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:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Behavioral stress and aging are associated with an increase in vascular disease. This study determined the mechanisms contributing to changes in endothelium-dependent relaxation of isolated coronary arteries (300-350 micrometers) induced by exposure to 10 days of air-jet stress (2 h/day) in young (3 mo) and old (18 mo) male borderline hypertensive rats (BHR). Aging, alone, did not alter endothelium-dependent relaxation to acetylcholine (ACh) quantitatively but did alter the mechanisms contributing to relaxation to ACh, which was largely dependent on nitric oxide synthase (NOS) in vessels from old, but not young, BHR. Behavioral stress resulted in an enhanced relaxation to ACh that was dependent on NOS in vessels from young stressed compared with young control BHR. Conversely, relaxation to ACh was reduced in coronary arteries from old stressed compared with old control BHR. In vessels from old control BHR, there was an NOS-independent component of relaxation mediated by opening of K+ channels that was absent in vessels from old stressed BHR. The superoxide anion scavenger, tiron, partially restored relaxation, and inhibition of cyclooxygenase largely restored relaxation to ACh in vessels from old stressed BHR. In summary, the effect of behavioral stress was age dependent. ACh-induced relaxation of coronary arteries was enhanced in an NOS-dependent manner in young BHR and was impaired in old BHR due to superoxide anions, vasoconstrictor cyclooxygenase products, and a loss of K+ channel-mediated relaxation.
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PMID:Effect of behavioral stress on coronary artery relaxation altered with aging in BHR. 995 Sep 22

Dilator products of nitric oxide synthase (NOS) and cyclooxygenase (COX) may contribute to the low normal pulmonary artery pressure (Ppa). In isolated perfused lungs of ferrets, rabbits and rats we investigated this hypothesis by blockade of NOS with L-NAME (L-nitro-arginine methyl ester) and COX with meclofenamate. There were species differences. Inhibition of either enzyme caused little rise in Ppa in ferrets and rats but inhibition of both enzymes caused huge increases in Ppa. We suggest this might be due to intracellular connections between the excitatory pathways for NOS and COX dilators, such that inhibition of one enzyme leads to activation of the other. Impairment of these endothelial-based enzymes in pulmonary vascular disease might lead to severe pulmonary hypertension. By contrast, in rabbits, comparable doses of L-NAME lead to large rises in Ppa which were reversed rather than amplified by COX blockade. NO seems to protect against some pressor/oedema forming product of COX in this species.
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PMID:Role of nitric oxide synthase and cyclooxygenase in pulmonary vascular control in isolated perfused lungs of ferrets, rats and rabbits. 1050 58

For the long-term prevention of thromboembolic events in patients with atherosclerotic vascular disease, aspirin is the preferred antiplatelet drug. Only clopidogrel was shown to be more effective and at least as safe than medium-dose aspirin in direct comparative large-scale trials. Aspirin inhibits the cyclooxygenase dependent pathway of platelet aggregation while ticlopidine and clopidogrel selectively bind to adenosine diphosphate (ADP) receptors on the platelet surface. Compounds which inhibit the synthesis of thromboxane synthase, block the thromboxane receptor or have the dual activity were effective in experimental thrombosis models in animals but not predictive of results in humans. Activation of the platelet glycoprotein (GPIIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GPIIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic as well as non-peptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as two weeks whereas synthetic GPIIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion but have the advantage of being also orally active. In the secondary prevention of atherothrombosis, large scale trials were successfully conducted with aspirin, dipyridamole and clopidogrel. In the first large-scale trials with GPIIb/IIIa inhibitors with abciximab was investigated. In aggregate, this class of platelet inhibitors, combined with aspirin and heparin, was shown to reduce ischaemic events in patients with high- and low-risk coronary intervention, stents, unstable angina and non-Q-wave infarction with long-term preservation of the initial benefit. With synthetic GPIIb/IIIa inhibitors there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses presently used, bleeding occurs more often with the synthetic GPIIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours) but there are no direct comparisons between these drugs.
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PMID:8th Seah Cheng Siang Memorial Lecture: new antithrombotic agents. 1057 18

P2Y(2) receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y(2) receptor expression. Using a competitive reverse transcription-polymerase chain reaction, we detected that interleukin (IL)-1beta induced a time- and dose-dependent upregulation of P2Y(2) receptor mRNA, which was dramatically enhanced when combined with interferon-gamma or tumor necrosis factor-alpha. Lipopolysaccharide also significantly increased the expression of P2Y(2) receptor mRNA. The upregulation of P2Y(2) receptor mRNA was paralleled at the functional level because IL-1beta significantly increased the UTP-stimulated DNA synthesis and the release of intracellular Ca(2+). Actinomycin D completely blocked the upregulation of P2Y(2) receptor mRNA expression by IL-1beta, indicating de novo mRNA synthesis. There was no cAMP accumulation in the cells stimulated with IL-1beta. The cyclooxygenase inhibitor indomethacin and the protein kinase C inhibitor RO-31-8220 inhibited IL-1beta-induced upregulation of P2Y(2) receptor mRNA expression, whereas rapamycin and PD098059 had no effects. Furthermore, neither P38 mitogen-activated protein kinase inhibitor SB20358 alone nor its combination with PD098059 blocked the effect of IL-1beta on the expression of P2Y(2) receptor mRNA. Our results demonstrate that inflammatory mediators upregulate vascular P2Y(2) receptors at the transcriptional and at the functional level through protein kinase C and cyclooxygenase but not cAMP, extracellular signal-regulated kinases 1 and 2, or P38-dependent pathways. This may result in increased growth-stimulatory or contractile effects of extracellular UTP and ATP, which may be of importance in the development of vascular disease.
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PMID:Cytokines induce upregulation of vascular P2Y(2) receptors and increased mitogenic responses to UTP and ATP. 1097 50

Hyperhomocysteinemia is a major and independent risk factor for vascular disease. Oxidative stress is a possible mechanism for homocysteine (Hcy)-induced endothelial dysfunction. Herein, we evaluated the antioxidant property of melatonin as related to the vasospastic effect of Hcy on the human umbilical artery. Helical strips of human umbilical arteries with intact endothelium were obtained at elective Caesarean delivery between 37 and 39 wks of gestation. Changes in 5-hydroxytryptamine (5-HT)-induced vasoconstriction were measured. Arterial strips were treated with FeSO4 (10 microM) and Hcy (10 or 100 microM) or pre-treated with a hydroxyl radical (.OH) scavenger (mannitol, 20 mM), a cyclooxygenase inhibitor (indomethacin, 20 microM), nitric oxide (NO) synthesis inhibitor (L-NG-monomethylarginine, LNMA, 200 microM), or melatonin (1 or 10 microM). Hcy potentiated 5-HT-induced constriction in a concentration-dependent manner. Pre-treatment with mannitol significantly suppressed the vasospastic effect of Hcy. LNMA augmented the vasospastic effect of Hcy, but indomethacin did not. Melatonin significantly suppressed the vasospastic effect of Hcy in a concentration-dependent manner. These findings suggest that Hcy potentiates 5-HT-induced vasoconstriction in the human umbilical artery, possibly by suppressing bioavailable NO. Melatonin protects against the vasospastic effect of Hcy, most likely by scavenging.OH arising from Hcy autooxidation.
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PMID:Melatonin suppresses homocysteine enhancement of serotonin-induced vasoconstriction in the human umbilical artery. 1158 59

Prostaglandin formation is enhanced in vascular disease, in part through induction of cyclooxygenase (COX-2) in vascular smooth muscle cells. Because COX regulates cell growth and migration, we examined whether the COX expression plays a role in the development of intimal hyperplasia after vascular injury. Rats undergoing balloon angioplasty of the carotid artery were randomized to receive a selective COX-2 inhibitor (SC-236), a selective COX-1 inhibitor (SC-560) or a combination of the two. Normal, uninjured vessels showed COX-1, but no COX-2 expression. Fourteen days after balloon injury, both COX-1 and COX-2 were expressed in the neointima. Balloon angioplasty resulted in a marked increase in the urinary excretion of prostaglandin (PG) E(2,) PGF(2alpha), and thromboxane (TX) B(2). Both the COX-1 inhibitor SC-560 and the COX-2 inhibitor SC-236 suppressed the generation of PGE(2) and PGF(2alpha), particularly when combined, suggesting a role for both isozymes in the generation of prostaglandins in this model. In contrast, TXA(2) was markedly suppressed by the COX-1 inhibitor SC-560. COX-2 inhibition with SC-236 had no effect on intimal hyperplasia at day 14 (0 versus 8.5%; n = 7 in controls). In contrast, intimal hyperplasia was reduced by SC-560 when administered alone (by 42%; n = 7, p < 0.05) or in combination with SC-236 (by 40%; n = 7, p < 0.05). COX-1 may play a role in the development of intimal hyperplasia, potentially through the inhibition of platelet TXA(2). Despite being expressed in the neointima, COX-2 does not play a role in the development of intimal hyperplasia after vascular injury.
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PMID:Cyclooxygenase isozyme expression and intimal hyperplasia in a rat model of balloon angioplasty. 1180 96

Vascular smooth muscle cell (SMC) migration and proliferation contribute to neointimal hyperplasia and restenosis after vascular injury. The epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess vasodilatory, antiinflammatory, and fibrinolytic properties. To determine whether these compounds also possess antimigratory and antiproliferative properties, we stimulated rat aortic SMCs with either 20% serum or platelet-derived growth factor (PDGF-BB, 20 ng/mL). In a concentration-dependent manner, treatment with EETs, particularly 11,12-EET, inhibited SMC migration through a modified transwell filter by 53% to 60%. EETs, however, have no inhibitory effects on PDGF-stimulated SMC proliferation. Adenoviral-mediated overexpression of the CYP isoform, CYP2J2, in SMCs also inhibited serum- and PDGF-induced SMC migration by 32% and 26%, respectively; both effects of which were reversed by the CYP inhibitors SKF525A or clotrimazole, but not by the K(Ca) channel blocker, charybdotoxin, or the cyclooxygenase inhibitor, diclofenac. The effect of EETs correlated with increases in intracellular cAMP levels. Indeed, forskolin and 8-bromo-cAMP exert similar inhibitory effects on SMC migration as 11,12-EET and the effects of 11,12-EET were blocked by cAMP and protein kinase A (PKA) inhibitors. These findings indicate that EETs possess antimigratory effects on SMCs through the cAMP-PKA pathway and suggest that CYP epoxygenase-derived eicosanoids may play important roles in vascular disease and remodeling.
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PMID:Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. 1201 58

Activation of the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), is a newly defined target for limiting vascular pathologies. PPARgamma is expressed in human and animal models of vascular disease, with particularly high levels being present in the cells of the neointimal microenvironment. In the present study, we show that intimal smooth muscle cells in vitro contain higher amounts of functional PPARgamma than medial smooth muscle cells. The PPARgamma ligand rosiglitazone more potently induced CD36 expression at low concentrations, and cell death by apoptosis at higher concentrations in intimal compared with medial smooth muscle cells. Intimal smooth muscle cells also contained high levels of cyclooxygenase-2 protein, and released a more diverse and larger amount of eicosanoids on arachidonic acid stimulation. Furthermore, when exogenous arachidonic acid was added, PPAR reporter gene activation was induced in a cyclooxygenase inhibitor-sensitive manner, an effect that correlated with an increase in CD36 expression. In summary, intimal smooth muscle cells contain functionally higher levels of PPARgamma, PPARgamma ligands have high- and low-potency targets in vascular smooth muscle cells, and cyclooxygenase can serve as a source of potential endogenous PPAR ligands. Intimal vascular smooth muscle cells therefore represent a potentially important target for the antiproliferative, and antiatherosclerotic actions of PPARgamma ligands.
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PMID:Intimal smooth muscle cells as a target for peroxisome proliferator-activated receptor-gamma ligand therapy. 1216 46

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. However, their long-term use is limited by gastrointestinal (GI) side effects such as gastric ulcers. NSAIDs act by inhibiting an enzyme called cyclooxygenase. Cyclooxygenase (COX) catalyses the generation of prostaglandins from arachidonic acid. Two isoforms of the enzyme exist--COX-1 and COX-2--both of which are targets for NSAIDs. Although they are associated with GI toxicity, NSAIDs have important antithrombotic and anti-inflammatory effects. The GI injury has been attributed to COX-1 inhibition and the anti-inflammatory effects to COX-2 inhibition. As COX-2 is traditionally viewed as an inducible enzyme, selective inhibition of COX-2 by 'coxibs' (selective COX-2 inhibitors) has been employed to achieve anti-inflammatory and analgesic effects without GI side effects. However, recently there have been suggestions that chronic administration of coxibs might increase the risk of cardiovascular events, such as atherosclerosis, compared with traditional NSAIDs. In vascular disease, there is increased expression of both COX-1 and COX-2, resulting in enhanced prostaglandin generation. The specific role of COX-1 and COX-2 in vascular regulation is still unknown but such knowledge is essential for the effective use of coxibs. Although more evidence is pointing to selective COX-1 inhibition as a therapeutic measure in inflammatory atherosclerosis, there are some studies that suggest that inhibition of COX-2 might have a potential benefit on atherosclerosis.
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PMID:Cyclooxygenase isoforms and atherosclerosis. 1498 12

The cyclooxygenase (COX)-2 enzyme has been implicated in the pathogenesis of several inflammatory diseases. However, its role in diabetic vascular disease is unclear. In this study, we evaluated the hypothesis that diabetic conditions can induce COX-2 in monocytes. High glucose treatment of THP-1 monocytic cells led to a significant three- to fivefold induction of COX-2 mRNA and protein expression but not COX-1 mRNA. High glucose-induced COX-2 mRNA was blocked by inhibitors of nuclear factor-kappaB (NF-kappaB), protein kinase C, and p38 mitogen-activated protein kinase. In addition, an antioxidant and inhibitors of mitochondrial superoxide, NADPH oxidase, and glucose metabolism to glucosamine also blocked high glucose-induced COX-2 expression to varying degrees. High glucose significantly increased transcription from a human COX-2 promoter-luciferase construct (twofold, P < 0.001). Promoter deletion analyses and inhibition of transcription by NF-kappaB superrepressor and cAMP-responsive element binding (CREB) mutants confirmed the involvement of NF-kappaB and CREB transcription factors in high glucose-induced COX-2 regulation. In addition, isolated peripheral blood monocytes from type 1 and type 2 diabetic patients had high levels of COX-2 mRNA, whereas those from normal volunteers showed no expression. These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications.
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PMID:Molecular mechanisms of high glucose-induced cyclooxygenase-2 expression in monocytes. 1498 66


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