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)

High levels of fibrinogen are recognized as an important vascular risk factor; however, it is not known if the increase of plasma fibrinogen is directly responsible for this risk, or is only a marker of vascular inflammation. To support this second hypothesis, Oncostatin M (OSM) is a potent stimulator of fibrinogen biosynthesis and induces smooth muscle cell proliferation. In the same way, we analysed whether interleukin-4 (IL-4), interleukin-10 (IL-10) or interleukin-13 (IL-13), which protect vessel walls from monocytes injuries leading to atherosclerosis, could influence fibrinogen biosynthesis. The two levels of regulation of fibrinogen biosynthesis were tested: firstly, the direct effect of these cytokines on fibrinogen production by the hepatoma cell line Hep G2, and secondly their effect on the secretion of hepatocyte stimulating factor (HSF) activity in the supernatant of lipopolysaccharide (LPS)-activated monocytes. IL-4 and IL-13 added to Hep G2 cells down-regulated both the increase of fibrinogen secretion induced by IL-6 and fibrinogen mRNA levels, this effect being more pronounced when Hep G2 were preincubated with the two cytokines before IL-6 addition. The effect of IL-10 was evidenced only on mRNA expression. IL-10 and IL-13 dose-dependently decrease HSF activity secreted by LPS-activated monocytes, whereas IL-4 had no effect. However, the three cytokines decreased HSF activity when monocytes were incubated with the cytokines before LPS activation. The effects of these cytokines on HSF activity are related to variations of IL-6 and OSM secretion. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since cytokines which have a protective vascular effect down-regulate fibrinogen production.
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PMID:Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13. 870 33

Dietary omega-3 fatty acids retard coronary atherosclerosis. Previously, we demonstrated that dietary omega-3 fatty acids reduce platelet-derived growth factor (PDGF)-A and PDGF-B mRNA levels in unstimulated, human mononuclear cells (MNCs). In a randomized, investigator-blinded intervention trial, we have now compared the effect of ingestion of 7 g/d omega-3, omega-6, or omega-9 fatty acids for 4 weeks versus no dietary intervention on PDGF-A, PDGF-B, heparin-bound epidermal growth factor (HB-EGF), monocyte chemoattractant protein-1 (MCP-1), and interleukin-10 gene expression in unstimulated MNCs and in monocytes that were adherence-activated ex vivo in a total of 28 volunteers. In unstimulated MNCs, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were reduced by 25+/-10%, 31+/-13%, and 40+/-14%, respectively, after omega-3 fatty acid ingestion, as assessed by quantitative polymerase chain reaction (all P<0.05). In monocytes that were adherence-activated ex vivo for 4 and 20 hours, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were reduced by 25+/-13%, 20+/-15%, and 30+/-8%, respectively (all P<0.05). Interleukin-10 and HB-EGF mRNA steady-state levels were not influenced by omega-3 fatty acid ingestion. Expression of all respective mRNAs in control volunteers or in those ingesting omega-6 or omega-9 fatty acids were not altered. We conclude that human gene expression for PDGF-A, PDGF-B, and MCP-1, factors thought relevant to atherosclerosis, is constitutive, is constant, and can be reduced only by dietary omega-3 fatty acids in unstimulated and adherence-activated monocytes.
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PMID:Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes. A randomized volunteer study. 988 67

Inflammation is one of the most important mechanisms that contribute to coronary artery disease (CAD). One of the micro-organisms that is mentioned as a source of the inflammation is Chlamydia pneumoniae. In this study, we investigated the relationship between titres of IgG and IgA antibodies to C. pneumoniae and the clinical course, during hospitalisation and during an 18-month follow-up, in 211 patients admitted to hospital with unstable angina pectoris. Slightly more patients who were refractory during their hospitalisation were positive for C. pneumoniae antibodies than patients who could be stabilised by drug treatment (53 vs. 43%, for IgG and 16 vs. 11% for IgA, respectively)(n.s.). In logistic regression analysis no significant predictive values were observed for the relationship between antibody titres and clinical course. The antibody titres to C. pneumoniae were lower in the unstable angina patients who had plasma levels of interleukin-10 (IL-10) above 5 pg/ml than in the patients with levels below 5 pg/ml, and higher in smokers than in non-smokers. No associations were observed between antibody titres to C. pneumoniae and C-reactive protein (CRP), interleukin-6 (IL-6), age, total cholesterol levels, fibrin degradation products (FDP), plasminogen activator inhibitor-1 (PAI-1) and erythrocyte sedimentation rate (ESR). In conclusion, there was no significant association between antibody titres to C. pneumoniae and risk of events during hospitalisation and the 18-month follow-up period in patients admitted for unstable angina pectoris.
Atherosclerosis 2000 Dec
PMID:Antibodies to Chlamydia pneumoniae and clinical course in patients with unstable angina pectoris. 1116 40

The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IkappaB/nuclear factor-kappaB system. Much recent work shows that vascular inflammation can be limited by anti-inflammatory counteregulatory mechanisms that maintain the integrity and homeostasis of the vascular wall. The anti-inflammatory mechanisms in the vascular wall involve anti-inflammatory external signals and intracellular mediators. The anti-inflammatory external signals include the anti-inflammatory cytokines, transforming growth factor-beta, interleukin-10 and interleukin-1 receptor antagonist, HDL, as well as some angiogenic and growth factors. Physiological laminar shear stress is of particular importance in protecting endothelial cells against inflammatory activation. Its effects are partly mediated through NO production. Finally, endogenous cytoprotective genes or nuclear receptors, such as the peroxisome proliferator-activated receptors, can be expressed by vascular cells in response to proinflammatory stimuli to limit the inflammatory process and the injury.
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PMID:Anti-inflammatory mechanisms in the vascular wall. 1134 96

Excessive intake of saturated fatty acids and/or linoleic acid favors the induction of an array of lipid mediators and cytokines enhancing inflammatory responses. Conversely, dietary supplementation with (n-3) fatty acids or vitamin D ameliorates inflammation and autoimmune diseases. Although it was well accepted that conjugated linoleic acid (CLA) prevented diseases with a common inflammatory pathogenesis (i.e., cancer and atherosclerosis), no studies were available on the roles of CLA in mucosal inflammation. The present study was designed to investigate the anti-inflammatory actions and molecular mechanisms underlying the regulation of colonic health by CLA. We hypothesized that colonic inflammation can be ameliorated by dietary CLA supplementation. To test this hypothesis, inflammation of the colonic mucosa was triggered by challenging pigs fed either soybean oil-supplemented or CLA-supplemented diets with an enteric bacterial pathogen (i.e., Brachyspira hyodysenteriae). Immunoregulatory cytokines and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression were assayed in colonic lymph nodes and colon of pigs. Colonic mucosal lesions and lymphocyte subset distribution were evaluated by histology and immunohistochemistry. Supplementation of CLA in the diet before the induction of colitis decreased mucosal damage; maintained cytokine profiles (i.e., interferon-gamma and interleukin-10) and lymphocyte subset distributions (i.e., CD4+ and CD8+), resembling those of noninfected pigs; enhanced colonic expression of PPAR-gamma; and attenuated growth failure. Therefore, CLA fed preventively before the onset of enteric disease attenuated inflammatory lesion development and growth failure.
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PMID:Nutritional regulation of porcine bacterial-induced colitis by conjugated linoleic acid. 1209 86

Transfected muscle can be used as a secreting tissue for therapeutic proteins. Skeletal muscle transfection is increased by suitable electric pulse application (electrotransfer). We and others had shown that electrotransfer of interleukin-10 encoding plasmid is an effective strategy in animal models of chronic diseases such as myocarditis, atherosclerosis, or rheumatoid arthritis. In the present work, we have studied murine interleukin-10 production and secretion after i.m. electrotransfer. In immunocompetent mice, serum and muscle mIL-10 levels were enhanced by electrotransfer. Serum mIL-10 concentration reached rapidly a peak level 2 days after electrotransfer. It then decreased to background at day 14. Muscle mIL-10 mRNA and protein remained more stable, being detectable up to 84 days after electrotransfer. A boost reinjection led to similar high level of circulating mIL-10. The fast decrease of serum mIL-10 was not observed in SCID mice.
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PMID:Interleukin-10 expression after intramuscular DNA electrotransfer: kinetic studies. 1243 85

Gene therapy could improve human saphenous vein (HSV) coronary vein-graft patency by reducing early thrombosis, neointimal hyperplasia and atherosclerosis. Mouse and rabbit models use veins with much thinner walls than pig or HSVs but atherosclerosis can be more easily induced; none of these models shows early thrombosis. Prostacyclin synthase, tissue factor pathway inhibitor, and tissue plasminogen activator might decrease thrombus formation. Tissue inhibitors of metalloproteinases (TIMPs) reduce intimal migration of smooth muscle cells, while TIMP-3 and the p53 tumor suppressor protein promote apoptosis. Prostacyclin synthase and nitric oxide synthase, and cell cycle inhibitors, such as E2F decoy oligonucleotides (D-E2F), reduce neointima formation. This might be enough by itself to decrease later atherosclerosis. Alternatively, direct targeting with nitric oxide synthase, decoy adhesion molecules, or interleukin-10 might be possible.
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PMID:Gene therapy for all aspects of vein-graft disease. 1264 67

Unstable atherosclerotic disease is related to systemic inflammation. While this inflammation remains at a subclinical level in otherwise healthy individuals, chronic elevation of pro-inflammatory cytokines is a common feature in patients with end-stage renal disease (ESRD). Current hypotheses on the pathogenetic links between inflammation and atherosclerosis emphasize that cytokine-producing monocytes/macrophages can actively infiltrate atherosclerotic plaques. A high activation level of this cell type may contribute to plaque growth. In the healthy, some 15% to 20% of circulating monocytes may be activated for cytokine production. This percentage is much higher in dialysis patients (50%), which may contribute to the rapid progression of atherosclerosis. Anti-inflammatory mechanisms such as interleukin-10 (IL-10) limit the production of a broad range of pro-inflammatory factors. Animal models, as well as clinical findings, suggest an involvement of this cytokine in the pathogenesis of vascular lesions. In hemodialysis (HD) patients, a protective role of IL-10 against systemic inflammation could be proven. A high interindividual variability in IL-10 production leads to distinct patient groups who can or cannot effectively limit the uremia- and dialysis-induced inflammation. Single nucleotide polymorphisms (SNPs) in the promotor of the IL-10 gene may genetically explain this heterogeneity. The IL-10 genotype strongly influences the range of variation of C-reactive protein (CRP), the most widely used marker of inflammation in dialysis patients. By limiting the inflammatory activation in ESRD patients, the IL-10 genotype is predictive for the risk of cardiovascular disease, meaning that the IL-10 "high-producer" genotype is associated with a lower event rate, and even mortality, than the IL-10 "low-producer" genotype.
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PMID:Uremia-associated immune defect: the IL-10-CRP axis. 1269 15

The immunologic response in atherosclerosis involves not only intrinsic cells of the artery wall, but also circulating leukocytes, lymphocytes, and macrophages. Interaction of various arms of the immune response modulates plaque development and stability, and it is conceivable that immunologic effects of some cardiovascular therapies may contribute to their mechanism of benefit. The preponderance of data has accrued with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Statin effects, such as inhibition of T cell activation, tissue factor expression, or reduction of platelet hyperreactivity, may elicit beneficial effects in vitro and in vivo in patients with coronary artery disease. Moreover, aspirin may limit oxidation of lipoproteins and fibrinogen, and it may inhibit cytokine-induced nitric oxide synthase II expression. The hypothesis that selective inhibition of cyclooxygenase-2 (COX-2) may increase risk of myocardial infarction is controversial and may also be of questionable clinical significance. Finally, angiotensin-converting enzyme (ACE) inhibitors not only reduce proinflammatory mediators, such as interleukin-6, but also enhance the concentration of anti-inflammatory cytokines, such as interleukin-10. Because ACE is expressed at the shoulder region of atherosclerotic plaques, and ACE activity is enhanced in unstable plaques, ACE inhibition may also contribute to plaque stability. This article reviews the potential immunomodulatory potencies of aspirin, COX-2 inhibitors, statins, and ACE inhibitors as established pharmacotherapy in patients with coronary artery disease.
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PMID:Role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, angiotensin-converting enzyme inhibitors, cyclooxygenase-2 inhibitors, and aspirin in anti-inflammatory and immunomodulatory treatment of cardiovascular diseases. 1281 30

The designation of atherosclerosis as a chronic inflammatory process represents an interesting paradigmatic shift for cardiologists. The plasma concentrations of interleukin-6 and its hepatic byproduct, C-reactive protein, may reflect the intensity of occult plaque inflammation and the vulnerability to rupture. Monocyte chemoattractant protein-1 and interleukin-8 play a crucial role in initiating atherosclerosis by recruiting monocytes/macrophages to the vessel wall, which promotes atherosclerotic lesions and plaque vulnerability. In addition, circulating levels of these proinflammatory cytokines increase in patients with acute myocardial infarction and unstable angina, but not in those with stable angina. Also, the plasma concentrations of these cytokines increase after percutaneous coronary intervention, causing late restenosis after the procedure. Angiotensin II and other atherogenic factors induce these cytokines in the cardiovascular tissues through the activation of transcription factors, such as nuclear factor-kappaB or peroxisome proliferator-activated receptors. Conversely, HMG-CoA reductase inhibitors (statins) can potently inhibit these proinflammatory factors in the vessels. A small GTP-binding protein, Rho, may be a key molecule to explain the anti-inflammatory effects of statins. Interleukin-10 also exerts anti-inflammatory effects on the cardiovascular tissues, possibly by deactivating proinflammatory cytokines and inducible nitric oxide synthase. Gene therapy using interleukin-10 may be a promising means for untreatable or complicated cases of cardiovascular diseases. Thus, therapeutic modulations of these inflammatory cytokines may be useful in the prevention of atherosclerosis and future cardiovascular events.
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PMID:Inflammatory cytokines and cardiovascular disease. 1456 Nov 60


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