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)

Interleukin (IL)-1 beta-converting enzyme (ICE) cleaves the biologically inactive precursor form of IL-1 beta into mature, bioactive IL-1 beta. Because of the potent effects of IL-1 in blood vessels, we conducted an in situ hybridization study to determine whether ICE mRNA is constitutively expressed in adult rat brain vasculature. Using in situ hybridization histochemistry, we were able to demonstrate that mRNA in blood vessels scattered throughout the brain. In a second set experiments, we found that the genes encoding not only ICE, but also IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1ra), and the IL-1 type I receptor are expressed in brain vasculature. To our knowledge this is the first report documenting the expression of the genes encoding all of the functional elements of the IL-1 system in the same tissue. Our findings have three pathophysiological implications. First, they indicate a possible site where peripheral IL-1 may act in the brain. The vascular IL-1 system stimulates the production of nitric oxide and prostanoids, which could act as mediators of the effects of peripheral IL-1 in the central nervous system. Additionally, vascular IL-1 is known to activate adhesion molecules; our data that the genes encoding the IL-1 system are expressed in brain vasculature further support the concept that IL-1 is implicated in the pathophysiology of atherosclerosis and stroke. Finally, in the context of previous studies documenting that IL-1ra inhibits the effects of IL-1 on endothelial cells, our findings of endogenous IL-1ra mRNA in brain vasculature indicate that IL-1ra might be an endogenous vascular protective agent.
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PMID:Localization of interleukin-1 beta converting enzyme mRNA in rat brain vasculature: evidence that the genes encoding the interleukin-1 system are constitutively expressed in brain blood vessels. Pathophysiological implications. 864 63

The paper presents the molecular biology and biological activity of IL-1 alpha, IL-1 beta and IL-1 receptor antagonist. The role of IL-1 family in pathogenesis of a various disease including myeloid leukemias and other neoplastic diseases, diabetes mellitus, inflammatory diseases, sepsis syndrome and atherosclerosis is presented. Potential therapeutic value of IL-1 and IL-1 receptor antagonist is also discussed.
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PMID:[Biological properties and clinical importance of interleukin 1]. 865 31

The plasmin/plasminogen system of enzymes may be involved in leukocyte migration through the endothelial cell layer of the vascular wall during inflammatory processes associated with vascular injury, atherosclerosis, and sepsis. Synthesis of plasminogen activator inhibitor type 1 (PAI-1) by the endothelium may protect these cells and the subendothelial cell matrix from excessive degradation and retard leukocyte migration. We report in this work for the first time the down-regulation of both basal and thrombin- or endotoxin-induced PAI-1 in cultured human endothelial cells by the activated T cell product, IFN-gamma. Down-regulation of basal and thrombin- or endotoxin-induced endothelial PAI-1 protein by IFN-gamma was found to be both time and dose dependent. Decreases of up to 71% relative to thrombin- or endotoxin-treated controls, using an optimal IFN-gamma concentration of between 20 and 200 U/ml, were found for human macrovascular and microvascular endothelial cells. However, IFN-gamma did not appear to affect IL-1 alpha- and TNF-alpha-induced levels of PAI-1 protein or mRNA in these cells. Northern blot analysis paralleled protein results, showing decreases in specific endothelial cell thrombin- or LPS-induced PAI-1 mRNA expression, respectively, after incubation with IFN-gamma for 24 h. These results suggest a means by which the migration of circulating leukocytes through endothelial cell layers during inflammation may be facilitated.
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PMID:IFN-gamma inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. 880 64

Oxidatively modified low-density lipoprotein has been identified in early atherosclerotic lesions and may play an important role in atherogenesis. Minimally modified low-density lipoprotein (MM-LDL) derived by prolonged storage under sterile conditions results in mild oxidation and is recognised by the LDL receptor rather than the scavenger receptor. Therefore, it may be closer to the real pathophysiological circumstances in the initial state of atherosclerosis. Using a reverse transcription-polymerase chain reaction (RT-PCR) technique, the present study demonstrates that MM-LDL is capable of inducing gene expression of both interleukin-1 alpha (IL-1 alpha) and interleuking-1 beta (IL-1 beta) in human peripheral blood mononuclear cells in a dose-dependent manner. Concomitant treatment of the cells with the anti-oxidant probucol results in an inhibitory effect in steady-state levels of both IL-1 alpha and IL-1 beta mRNA and the effects were also shown in a dose-dependent fashion. We also found an inhibitory effect of MM-LDL on gene expression of platelet-derived growth factor B chain (PDGF-B) mRNA levels by mononuclear cells. Hence MM-LDL is biologically active and may contribute to the early stages of atherogenesis by stimulating the inflammatory cytokine IL-1 and the efficacy of probucol in inhibiting the progression of atherosclerosis may be due, both to its inhibition of IL-1 expression by intimal macrophages, and its prevention of LDL oxidation.
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PMID:RT-PCR study on the effects of minimally modified low-density lipoproteins and probucol treatment on gene expressions of interleukin-1 and platelet-derived growth factor B-chain in human peripheral blood mononuclear cells. 893 90

Serum amyloid A apolipoproteins (apoSAA) appear to compromise the ability of high density lipoprotein to protect against atherosclerosis and it is of interest to determine whether aortic smooth muscle cells can contribute to local pools of apoSAA in the presence of cytokines that are known to stimulate acute phase apoSAA (A-apoSAA) synthesis in the liver. In this study, the regulation of A-apoSAA synthesis was monitored in cultured neonatal rabbit aortic smooth muscle cells. Constitutive apoSAA3 gene expression was minimal, and only detectable by amplification of the mRNA by reverse transcriptase-polymerase chain reaction. ApoSAA3 gene expression and protein synthesis were stimulated by IL-1 alpha; as little as 0.01 ng/ml of IL-1 alpha stimulated an increase in steady state levels of apoSAA3 mRNA. Interestingly, IL-6 (which is required in addition to IL-1 alpha for the optimal synthesis of A-apoSAA by human hepatoma cells) had little if any effect on apoSAA3 synthesis by the smooth muscle cells. In a time course, it was shown that the stimulation of apoSAA3 mRNA levels was apparent by 1-2 h after the addition of cytokine, and that levels remained elevated in the presence of the cytokine for at least 48 h. Immunoprecipitation using an antiserum directed against apoSAA3 revealed that IL-1 alpha stimulated the synthesis and secretion of apoSAA3 protein in a manner that was consistent with apoSAA3 mRNA expression. The implications of these findings in atherogenesis are discussed.
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PMID:Regulation of extrahepatic apolipoprotein serum amyloid A (ApoSAA) gene expression by interleukin-1 alpha alone: synthesis and secretion of ApoSAA by cultured aortic smooth muscle cells. 931 18

Endothelial cells are known to be involved in different growth promoting processes like angioneogenesis, atherosclerosis or haematopoiesis. A great number of polypeptide growth factors crucial in this context have been isolated and they may be expressed in endothelial cells in either a constitutional or an inducible manner. The aim of the study was to examine the cytokine-inducibility of growth factor gene expression in endothelial cells. As uniform stimulators interleukin 1-alpha (IL-1alpha) and tumour necrosis factor (TNF)-alpha were chosen. Human umbilical arterial endothelial cells (HUAEC) were treated with either IL-1alpha or TNF-alpha and the gene expression of various growth factors was detected by reverse transcription-polymerase chain reaction (RT-PCR). We could demonstrate in HUAEC that stimulation with IL-1alpha- and TNF-alpha led to the mRNA expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) which are crucial in the process of angioneogenesis and atherosclerosis as well as of the granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) and stem cell factor (SCF) which are main growth factors in haematopoiesis. The demonstration of the inducibility of a wide range of various growth factor genes in endothelial cells is of major interest regarding the growth regulatory role of the endothelium.
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PMID:Cytokine-inducible growth factor gene expression in human umbilical endothelial cells. 1036 46

In this study, the effect of low density lipoproteins (LDL) on the ability of the vascular endothelium to respond to vascular cell adhesion molecule 1 (VCAM-1) activation by a cytokine was investigated. After a 4-day pre-exposure to 240 mg/dl of LDL, human umbilical vein endothelial cells (HUVECs) were hyperresponsive to minute amounts of interleukin 1 alpha (IL-1 alpha) as demonstrated by an augmentation of VCAM-1 gene expression. Furthermore, in response to LDL exposure, endothelial recruitment of monocytes induced by minute amounts of IL-1 alpha was increased. This enhancing effect was blocked by an anti-VCAM antibody. The increased response appears not to be due to changes in IL-1 binding affinity or induction of endogenous IL-1 alpha. Transient transfection of HUVECs with a reporter driven by the VCAM promoter showed that LDL increased cellular response to IL-1 alpha by 46%. LDL itself does not increase NF-kappa B binding in endothelial cells (ECs). However, after a 2-day LDL incubation, NF-kappa B binding could be induced by over 63% with a very low dose of IL-1 alpha. IL-1 alpha at this dose (which activates NF-kappa B, but not AP-1) also enhanced LDL-activated AP-1 binding. This cross-enhanced effect may be an important intracellular signaling mechanism for EC activation. The results from this study provide new clues to understanding the mechanisms governing combined risk factors for atherosclerosis.
Atherosclerosis 1999 Jun
PMID:Low-density lipoprotein augments interleukin-1-induced vascular adhesion molecule expression in human endothelial cells. 1040 96

Human vascular smooth muscle cells (VSMC) are a component of blood vessels, and secrete a variety of cytokines in atherosclerotic loci. Interleukin-11 (IL-11), a member of IL-6-like cytokines, is reported to be involved in inflammation and tissue remodeling, both of which are observed in atherosclerosis. However, no information is available as to the production of IL-11 by VSMC. Therefore, the expression of IL-11 in VSMC is investigated. The amounts of IL-11 protein and mRNA were determined by enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis, respectively. The expression of IL-11 in VSMC was also immunohistochemically determined. IL-1 alpha, transforming growth factor-beta (TGF beta) and, to a lesser extent, tumor necrosis factor-alpha (TNF alpha) stimulated the IL-11 production by VSMC, and the stimulatory effects of IL-1 alpha and TGF beta on IL-11 production were dose-dependent. IL-1 alpha and TNF alpha synergistically augmented TGF beta-stimulated IL-11 production by VSMC. Immunohistochemical staining also revealed the expression of IL-11 protein in VSMC. Furthermore, IL-1 alpha, TGF beta, and TNF alpha induced IL-11 gene expression in VSMC. Because IL-6-like cytokines are reported to be cytoprotective, monokine-stimulated IL-11 may have a potent protective role in atherosclerotic lesions.
Atherosclerosis 1999 Jun
PMID:Monokine stimulation of interleukin-11 production by human vascular smooth muscle cells in vitro. 1040 98

Elevated levels of antibodies to 60 kDa heat shock proteins are associated with severe coronary heart disease and carotid atherosclerosis. The presence of self hsp60-reacting antibodies can only be partially explained by microbial infections and induction by bacterial hsp65 proteins, since important differences (including the epitope specificity and complement activating ability) between hsp60 and hsp65 reacting antibodies have been shown. The aim of this study was to investigate the possible effects of genetic polymorphisms of different genes of proinflammatory cytokines on anti-hsp60 autoantibody levels. One hundred and seventy-six male blood donors were recruited and antibody levels to human hsp60 and Mycobacterium bovis hsp65 were determined by ELISA. Also in these donors, polymorphisms of the promoter of the IL-6 gene at position -174, the biallelic base exchange of the IL-1 beta gene at the -511 position and the IL-1 alpha gene at position -889 were investigated by PCR. A strong association between IL-6 -174 polymorphism and anti-hsp60 antibody levels was seen; the effect on anti-hsp65 antibody was less marked. Carriers of allele C at this position had significantly lower levels of anti-hsp60 and anti-hsp65 antibodies. A lack of associations between IL-1 beta and IL-1 alpha gene polymorphisms and antibody levels was detected. This is the first study in which associations between genetic polymorphisms and autoantibody levels have been described in healthy subjects. Further studies are needed to gain insight into the detailed mechanism of how the IL-6 gene polymorphism at position -174 influences anti-hsp60 autoantibody levels.
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PMID:The promoter polymorphism of the IL-6 gene is associated with levels of antibodies to 60-kDa heat-shock proteins. 1186 86


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