Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P) present in tobacco smoke and tar, have been implicated in the development of atherosclerosis as well as cancer. Increased expression of cyclooxygenase-2 (COX-2) has been detected both in atherosclerotic lesions and in epithelial cancers. To determine whether polycyclic aromatic hydrocarbons might directly affect COX expression in vascular cells, we investigated the effects of B[a]P on COX-2 expression in human and rat arterial smooth muscle cells (SMC). Treatment with B[a]P increased levels of COX-2 protein and mRNA and enhanced prostaglandin synthesis. Nuclear runoff assays and transient transfections revealed increased COX-2 gene transcription after treatment with B[a]P. Experiments were done to define the signaling mechanism by which B[a]P induced COX-2. B[a]P caused a rapid increase in phosphorylation of extracellular signal-regulated kinase (ERK); pharmacologic inhibition of mitogen-activated protein kinase kinase blocked B[a]P-mediated induction of COX-2. Depletion of the intracellular antioxidant, glutathione, with buthionine sulfoximine significantly increased B[a]P-mediated induction of COX-2 while exposure to N-acetylcysteine, a precursor of glutathione, suppressed the induction of COX-2 by B[a]P. Several lines of evidence suggest that the induction of COX-2 by B[a]P is mediated, at least in part, by NF-kappaB. Treatment with B[a]P increased binding of NF-kappaB to DNA. Moreover, B[a]P-mediated stimulation of COX-2 promoter activity was blocked when a construct containing a mutagenized NF-kappaB site was used. Pharmacological inhibitors of NF-kappaB blocked the induction of COX-2 protein and the stimulation of COX-2 promoter activity by B[a]P. Taken together, these data are likely to be important for understanding the atherogenic effects of tobacco smoke.
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PMID:Benzo[a]pyrene induces the transcription of cyclooxygenase-2 in vascular smooth muscle cells. Evidence for the involvement of extracellular signal-regulated kinase and NF-kappaB. 1067 33

We have previously shown the expression of group X secretory phospholipase A(2) (sPLA(2)-X) in mouse splenic macrophages and its powerful potency for releasing fatty acids from various intact cell membranes. Here, we examined the potency of sPLA(2)-X in the production of lipid mediators in murine peritoneal macrophages. Mouse sPLA(2)-X was found to induce a marked release of fatty acids including arachidonic acid and linoleic acid, which contrasted with little, if any, release by the action of group IB and IIA sPLA(2)s. In resting macrophages, sPLA(2)-X elicited a modest production of prostaglandin E(2) and thromboxane A(2). After the induction of cyclooxygenase-2 (COX-2) by pretreatment with lipopolysaccharide, a dramatic increase in the production of these eicosanoids was observed in sPLA(2)-X-treated macrophages, which was completely blocked by the addition of either the specific sPLA(2) inhibitor indoxam or the COX inhibitor indomethacin. In accordance with its higher hydrolyzing activity toward phosphatidylcholine, mouse sPLA(2)-X induced a potent production of lysophosphatidylcholine. These findings strongly suggest that sPLA(2)-X plays a critical role in the production of various lipid mediators from macrophages. These events might be relevant to the progression of various pathological states, including chronic inflammation and atherosclerosis.
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PMID:Group X secretory phospholipase A(2) induces potent productions of various lipid mediators in mouse peritoneal macrophages. 1134 59

Anti-thrombotic therapy with aspirin, which at low doses acts as a selective inhibitor of platelet cyclooxygenase 1 (COX-1) activity, is well established. However, a major limitation of aspirin treatment is its gastrointestinal toxicity, which is thought to be linked to the suppression of COX-1-mediated production of cytoprotective prostaglandins. Selective COX-2 inhibitors are effective anti-inflammatory agents with lower gastrointestinal toxicity than aspirin. These inhibitors might also downregulate vascular and leukocyte inflammatory components that play a major part in atherothrombotic disease. However, some selective COX-2 inhibitors appear to increase cardiovascular risk. Newly developed dual COX-5-lipoxygenase (5-LOX) inhibitors share the anti-inflammatory effect and gastric safety of COX-2 inhibitors, but also inhibit COX-1-mediated platelet function and 5-LOX-mediated synthesis of gastrotoxic leukotrienes. Dual inhibitors might thus be beneficial in the treatment of atherosclerosis, where platelet-leukocyte interaction dominates the underlying inflammatory process.
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PMID:Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors. 1276 24

Slow, time-dependent, irreversible, highly selective inhibitors of COX-2 such as celecoxib, etoricoxib, rofecoxib and valdecoxib, so-called coxibs, are a new group of drugs widely used in rheumatology as well as in other fields of medicine. The tolerability of these drugs is at least equivalent to that of commonly used non-selective COX inhibitors (e.g. diclofenac, ibuprofen, naproxen). The unquestionable superiority of selective COX-2 blockade includes a low risk of gastrointestinal side effects. However, similarly to the other COX inhibitors, coxibs must be carefully administered to patients with coexistent liver and renal disease, generalised atherosclerosis, ischaemic heart disease, and to the elderly and children. Pregnancy and lactation require precise monitoring of adverse effects on the fetus, neonate and infant, or discontinuation of therapy with the drug.
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PMID:[Coxibs: highly selective cyclooxygenase-2 inhibitors. Part II. Side effects]. 1286 1

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Prostaglandins (PGs), thromboxanes (Txs), and leukotrienes (LTs) play a relevant role in cardiovascular physiology and pathophysiology. Recent reports concerning cardiovascular risk associated with cyclooxygenase-2 selective inhibitors have prompted questions about the "protective" or "deleterious" role of each COX isoform in cardiovascular disease, and the cloning and expression of inducible PGE-synthase (PGES) open the possibility that PGES could be a new therapeutical target in this context. Predominance of constricting or relaxing prostanoids depends not only on COX activity but also to downstream enzymes such as PGI-synthase (PGIS) and PGES. In the vessel wall, PGIS and PGES seem to be major downstream enzymes in the endothelium and smooth muscle, respectively. Like COX, activity of these enzymes can also be regulated by several factors, which include nitrogen oxides, cytokines, and lipid peroxides. LTs are important inflammatory mediators also involved in the pathophysiology of cardiovascular disease, which are targets for pharmacological intervention. Unlike COX pathway, the biosynthesis of chemotactic and vaso-constrictor LTs in the vasculature strongly depends on leukocyte recruitment and activation, and on cell-cell interaction between leukocytes and vascular cells in the inflamed areas. The present review emphasizes the role of vascular-derived prostanoids and LTs on atherosclerosis.
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PMID:Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis. 1517 May 90

Rheumatoid arthritis (RA) is associated with a reduced life expectancy considered to be partly caused by cardiovascular events. A growing concern is that accelerated atherosclerosis is driven by inflammatory mechanisms similar to those responsible for RA. Therefore, selective COX-2 inhibitors, which are widely used for the symptomatic treatment of pain and inflammation in RA, may have an impact on atherosclerotic processes. Their anti-inflammatory properties might provoke anti-atherogenic effects but on the other hand, selective inhibition of anti-thrombotic prostacyclin and COX-2 independent effects might promote the risk of increased prothrombotic activity. In the current study, the effects of the presently marketed selective COX-2 inhibitors celecoxib and rofecoxib on vascular cells have been investigated. Celecoxib inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. At high concentrations, it induced apoptosis and the modulation of inhibitory cell cycle proteins. In contrast rofecoxib-even at high concentrations-had no effect on cell proliferation, apoptosis or cell cycle distribution indicating that celecoxib and rofecoxib do not affect the same signal transduction pathways in endothelial cells. Both drugs did not affect apoptosis induction or cell cycle proliferation in human vascular smooth muscle cells. The observed effects on endothelial cells appear to be COX-independent since both drugs selectively inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for inhibition of prostacyclin production. Regarding endothelial apoptosis as a relevant event in the initiation and progression of atherosclerosis the present data put forward the hypothesis that the presently marketed COX-2 inhibitors have a different impact on atherosclerotic processes.
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PMID:Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human vascular cells. 1519 6

Conjugated linoleic acid (CLA) refers to a group of polyunsaturated fatty acids that exist as positional (18:2) and stereo (cis/trans) isomers of conjugated dienoic octadecadienoate. Reports consistently indicate that CLA may inhibit both the onset and progression of atherosclerosis, via an as yet unknown mechanism(s). In an effort to identify the putative biochemical effects of CLA on bovine aortic endothelial cells (BAECs), the authors examined both the temporal and dose-dependent effects of a commercial CLA isomeric mixture on the expression and enzymatic function of endothelial nitric oxide synthase (eNOS) and cyclooxygenase-I/II (COX-I/II) in these cells. Initial investigations indicated that CLA mix (0 to 10 microg/mL, 0 to 24 h) failed to regulate either the expression or activity of eNOS in BAECs under basal conditions. Pretreatment of BAECs with CLA mix (10 microg/mL) for either 3 or 24 h, followed by incubation with 5 microM bradykinin (BK) for 3 h, however, increased BK-stimulated nitrite release by 2.4 +/- 0.6- and 3.0 +/- 0.4-fold, respectively, more than control cells (BK-stimulation without CLA pretreatment). Under basal conditions, CLA mix (10 microg/mL, 0 to 24 h) had no significant effect on either COX-I or COX-II expression, genes that could be readily induced in response to hemodynamic stimuli. CLA could, however, significantly attenuate BAEC release of 6-keto-prostaglandin F(1alpha) (6k-PGF(1alpha)), a stable breakdown product of prostaglandin I2 (PGI2) within the cyclooxygenase pathway, in a dose- and time-dependent manner. In conclusion, therefore, the results suggest that CLA may potentiate agonist-stimulated eNOS activation whilst attenuating COX-dependent PGI2 synthesis in BAECs. This ability to increase agonist-stimulated nitric oxide (NO) levels, whilst reducing production of inflammatory mediators within vascular ECs, supports a putative atheroprotective role for CLA and provides an important biochemical insight into its purported ability to modulate endothelium-mediated vascular homeostasis.
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PMID:Modulation of nitric oxide and 6-keto-prostaglandin F(1alpha) production in bovine aortic endothelial cells by conjugated linoleic acid. 1537 Feb 99

Clinical investigations have demonstrated a link between use of the sulfone cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, and increased risk for atherothrombotic events. This increased risk was not observed for a sulfonamide COX-2 inhibitor (celecoxib), indicating a potential non-enzymatic mechanism for rofexocib. To test this hypothesis, we compared the independent effects of COX-2 inhibitors on human LDL oxidation, an important contributor to atherosclerotic cardiovascular disease. The results showed that rofecoxib (100 nM) significantly decreased (>40%, p<0.001) the lag time for LDL conjugated diene formation and increased levels of thiobarbituric-acid-reactive-substances (TBARS) in vitro. The pro-oxidant activity of rofecoxib was dose-dependent and attenuated by 70% (p<0.001) with the antioxidant, Trolox. Rofecoxib and etoricoxib (100 nM) also caused a marked increase (>35%, p<0.001) in non-enzymatic generation of isoprostanes, as measured by mass spectroscopy. Addition of rofecoxib to fresh human plasma reduced the oxygen radical antioxidant capacity (ORAC) by 34% (p<0.0001). By contrast, other selective (celecoxib, valdecoxib, meloxicam) and non-selective COX inhibitors (ibuprofen, naproxen, diclofenac) had no significant effect on LDL oxidation rates or plasma ORAC values, even at suprapharmacologic levels. X-ray diffraction analysis showed that sulfone COX-2 inhibitors interact differently with membrane phospholipids, suggesting a physico-chemical basis for the pro-oxidant activity. These results demonstrate that sulfone COX-2 inhibitors increase the susceptibility of biological lipids to oxidative modification through a non-enzymatic process. These findings may provide mechanistic insight into reported differences in cardiovascular risk for COX-2 inhibitors.
Atherosclerosis 2004 Dec
PMID:Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs. 1553 Aug 95

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.
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PMID:Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. 1580 19


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