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)

Monocyte adhesion to the arterial wall is a key event in the atherosclerotic process. We studied the interactions between human coronary arterial intimal smooth muscle cells (SMCs) and monocytes by examining (i) whether SMCs mediate monocyte adhesion when stimulated by oxidatively modified low density lipoprotein (LDL) or by the cytokines TNF alpha and IL-1, and (ii) the role of the adhesion molecules VCAM-1 and ICAM-1 (vascular cell and intercellular adhesion molecule, respectively) in this process. Preincubation of SMCs with both TNF alpha and IL-1 caused a significant 2-fold increase in VCAM-1 and ICAM-1 expression and a more than 9-fold increase in monocyte adhesion. The latter was significantly inhibited (by 1/3) by neutralising antibodies to VCAM-1 and ICAM-1. Modified LDL also induced a significant 3-fold increase in monocyte adhesion to SMCs, but did not induce VCAM-1 or ICAM-1 expression, nor was this adhesion inhibited by neutralising antibodies to VCAM-1 or ICAM-1. Oxidatively modified LDL, like the proinflammatory cytokines TNF alpha and IL-1, has the ability to enhance monocyte adhesion to human SMCs in vitro. LDL-induced monocyte adhesion to SMCs is distinct from that induced by TNF alpha and IL-1 in its lack of dependence on the classical adhesion pathways involving smooth muscle VCAM-1 and ICAM-1. SMCs are identified as a new cell population which may play an active role in recruiting monocytes to the arterial intima and atherosclerotic plaque.
Atherosclerosis 1996 Dec 20
PMID:Modified low density lipoprotein and cytokines mediate monocyte adhesion to smooth muscle cells. 912 6

Inflammation contributes to a variety of arterial diseases including atherosclerosis. Interleukin 1beta (IL-1beta) in its activated mature 17-kDa form may mediate aspects of vascular inflammation. As shown previously, human vascular wall cells, such as smooth muscle cells (SMC), express the IL-1beta precursor upon stimulation and the IL-1beta-converting enzyme (ICE) constitutively but do not produce mature IL-1beta or express ICE activity. How SMC, the most numerous cell type in arteries, may release active IL-1beta has therefore remained a perplexing problem. We report here that stimulation of human vascular SMC and endothelial cells (EC) through CD40 ligand, a mediator recently localized in human atheroma, induced elaboration of the IL-1beta precursor as well as activation of cell-associated ICE. In addition to the constitutively expressed 45- and 30-kDa immunoreactive ICE proteins, vascular cells incubated with recombinant human CD40 ligand (rCD40L) (but not IL-1 or TNF) showed an increase of a 20-kDa immunoreactive ICE protein by Western blot analysis. Furthermore, SMC and EC stimulated through rCD40L processed recombinant human IL-1beta precursor (pIL-1beta), generating a cleavage product of approximately 17 kDa. Appearance of both the 20-kDa immunoreactive ICE protein and pIL-1beta processing activity required at least 6 h of stimulation with 0.3 or 1.0 microg/ml rCD40L, respectively, and was inhibited by pre-incubation of the ligand with an anti-CD40L antibody. Stimulation of vascular SMC and EC through rCD40L resulted in the release of biologically active IL-1beta, indicating processing of the native IL-1beta precursor induced by the ligand. These findings establish a novel mechanism of IL-1beta activation in human vascular cells and, moreover, indicate a new pathway of ICE-activation, which could participate in inflammatory aspects of atherogenesis and other disease states.
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PMID:Ligation of CD40 activates interleukin 1beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1beta. 923 62

T-cells and monocytes are the first cells infiltrating the arterial intima during the early stages of atherogenesis. Recently our laboratory has provided evidence that T-cells isolated from atherosclerotic intima reacts against heat shock protein 60 (Hsp60). Transmigration of activated T-cells into the intima is mediated by adhesion molecules (ICAM-1; VCAM-1; ELAM-1) expressed on activated endothelial cells. Here we studied the potential of cytokines (TNF-alpha, IFN-gamma, IL-1). Escherichia coli lipopolysaccharide (LPS), native and oxidized low-density lipoprotein (LDL; oxLDL) and high temperature to induce adhesion molecules as well as Hsp60 and Hsp70 expression in human endothelial cells (EC). On Northern blots, a strong signal for ICAM-1, VCAM-1 and ELAM-1 was detected after 4 h, which thereafter declined, but did not reach the basal level of untreated control cells. Heat shock induced the expression of Hsp60 and Hsp70 but not of adhesion molecules. EC were cultivated in serum-free medium, which led to the expression of adhesion molecule transcripts. Addition of LDL or oxLDL to these ECs did not alter the expression of these transcripts. The production of adhesion molecule proteins was analysed by flow cytometry. In human venous endothelial cells (HVEC) and human arterial endothelial cells (HAEC) ICAM-1 and VCAM-1 production was permanently highly induced, whereas the high level of ELAM-1 production at 4 h disappeared after 24 h. Furthermore, only HAEC, but not HVEC, produced ICAM-1, VCAM-1 and ELAM-1 after stress by moderately and highly oxLDL. LDL and oxLDL did not induce the production of Hsp60 and Hsp70. The present study demonstrates the co-expression of Hsp60 and adhesion molecules in arterial and venous EC in response to cytokine and LPS exposure, and that oxLDL is an efficient inducer of adhesion molecules in arterial EC and not in venous EC. These features provide the prerequisites for a cellular immune reaction against Hsp60 expressed by stressed EC in the initial stages of atherosclerosis.
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PMID:Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytokines and oxidized low-density lipoproteins. 925 Apr

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
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PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

The regulation of macrophage lipoprotein lipase (LPL) by cytokines is of potentially crucial importance in the pathogenesis of atherosclerosis. The effect of combinations of interleukin 1 (IL-1), 6 (IL-6), and 11 (IL-11), interferon gamma (INF-gamma), leukaemia inhibitory factor (LIF) and tumour necrosis factor alpha (TNF-alpha) on the expression of LPL in macrophages was studied using the murine J774.2 cell line. The suppression of heparin-releasable LPL activity produced by combinations of IL-1 and IL-11, IL-1 and TNF-alpha, IL-11 and TNF-alpha, and, IL-11 and INF-gamma was substantially lower than that expected from the additive action of the corresponding two cytokines. By contrast, co-exposure of cells to LIF and IFN-gamma, IL-6 and LIF, and INF-gamma and TNF-alpha resulted in a more than additive, synergistic, suppression of LPL activity with the maximum reduction and maximum degree of synergism produced by combinations of IFN-gamma and TNF-alpha. The synergism between IFN-gamma and TNF-alpha was observed over a range of complementary dose combinations and also occurred when the cells were exposed first to INF-gamma (priming), washed, and then stimulated subsequently with TNF-alpha. The reduction in LPL activity by combinations of IFN-gamma and TNF-alpha and the priming action of IFN-gamma were accompanied by a comparable decrease in LPL mRNA concentrations, thereby indicating that the major control responsible for the changes in LPL activity was being exerted at the level of mRNA metabolism (decreased transcription or RNA stability). These results suggest that the modulation of macrophage LPL function in atherosclerosis by cytokine combinations may be more important than the presence or absence of any given cytokine.
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PMID:Synergism between interferon gamma and tumour necrosis factor alpha in the regulation of lipoprotein lipase in the macrophage J774.2 cell line. 950 44

By extrapolation from the responses of cultured human umbilical vein endothelial cells (EC) and bovine aortic EC to short-term cytokine stimulation, EC activation is postulated as a likely component of the host response in acute allograft rejection and cardiac transplant-associated accelerated arteriosclerosis. To investigate the extent to which EC activation occurs in vivo in humans and to identify potential targets for therapeutic interventions, we compared the phenotypic characteristics of vascular EC as seen during clinicopathologically significant vs non-significant acute cardiac allograft rejection. We used monoclonal and monospecific polyclonal antibodies to coagulation molecules [tissue factor, thrombomodulin (TM), antithrombin III (AT-III), fibrinogen/fibrin, cross-linked fibrin and von Willebrand factor (vWF)], adhesion molecules (P-selectin, ICAM-1) and major histocompatibility complex (MHC) class I and II molecules. In addition we sought evidence of local cytokine production (IL-1, IL-2R, IL-4, IL-6, IL-7, IL-8, TNF-alpha, PDGF-AA, PDGF-BB), which might mediate alterations in expression of these proteins. We found that in clinically significant grades of cardiac allograft rejection requiring increased immunosuppression, in contrast to lesser grades of rejection not requiring clinical intervention, there was increased microvascular EC activation and differential expression of cytokines. EC changes associated with more extensive cardiac allograft rejection requiring treatment included: (i) disruption of the normal anticoagulant state with downregulation of TM and AT-III, upregulation of tissue factor and vWF expression, and associated extensive fibrin deposition; (ii) upregulation of MHC class I antigens, which are potential targets for host cytotoxic T lymphocytes; (iii) increased expression of the leucocyte adhesion molecules P-selectin and ICAM-1; (iv) expression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha; and (v) increased expression of PDGF-AA and BB, which are known to promote migration and proliferation of intimal cells, and hence may contribute to development of transplant-associated atherosclerosis. Collectively these findings suggest that immune events resulting in EC surface changes and/or production of key cytokines play a role in the pathogenesis of acute transplant rejection and may contribute to the long-term complication of accelerated arteriosclerosis in allograft coronary arteries.
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PMID:Endothelial activation and cytokine expression in human acute cardiac allograft rejection. 953 4

Atherosclerosis is an inflammatory-fibroproliferative process that may represent a possible milieu in which transforming growth factor-beta (TGF-beta) can be involved. Vascular smooth muscle cells (VSMC) may represent a source or a target of a large number of growth factors and proinflammatory cytokines, including interleukin-1 and its receptor antagonist (IL-1Ra). We tested the effect of TGF-beta1, on IL-1Ra production and gene expression in rat VSMC cultures. We found a significant dose (3-30 ng/ml) and time-dependent (0-48 h) increase in IL-1Ra immunoactivity in the supernatant of conditioned medium and cell lysates. The maximal effect was observed with TGF-beta at 30 ng/ml and after 24 h incubation time, respect to untreated cells (320 +/- 26 vs. 211 +/- 20 pg/ml; P < 0.01). Furthermore, TGF-beta1 induced an increased mRNA expression which began at 2 h and peaked at 18 h incubation time (about a 6-fold increase with respect to unstimulated cells). The effect of TGF-beta1 on IL-1Ra production was completely inhibited by an anti-IL-1beta antibody (10 microg/ml) (from 320 +/- 81 to 181 +/- 46 pg/ml). These experiments suggest that TGF-beta1, potentially produced in the vascular wall during atherogenesis, may play a pathophysiological role in the autocrine control of IL-1 actions, via VSMC IL-1Ra production.
Atherosclerosis 1998 Feb
PMID:Transforming growth factor beta1 induces IL-1 receptor antagonist production and gene expression in rat vascular smooth muscle cells. 954 9

Why LDL entrapped in the subendothelium should trigger events leading to chronic inflammation and to arterial wall injury is a major enigma of modern medicine. Oxidation of LDL in vitro renders the molecule potentially atherogenic, and the concept that oxidation is the major single event underlying the transformation of LDL to a proinflammatory molecule dominates the world literature. Here, an alternative hypothesis on the pathogenesis of atherosclerosis will be presented. We have found that non-oxidative, enzymatic modification of LDL with ubiquitous enzymes (protease + cholesterol esterase + neuraminidase) also transforms the molecule to an atherogenic moiety. Enzymatically altered LDL (E-LDL) shares major properties in common with lipoproteins that have been isolated from atherosclerotic lesions. It activates complement via the alternative pathway and is recognized by a scavenger receptor on human macrophages, thus inducing foam cell formation. Uptake of E-LDL is accompanied by potent induction of MCP-1 synthesis and secretion. In contrast, E-LDL does not stimulate IL-1 or TNF-production and is only a weak inducer of IL-6. Monoclonal antibodies were produced that recognize neoepitopes on E-LDL, but that do not react with native or oxidized LDL. With the use of these antibodies, extensive deposition of E-LDL in very early atherosclerotic lesions was demonstrated. Activated complement components colocalized with E-LDL, corroborating the concept that subendothelially deposited LDL is enzymatically transformed to a complement activator at the earliest stages in lesion development. The pathogenetic relevance of unhalted complement activation in atherogenesis was demonstrated with the use of C6-deficient rabbits. It was found that C6-deficiency markedly protected against development of diet-induced atherosclerosis in the experimental animals. In sum, our hypothesis departs from the mainstream of atherosclerosis research and derives from the recognition that extracellular exposition of free cholesterol in LDL-particles by itself confers pro-inflammatory properties onto the lipoprotein molecule. We believe that the degrading enzymes are ubiquitously present in the extracellular matrix, so the only requirement for atherogenesis to occur is the deposition of large amounts of LDL. Oxidative processes or infections probably play only minor roles, and reduction of LDL plasma levels will predictably represent the single most important prophylactic measure against development and progression of atherosclerosis.
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PMID:[An alternative hypothesis of the pathogenesis of atherosclerosis]. 964 97

Inflammatory processes play an important role in atherogenesis, and proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumour necrosis factor alpha (TNFalpha) are thought to be mediators in this phenomenon. We have previously established that peritoneal macrophages of LDL-receptor knock-out mice, which are hypercholesterolemic and are prone to atherosclerosis, have an increased LPS-induced cytokine production capacity, ex vivo. The aim of the present study was to investigate whether the process leading to atherosclerosis in patients with familial hypercholesterolemia (FH) is associated with increased cytokine production capacity of peripheral blood mononuclear cells (PBMC) and/or increased expression of adhesion molecules on monocytes and lymphocytes. Furthermore, we assessed the effect of cholesterol lowering on the production capacity of PBMC, as these drugs are beneficial with regard to cardiovascular diseases. LPS-induced IL-1beta and TNFalpha production by PBMCs of 21 heterozygous FH patients appeared to be similar to the production by PBMCs of 21 healthy volunteers. In addition, expression of the LPS-receptors CD14 and beta2-integrins in nine patients and controls did not differ either. In a second series of experiments, HMG-CoA synthesis inhibitors were ineffective to change the LPS-induced production by PBMC of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, and TNFalpha. In conclusion, cytokine production capacity of blood cells or the expression of LPS-receptors on circulating PBMC do not deviate in subjects with FH and also do not change as a result of treatment with cholesterol synthesis inhibitors.
Atherosclerosis 1998 Jul
PMID:LPS-induced cytokine production and expression of LPS-receptors by peripheral blood mononuclear cells of patients with familial hypercholesterolemia and the effect of HMG-CoA reductase inhibitors. 969 2

Numerous epidemiological studies have suggested an association between the acute phase response and atherosclerosis. Paraoxonase (PON) is an HDL associated enzyme that protects LDL from oxidative stress. Here we demonstrate that serum PON activity decreases following endotoxin (LPS) administration in Syrian hamsters. This decrease is seen within 24 h following LPS treatment and doses as low as 100 ng/100 g body weight of LPS elicit a reduction in serum PON activity. LPS also induces a marked decrease in PON1 mRNA in the liver (80% decrease). The decrease in mRNA levels is observed as early as 4 h and is sustained for at least 48 h after a single LPS treatment. Moreover, TNF and IL-1, cytokines which mediate the acute phase response, also decrease serum PON activity and PON mRNA levels in the liver. Additionally, TNF and IL-1 treatment of HepG2 cells results in a decrease in PON mRNA levels indicating that these cytokines are capable of directly affecting liver cells. Along with other changes in lipid metabolism that occur during the acute phase response, the decrease in PON could be another factor linking the acute phase response with increased atherogenesis.
Atherosclerosis 1998 Aug
PMID:Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. 971 37


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