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)

Diabetes mellitus (DM) is accompanied by several cardiovascular complications such as coronary artery disease, atherosclerosis, hypertension, cerebral and myocardial infarction, etc. DM induces the alteration of platelet functions including activation, hyperaggregation, adhesiveness, and formation of thrombi. Release of AA from phospholipids of the PM, synthesis of TxA(2),PGE(2), activity of PLA(2), and PLC are increased in the platelets of the DM patients. Stimulation of PLA(2) activity and accumulation of bioactive metabolites such as AA, its oxygenated derivatives, prostaglandins and PAF can evoke glucose production, also. In this study we explored the effect of the 1,4-dihydropyridine compound cerebrocrast at a low concentration (10(-6)-10(-8)M) on the level of intracellular calcium in unstimulated human platelets and those stimulated with thrombin as well as release of [(3)H] AA from phospholipids of platelet PM. Cerebrocrast at a concentration of 10(-6) M decreased the basal level of intracellular calcium concentration (platelets were loaded with Fura-2) in unstimulated as well as in thrombin stimulated platelets. Cerebrocrast at concentrations of 10(-6), 10(-7), 10(-8) M inhibited release of [(3)H] AA from phospholipids of platelet PM. We conclude that blockade of human platelet activation with cerebrocrast can prevent aggregation, adhesion and formation of thrombi. The inhibition of [(3)H] AA release from phospholipids of platelet PM can prevent formation of eicosanoids such as TxA(2), PGG(2), and PGH(2) plus AA oxygenated derivatives. These effects of cerebrocrast are very significant in the treatment of DM-evoked cardiovascular complications.
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PMID:Effect of cerebrocrast on the function of human platelets and release of the arachidonic acid from plasma membrane. 1197 14

Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. Therefore, using cDNA microarrays, we screened for genes regulated by prostaglandin E(2) (PGE(2)), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (MPhi). PGE(2) (50 nm) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1alpha and -1beta, and interferon-inducible protein-10. PGE(2) also inhibited the tumor necrosis factor-alpha-, interferon-gamma-, and interleukin-1beta-mediated expression of these chemokines. In contrast to the case of MPhi, PGE(2) did not suppress chemokine expression in human endothelial and smooth muscle cells (SMC) treated with LPS and pro-inflammatory cytokines. To assess the potential paracrine effect of endogenous PGE(2) on macrophage-derived chemokine production, we co-cultured MPhi with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE(2) production exceeded that in the mono-cultures, and MIP-1beta declined significantly compared with MPhi cultured without SMC. We further documented prominent expression of the PGE(2) receptor EP4 in MPhi in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE(2)-mediated suppression of chemokine production. Thus, endogenous PGE(2) may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor.
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PMID:Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. 1221 36

Conjugated linoleic acid (CLA) is a mixture of positional (e.g. 7,9; 9,11; 10,12; 11,13) and geometric (cis or trans) isomers of octadecadienoic acid. This compound was first shown to prevent mammary carcinogenesis in murine models. Later investigations uncovered a number of additional health benefits, including decreasing atherosclerosis and inflammation while enhancing immune function. The mechanisms of action underlying these biological properties are not clearly understood. The aim of this review is to highlight recent advances in CLA research related to experimental inflammatory bowel disease. In addition, two possible mechanisms of action (i.e. endoplasmic and nuclear) were discussed in detail in the context of enteric inflammatory disorders. Conjugated linoleic acid was first implicated in down-regulating the generation of inducible eicosanoids (i.e. PGE(2) and LTB(4)) involved in early micro-inflammatory events (endoplasmic). More recently, CLA has been shown to modulate the expression of genes regulated by peroxisome proliferator-activated receptors (PPARs; nuclear). In pigs, prolonged dietary CLA treatment stimulated the expression of PPAR-gamma in the muscle. Thus, evidence supporting both mechanistic theories of CLA acting through eicosanoid synthesis and PPAR activity is available. The further understanding of the anti-inflammatory mechanisms of action of CLA may yield novel nutritional therapies for enteric inflammation.
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PMID:Colonic anti-inflammatory mechanisms of conjugated linoleic acid. 1246 64

Increased levels of isoprostanes have been detected in human atherosclerotic lesions. To examine a possible role for 8-iso-prostaglandin E(2) (8-iso-PGE(2)) in atherogenesis, we tested the effect of 8-iso-PGE(2) on adhesion of leukocytes to human umbilical vein endothelial cells (EC). We demonstrate that 8-iso-PGE(2) stimulates EC to bind monocytes, but not neutrophils. This effect was inhibited by the thromboxane A(2) receptor antagonist SQ29548. Moreover, 8-iso-PGE(2) increased levels of cyclic AMP in EC, and monocyte adhesion induced by 8-iso-PGE(2) was blocked by a protein kinase A inhibitor, H89. In addition, 8-iso-PGE(2 )induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase and stimulated expression of EGR-1. A specific inhibitor of p38 MAP kinase (SB203580) abrogated monocyte binding, whereas an inhibitor of the ERK pathway (PD98059) did not block monocyte adhesion induced by 8-iso-PGE(2). Activation of nuclear factor-kappaB (NF-kappaB) and expression of NFkappaB-dependent genes intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were not induced by 8-iso-PGE(2). Taken together, these results demonstrate that 8-iso-PGE(2) stimulates EC to specifically bind monocytes, but not neutrophils. This effect is mediated by cyclic AMP/protein kinase A- and p38 MAP kinase-dependent pathways and is independent of the classical inflammatory NFkappaB pathway. Thus, formation of 8-iso-PGE(2) may play an important role in chronic inflammatory diseases such as atherosclerosis by increasing adhesion and extravasation of monocytes.
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PMID:The isoprostane 8-iso-PGE2 stimulates endothelial cells to bind monocytes via cyclic AMP- and p38 MAP kinase-dependent signaling pathways. 1271 76

Infection with Chlamydia pneumoniae has been implicated as a potential risk factor for atherosclerosis. This study was designed to investigate the mechanisms of the anti-chlamydial activity of aspirin. A reporter gene assay for NF-kappa B activity, immunoblot analysis for cyclo-oxygenase (COX)-2 and radioimmunoassay for prostaglandin E(2) (PGE(2)) were performed. Following infection of HEp-2 cells with C. pneumoniae, NF-kappa B was activated, COX-2 was induced and PGE(2) was elevated. Aspirin inhibited NF-kappa B activation at a concentration of 0.1 mM, partially inhibited COX-2 induction and blocked PGE(2) synthesis completely. In addition, high doses of aspirin (1 and 2 mM) inhibited chlamydial growth in HEp-2 cells, decreasing the number and size of inclusion bodies; this effect could be overcome by adding tryptophan to the culture. Indomethacin also blocked the synthesis of PGE(2), but had no effect on COX-2 expression or chlamydial growth. These results indicate that aspirin not only has an anti-inflammatory activity through prevention of NF-kappa B activation but also has anti-chlamydial activity at high doses, possibly through depletion of tryptophan in HEp-2 cells.
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PMID:Aspirin inhibits Chlamydia pneumoniae-induced NF-kappa B activation, cyclo-oxygenase-2 expression and prostaglandin E2 synthesis and attenuates chlamydial growth. 1272 17

Atheroma macrophages internalize large quantities of lipoprotein-derived lipids. While most emphasis has been placed on cholesterol, lipoprotein-derived fatty acids may also play important roles in lesional macrophage biology. Little is known, however, about the trafficking or metabolism of these fatty acids. In this study, we first show that the cholesterol-fatty acyl esterification reaction, catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT), competes for the incorporation of lipoprotein-derived fatty acids into cellular phospholipids. Furthermore, conditions that inhibit trafficking of cholesterol from late endosomes/lysosomes to the endoplasmic reticulum (ER), such as the amphipathic amine U18666A and the Npc1+/- mutation, also inhibit incorporation of lipoprotein-derived fatty acids into phospholipids. The biological relevance of these findings was investigated by studying the suppression of agonist-induced prostaglandin E(2) (PGE(2)) and leukotriene C(4)/D(4)/E(4) production during lipoprotein uptake by macrophages, which has been postulated to involve enrichment of cellular phospholipids with non-arachidonic fatty acids (NAAFAs). We found that eicosanoid suppression was markedly enhanced when ACAT was inhibited and prevented when late endosomal/lysosomal lipid trafficking was blocked. Moreover, PGE(2) suppression depended entirely on acetyl-LDL-derived NAAFAs, not on acetyl-LDL-cholesterol, and was not due to decreased cPLA(2) activity per se. These data support the following model: lipoprotein-derived NAAFAs traffic via the NPC1 pathway from late endosomes/lysosomes to a critical pool of phospholipids. In competing reactions, these NAAFAs can be either esterified to cholesterol or incorporated into phospholipids, resulting in suppression of eicosanoid biosynthesis. In view of recent evidence suggesting dysfunctional cholesterol esterification in late lesional macrophages, these data predict that such cells would have highly suppressed eicosanoid synthesis, thus affecting eicosanoid-mediated cell signaling in advanced atherosclerosis.
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PMID:Suppression of macrophage eicosanoid synthesis by atherogenic lipoproteins is profoundly affected by cholesterol-fatty acyl esterification and the Niemann-Pick C pathway of lipid trafficking. 1463 86

Prostaglandin (PG) D synthase (PGDS) catalyzes the isomerization of PGH(2) to PGD(2), which acts as an endogenous somnogen and an allergic mediator. There are two distinct types of PGDS: one is lipocalin-type PGDS (L-PGDS) localized in the central nervous system, male genitals, and heart; and the other is hematopoietic PGDS (H-PGDS) in mast cells and Th2 lymphocytes. L-PGDS is the same as beta-trace, a major protein in human cerebrospinal fluid, and is also secreted into the seminal plasma and plasma. The L-PGDS concentration in various body fluids is useful as a marker for various diseases such as renal failure and coronary atherosclerosis. H-PGDS is a cytosolic enzyme and is a member of the Sigma class of glutathione S-transferase. We determined the X-ray crystallographic structures of H-PGDS and L-PGDS. We also generated the gene-knockout (KO) mice and the human enzyme-overexpressing transgenic mice for each PGDS. L-PGDS-KO mice lacked PGE(2)-induced tactile allodynia and rebound of non-rapid eye movement sleep after sleep deprivation. Human L-PGDS-overexpressing transgenic mice showed an increase in non-rapid eye movement sleep due to accumulation of PGD(2) in the brain after tail clipping. H-PGDS-KO mice showed an allergic reaction weaker than that of the wild-type mice.
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PMID:[Functional analyses of lipocalin-type and hematopoietic prostaglandin D synthases]. 1469 53

Cardiovascular disease (CVD) remains the leading cause of death in Western societies. Atherosclerosis is a major cardiovascular related disorder that is responsible for 50% of all mortality in the United States. Several epidemiological studies suggest that consumption of a plant-based diet is associated with a decreased incidence of cardiovascular abnormalities. Phytosterols, especially beta-sitosterol, are plant sterols that have been shown to exert protective effects against cardiovascular diseases as well as many types of cancer. Monocyte/macrophage cells are involved with the inflammatory process. Accumulation of these cells in arteries is one of the initial events leading to atherosclerosis. Macrophages are capable of supplying the atherosclerotic vessel with substantial amounts of prostaglandins. Prostaglandins have been shown by numerous studies to play a key role in the atherosclerosis process. They can affect platelet aggregation, vasodilation or constriction of blood vessels, and the adherence of monocytes to the vessel walls. The purpose of this study was to examine the effect of phytosterols on the release of PGE(2) and PGI(2) from lipopolysaccharide (LPS)-stimulated P388D(1)/MAB macrophage cells. P388D(1)/MAB cells were supplemented with 16 microM cholesterol, beta-sitosterol or campesterol using cyclodextrin as a vehicle. Phytosterol supplementation led to a significant decrease in cellular growth at various time points throughout a 7-day treatment period, especially after 3 days of treatment. Macrophages incorporated the supplemented phytosterols into their membranes which accounted for 26% of total membrane sterols. Cholesterol supplementation at 16 microM however, had no effect on membrane sterols. Supplementation with 16 microM concentration of beta-sitosterol or campesterol resulted in a significant inhibition of PGE(2) and PGI(2) release from macrophage cells as compared to the vehicle control. Of the two phytosterols, beta-sitosterol supplementation exhibited a greater inhibitory effect. PGE(2) release was decreased 68% by beta-sitosterol and 55% by campesterol, while cholesterol supplementation was not as effective, as it led to a 37% decrease. Similarly, release of PGI(2) from macrophages was inhibited 67% by beta-sitosterol and 52% by campesterol treatment, while enrichment of the cells with cholesterol, led to a 35% decrease in PGI(2) release. The decrease in prostaglandin release was not due to alteration in the expression of cPLA(2) and COX-2 enzymes which suggests that alterations in the activities of these enzymes may be responsible for the observed changes in prostaglandin release. It was concluded that phytosterol incorporation into macrophages may offer protection from atherosclerosis by reducing their prostaglandin release and thus slowing down the atheroma development.
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PMID:Phytosterols decrease prostaglandin release in cultured P388D1/MAB macrophages. 1512 Jul 14

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

Peripheral blood monocytes (PBMC) promote vascular inflammation and atherosclerosis. Chlamydia pneumoniae (Cp) infection of PBMC is found in atherosclerotic patients, appears refractory to antibiotics, and may predispose to vascular damage. In Cp-infected human PBMC we analyzed the role of cyclooxygenase-2 (Cox-2) for the proatherosclerotic key mediators prostaglandin E2 (PGE2) and interstitial collagenase (MMP-1). Cp infection resulted in rapid and sustained Cox-2 mRNA and protein stimulation depending on p38 and p44/42 MAPkinases. Subsequent upregulation of PGE synthase and MMP-1 was completely abrogated by the selective Cox-2 inhibitor NS398. Enhanced synthesis of PGE2 and MMP-1 in Cp infected PBMC is mediated through initiation of the p38 and p44/42 MAPK pathways and requires sustained Cox-2 activation. Selective Cox-2 inhibitors, currently under investigation for cardiovascular risk reduction, may represent a novel therapeutic option for patients with endovascular Cp infection as they target the actuated pathological signal transduction cascade in persistently infected PBMC.
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PMID:Cox-2 inhibition abrogates Chlamydia pneumoniae-induced PGE2 and MMP-1 expression. 1524 Jan 10


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