant and antiinflammatory effects. BHUx, standardized by HPLC fingerprinting and filtered through 0.2 microm filter paper, was employed for different studies under in vivo and in vitro conditions. Under in vivo conditions, BHUx significantly reduced inflammation in the carrageenan-induced rat paw oedema model of inflammation, suggesting its anti-inflammatory properties. In order to test the mechanism of action of BHUx, further in vitro studies were undertaken on cumene-hydroperoxide-induced lipid peroxidation (CHP) in liver homogenate, LPS-induced NO production in peritoneal macrophages and on key enzymes of arachidonic acid cascade, involved in the mediation of inflammation. Under the conditions, BHUx showed concentration-dependent inhibition of CHP-induced lipid peroxidation in liver homogenate, suggesting its antioxidant properties. Similarly the potent anti-inflammatory effects of BHUx are evident by (a) preferential inhibition of COX-2 (IC50 for COX-2 = 80 microg/ml and IC50 for COX-1 = 169 microg/ml), (b) low ratios in the IC50 values of COX-2/COX-1 (0.47), (c) decreased production of NO in LPS-induced peritoneal macrophages and (d) inhibition of 5-LOX (IC50 = 795 microg/ml). BHUx also showed a preference for inhibiting 15-lipoxygenase (IC50 = 44 microg/ml), a key enzyme implicated in LDL oxidation. These studies suggest that BHUx is acting mainly at three levels, i.e., as a potent natural antioxidant, by reduction of key inflammatory mediators of arachidonic acid cascade and by preventing 15-LOX-mediated LDL oxidations, to prevent atherosclerosis.
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PMID:Anti-inflammatory properties of BHUx, a polyherbal formulation to prevent atherosclerosis. 1526 16

Lipoxygenase (LOX) pathways are well appreciated for their ability to regulate key events contributing to the cardinal signs of inflammation. Recent evidence indicates that LOX genes are associated with osteoporosis. Also, overexpression of the 15-LOX Type 1 in transgenic rabbits leads to a reduced inflammatory phenotype and protection from periodontal disease, as well as atherosclerosis. Osteoporosis and inflammation-associated bone degradation, such as periodontitis, affect many individuals worldwide and are known to have pathogenesis that involves local mediators via communication between osteoclasts and osteoblasts during osteogenesis. Evidence has emerged indicating that LOX gene expression is associated with reduced bone strength in murine models of osteoporosis. Overexpression of the 15-LOX gene and its products, such as lipoxins, confers endogenous anti-inflammation. This article discusses the recent findings that may link aberrant LOX pathway expression in these diseases, suggesting new avenues for therapeutic approaches via activation of endogenous pathways for resolution of local inflammation.
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PMID:Clues for new therapeutics in osteoporosis and periodontal disease: new roles for lipoxygenases? 1558 68

12/15-Lipoxygenase (12/15-LOX) plays a pathogenic role in atherosclerosis. To characterize whether 12/15-LOX also contributes to endothelial dysfunction and hypertension, regulation of vessel tone and angiotensin II (ang II) responses were characterized in mice deficient in 12/15-LOX. There was a twofold increase in the magnitude of l-nitroarginine-methyl ester-inhibitable, acetylcholine-dependent relaxation or phenylephrine-dependent constriction in aortic rings isolated from 12/15-LOX(-/-) mice. Plasma NO metabolites and aortic endothelial NO synthase (eNOS) expression were also elevated twofold. Angiotensin II failed to vasoconstrict 12/15-LOX(-/-) aortic rings in the absence of L-nitroarginine-methyl ester, and ang II impaired acetylcholine-induced relaxation in wild-type, but not 12/15-LOX(-/-) rings. In vivo, 12/15-LOX(-/-) mice had similar basal systolic blood pressure measurements to wild type, however, blood pressure elevations in response to ang II infusion (1.1 mg/kg/day) were significantly attenuated (maximal pressure, 143.4 +/- 4 mmHg versus 122.1 +/- 5.3 mmHg for wild type and 12/15-LOX(-/-), respectively). In contrast, vascular hypertrophic responses to ang II, and ang II type 1 receptor (AT1-R) expression were similar in both strains. This study shows that 12/15-LOX(-/-) mice have increased NO biosynthesis and impaired ang II-dependent vascular responses in vitro and in vivo, suggesting that 12/15-LOX signaling contributes to impaired NO bioactivity in vascular disease in vivo.
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PMID:Elevated endothelial nitric oxide bioactivity and resistance to angiotensin-dependent hypertension in 12/15-lipoxygenase knockout mice. 1574 78

Lipoxygenases (LOXs) form a heterogeneous family of lipid-peroxidizing enzymes, and several LOX-isoforms (12/15-LOX, 5-LOX) have been implicated in atherogenesis. However, the precise role of these enzymes is still a matter of discussion. 12/15-LOXs are capable of oxidizing lipoproteins (low-density lipoprotein (LDL), high-density lipoprotein (HDL)) to atherogenic forms, and functional inactivation of this enzyme in murine atherosclerosis models slows down lesion formation. In contrast, rabbits that overexpress this enzyme were protected from lesion formation when fed a lipid-rich diet. To contribute to this discussion, we recently investigated the impact of 12/15-LOX overexpression on in vitro foam cell formation. When 12/15-LOX-transfected J774 cells were incubated in culture with modified LDL, we found that intracellular lipid deposition was reduced in the transfected cells when compared with the corresponding control transfectants. This paper briefly summarizes the current status of knowledge on the biological activity of different LOX-isoforms in atherogenesis and will also provide novel experimental data characterizing the role of 12/15-LOX in cellular LDL modification and for in vitro foam cell formation.
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PMID:The role of lipoxygenase-isoforms in atherogenesis. 1627 Feb 76

Lipoxygenases (LOXs) form a heterogeneous family of lipid-peroxidizing enzymes, which have originally been implicated in cell differentiation and biosynthesis of inflammatory mediators. More recent studies suggested a role of various LOX-isoforms in the pathogenesis of human diseases, including bronchial asthma, osteoporosis and atherosclerosis. According to their phylogenetic relatedness, LOX-isoforms may be classified into four subfamilies, three of which (12/15-LOX, 5-LOX, platelet 12-LOX) have been related to atherogenesis. Several lines of experimental evidence suggest a role for LOXs in atherosclerosis, but the mechanisms remain a matter of discussion. This review will briefly summarize the current understanding on the molecular enzymology of the LOX family and the current status of knowledge on the role of different LOX isoforms in atherogenesis. The available literature data will be critically reviewed and a short perspective on future developments in the field will be provided.
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PMID:Biologic relevance of lipoxygenase isoforms in atherogenesis. 1629

In addition to their role in many vital cellular functions, arachidonic acid (AA) and its eicosanoid metabolites are involved in the pathogenesis of several diseases, including atherosclerosis and cancer. To understand the potential mechanisms by which these lipid molecules could influence the disease processes, particularly cardiovascular diseases, we studied AA's effects on vascular smooth muscle cell (VSMC) motility and the role of cAMP-response element binding protein-1 (CREB-1) in this process. AA exerted differential effects on VSMC motility; at lower doses, it stimulated motility, whereas at higher doses, it was inhibitory. AA-induced VSMC motility requires its conversion via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways. AA stimulated the phosphorylation of extracellular signal-regulated kinases (ERKs), Jun N-terminal kinases (JNKs), and p38 mitogen-activated protein kinase (p38MAPK) in a time-dependent manner, and blockade of these serine/threonine kinases significantly attenuated AA-induced VSMC motility. In addition, AA stimulated CREB-1 phosphorylation and activity in a manner that was also dependent on its metabolic conversion via the LOX and COX pathways and the activation of ERKs and p38MAPK but not JNKs. Furthermore, suppression of CREB-1 activation inhibited AA-induced VSMC motility. 15(S)-Hydroxyeicosatetraenoic acid and prostaglandin F2alpha, the 15-LOX and COX metabolites of AA, respectively, that are produced by VSMC at lower doses, were also found to stimulate motility in these cells. Together, these results suggest that AA induces VSMC motility by complex mechanisms involving its metabolism via the LOX and COX pathways as well as the ERK- and p38MAPK-dependent and JNK-independent activation of CREB-1.
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PMID:Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility. 1638 63

Disodium disuccinate astaxanthin ('rac'-dAST; Cardax) is a water-dispersible C40 carotenoid derivative under development for oral and parenteral administration for cardioprotection of the at-risk ischemic cardiovascular patient. In experimental infarction models in animals (rats, rabbits, and dogs), significant myocardial salvage has been obtained, up to 100% at the appropriate dose in dogs. The documented mechanism of action in vitro includes direct scavenging of biologically produced superoxide anion; in vivo in rabbits, modulation of the complement activity of serum has also been shown. A direct correlation between administration of the test compound in animals and reductions of multiple, independent markers of oxidative stress in serum was recently obtained in a rat experimental infarction model. For the current study, it was hypothesized that oral Cardax administration would inhibit oxidative damage of multiple relevant biological targets in a representative, well-characterized murine peritoneal inflammation model. A previously developed mass spectrometry-based (LC/ESI/MS/MS) approach was used to interrogate multiple distinct pathways of oxidation in a black mouse (C57/BL6) model system. In vivo markers of oxidant stress from peritoneal lavage samples (supernatants) were evaluated in mice on day eight (8) after treatment with either Cardax or vehicle (lipophilic emulsion without drug) orally by gavage at 500 mg/kg once per day for seven (7) days at five (5) time points: (1) baseline prior to treatment (t=0); (2) 16 h following intraperitoneal (i.p.) injection with thioglycollate to elicit a neutrophilic infiltrate; (3) 4 h following i.p. injection of yeast cell wall (zymosan; t=16 h/4 h thioglycollate+zymosan); (4) 72 h following i.p. injection with thioglycollate to elicit monocyte/macrophage infiltration; and (5) 72 h/4 h thioglycollate+zymosan. A statistically significant sparing effect on the arachidonic acid (AA) and linoleic acid (LA) substrates was observed at time points two and five. When normalized to the concentration of the oxidative substrates, statistically significant reductions of 8-isoprostane-F(2alpha) (8-iso-F(2alpha)) at time point three (maximal neutrophil recruitment/activation), and 5-HETE, 5-oxo-EET, 11-HETE, 9-HODE, and PGF(2alpha) at time point five (maximal monocyte/macrophage recruitment/activation) were observed. Subsequently, the direct interaction of the optically inactive stereoisomer of Cardax (meso-dAST) with human 5-lipoxygenase (5-LOX) was evaluated in vitro with circular dichroism (CD) and electronic absorption (UV/Vis) spectroscopy, and subsequent molecular docking calculations were made using mammalian 15-LOX as a surrogate (for which XRC data has been reported). The results suggested that the meso-compound was capable of interaction with, and binding to, the solvent-exposed surface of the enzyme. These preliminary studies provide the foundation for more detailed evaluation of the therapeutic effects of this compound on the 5-LOX enzyme, important in chronic diseases such as atherosclerosis, asthma, and prostate cancer in humans.
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PMID:The effects of oral Cardax (disodium disuccinate astaxanthin) on multiple independent oxidative stress markers in a mouse peritoneal inflammation model: influence on 5-lipoxygenase in vitro and in vivo. 1646 47

12/15-Lipoxygenases (12/15-LOX) are members of the LOX family, which are expressed in mammals by monocytes and macrophages following induction by the T helper type 2 cytokines, interleukins-4 and -13. They oxygenate free polyenoic fatty acids but also ester lipids and even complex lipid-protein assemblies such as biomembranes and lipoproteins. The primary oxidation products are either reduced by glutathione peroxidases to corresponding hydroxy derivatives or metabolized into secondary oxidized lipids including leukotrienes, lipoxins and hepoxilins, which act as lipid mediators. Examination of knockout and transgenic animals revealed important roles for 12/15-LOX in inflammatory diseases, including atherosclerosis, cancer, osteoporosis, angiotension II-dependent hypertension and diabetes. In vitro studies suggested 12/15-LOX products as coactivators of peroxisomal proliferator activating-receptors (PPAR), regulators of cytokine generation, and modulators of gene expression related to inflammation resolution. Despite much work in this area, the biochemical mechanisms by which 12/15-LOX regulates physiological and pathological immune cell function are not fully understood. This review will summarize the biochemistry and tissue expression of 12/15-LOX and will describe the current knowledge regarding its immunobiology and regulation of inflammation.
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PMID:Inflammation and immune regulation by 12/15-lipoxygenases. 1667 71


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