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)

Nitric oxide (NO), which accounts for the biological properties of endothelium-derived relaxing factor, is generated by NO synthase (NOS). The vascular endothelium contains two types of NOS: one is constitutively expressed (cNOS), and the other is inducible. Endothelium-mediated vasorelaxation is impaired in atherosclerotic vessels. To determine whether tumor necrosis factor (TNF)-alpha, which is commonly found in atherosclerotic lesions, has an effect on NOS message, we measured cNOS mRNA levels in TNF-treated human umbilical vein endothelial cells (HUVECs) by RNA blot analysis with a cNOS cDNA probe. TNF-alpha markedly reduced cNOS mRNA levels in HUVECs in a dose- and time-dependent manner. In response to 3 ng/mL TNF-alpha, cNOS mRNA levels began to decrease at 4 hours and diminished to only 5% of control levels at 24 hours. As little as 0.1 ng/mL TNF-alpha reduced cNOS mRNA levels by 50%. This reduction in cNOS message in response to TNF-alpha depended on protein synthesis as it was blocked by cycloheximide. In nuclear runoff experiments, TNF-alpha did not change the rate of cNOS gene transcription. cNOS mRNA is very stable under basal conditions, with a half-life of 48 hours; however, treatment with TNF-alpha shortened this half-life to 3 hours. TNF-alpha thus appears to decrease cNOS mRNA levels by increasing the rate of mRNA degradation. TNF-induced reductions in cNOS mRNA levels may have an important effect on impaired endothelium-mediated vasorelaxation in atherosclerosis.
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PMID:Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. 768 52

The chemotactic cytokine, monocyte chemoattractant protein-1 (MCP-1), and its murine homologue, JE, have been detected in atherosclerotic lesions but not in normal arteries, implicating that these proinflammatory cytokines may be involved in the pathogenesis of atherosclerosis. Epidemiologic studies reveal that postmenopausal women receiving estrogen replacement for treatment of osteoporosis have a greatly reduced risk of developing cardiovascular disease. Because JE/MCP-1 and estrogen play regulatory roles in the development of atherosclerotic lesions, we chose to examine the effect of estrogen treatment on JE/MCP-1 mRNA expression in macrophages. 17 beta-estradiol (E2) inhibited LPS-stimulated JE/MCP-1 mRNA expression in ANA-1 and J774A.1 murine macrophage cell lines and in thioglycolate-elicited murine peritoneal macrophages. Inhibition of JE/MCP-1 mRNA ranged from 50 to 90%, with a maximal effect occurring at a concentration of 300 pg/ml E2. Conversely, E2 had little effect on LPS-stimulated TNF-alpha mRNA production. Treatment of LPS-stimulated macrophages with moxestrol, an estrogen agonist, resulted in a similar inhibition, and the addition of the estrogen antagonist, tamoxifen, reversed E2 inhibition of JE/MCP-1 mRNA expression. Progesterone failed to inhibit LPS-induced JE/MCP-1 mRNA expression. Immunohistochemical analysis revealed the presence of estrogen receptors in ANA-1 cells, indicating that E2 inhibition of LPS-induced JE/MCP-1 mRNA expression in murine macrophages may be mediated through the estrogen receptor. Thus, another mechanism whereby estrogen exerts antiatherogenic effects may be through prevention of macrophage accumulation in the atherosclerotic lesion.
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PMID:Estrogen modulation of JE/monocyte chemoattractant protein-1 mRNA expression in murine macrophages. 783 68

A critical step in development of atherosclerosis is the interaction of oxidized low-density lipoprotein (LDL) with mononuclear phagocytes. Oxidized LDL, as well as acetyl-LDL, is rapidly taken up into macrophages via a family of scavenger receptors. We report that macrophages treated with oxidized LDL have markedly lower levels of mRNA specific for the genes MCP-1, TNF-alpha, IL-1 alpha, and KC as measured by Northern blot analyses of lipopolysaccharide (LPS)-stimulated macrophages. By contrast, acetyl-LDL does not inhibit these genes at the doses at which oxidized-LDL is effective. Similar effects are observed whether the LDL is oxidized in the presence of Cu2+ or of Fe2+. Such inhibition also occurs when maleylated bovine serum albumin (BSA), which also clears by one or more scavenger receptors on macrophages, is used as the stimulant. Fe2+ or Cu2+ oxidized LDL inhibits release of nitric oxide when triggered by LPS and direct cytolysis of tumor cells when triggered by maleylated BSA or LPS. Taken together, the data presented indicate that oxidized LDL inhibits induction of several important gene RNAs as well as functional markers that characterize the development of inflammatory and fully activated macrophages.
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PMID:Effects of oxidized LDL on mononuclear phagocytes: inhibition of induction of four inflammatory cytokine gene RNAs, release of NO, and cytolysis of tumor cells. 788 14

The possible involvement of immunological mechanisms in the pathogenesis of atherosclerosis has been suggested intermittently since the early 1970s. Both humoral and cellular mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions, but the theories postulating the involvement of autoantibodies and immune complexes have met with considerable experimental support. Modified lipoproteins, particularly different forms of oxidized LDL, have been reported to elicit humoral immune responses in both experimental animals and humans. Oxidized LDL has been demonstrated in atheromatous lesions, anti-oxidized LDL antibodies have been detected in circulation and in atheromatous plaques, and immune complexes formed with LDL and anti-LDL have been isolated from the serum of patients with manifestations of atherosclerosis. In addition, in vitro-formed LDL-IC and IC isolated from patients have been demonstrated to cause intracellular accumulation of cholesteryl esters (CE) in human macrophages and fibroblasts. The accumulation of CE in macrophages exposed to LDL-IC is unique to this type of IC and is associated with a paradoxical overexpression of the native LDL receptor and with increase synthesis and release of interleukin 1 and TNF-alpha. The release of these cytokines in the subendothelial space may have a significant role in promoting the interaction of endothelial cells with mononuclear cells, causing endothelial cell damage directly or indirectly, and also in inducing smooth muscle cell proliferation. Thus, several lines of evidence suggest that humoral autoimmunity may play a significant role in the pathogenesis of atherosclerosis.
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PMID:Atherosclerosis and autoimmunity. 792 23

Angiogenesis, the growth and proliferation of blood vessels, may be important in the pathogenesis of atherosclerosis and thus in human atherosclerotic abdominal aortic aneurysms (AAAs). Endothelial migration or chemotaxis is a vital component of the angiogenic response. Here, human aortic endothelial cells (hAECs) were used to investigate the effect of AAA tissue supernatants on hAEC chemotaxis. AAA tissue conditioned media were found to be chemotactic for hAECs. We have previously shown that the angiogenic cytokines interleukin (IL)-8, and tumor necrosis factor (TNF)-alpha are present in AAAs and normal aortic explant conditioned media. Currently, we have found that basic fibroblast growth factor (bFGF) and platelet-derived growth factor can also be detected in these supernatants. In order to identify whether some of these soluble mediators contributed to the chemotactic activity of these supernatants, conditioned media were preincubated with either neutralizing anti-IL-8, anti-TNF-alpha, anti-bFGF antibodies or control serum. Anti-IL-8 and anti-TNF-alpha significantly inhibited AAA tissue supernatant-induced hAEC chemotaxis (p < 0.05), while anti-bFGF did not (p not significant). These results indicate that IL-8 and TNF-alpha may be important in chemotactic activity for hAECs in vitro and possibly in AAA neovascularization. The abrogation of angiogenesis using neutralizing antibodies may be a future goal in the therapy of certain disease states such as AAA where angiogenesis plays an important role.
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PMID:Interleukin-8 and tumor necrosis factor-alpha are involved in human aortic endothelial cell migration. The possible role of these cytokines in human aortic aneurysmal blood vessel growth. 794 19

We previously demonstrated that C-type natriuretic peptide (CNP), originally isolated from the porcine brain, is produced by endothelial cells and proposed that CNP can exert local control over vascular tone and growth as a local regulator from endothelial cells. Since cytokines play pivotal roles in the control of vascular tone and structure, we have examined effects of various cytokines on CNP secretion from endothelial cells using the specific radioimmunoassay for CNP. While interleukin (IL)-2 had no significant effect on CNP secretion, IL-1 alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha stimulated CNP secretion in a time- and dose-dependent manner. Among them, TNF-alpha, one of the key mediators for inflammation and vascular remodeling, induced more than two orders of magnitude increase in CNP secretion. In addition, lipopolysaccharide (LPS) potently stimulated CNP secretion. These results indicate that IL-1, TNF-alpha and LPS, the endotoxin itself, can regulate local vascular tone and growth through the activation of CNP secretion from endothelial cells. Therefore, CNP could be of clinical relevance as an autocrine/paracrine regulator from endothelial cells for systemic and local cytokine-associated disorders, such as endotoxin shock and atherosclerosis.
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PMID:Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells--evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. 824 33

Previously we have shown that incubation of heparinized blood with a low dose of lipopolysaccharides (5 ng/ml) resulted in a 60% higher generation of TxB2 in the blood of young men as compared with that of young women. In the present study, we investigated a group consisting of 38 healthy men and 38 healthy postmenopausal women aged 50-73 years with no drug use and no known chronic disease. In contrast to our earlier observation that young men produce more TxB2 than young women, no significant difference was observed between the men and women when all the participants above 50 years of age were included (5.7 +/- 0.6 ng/l for men versus 5.2 +/- 0.7 ng/l for women). However, a strong correlation was found with simple regression analysis when increasing TxB2 generation was compared with years after menopause (P < 0.0001). No such correlation was observed for increasing age of men and their TxB2 production. The LPS stimulation system of whole blood was also used to evaluate the production of tumor necrosis factor (TNF-alpha) in older people. Men were found to generate 60% more TNF-alpha than women, but no correlation was found between increasing age of women and TNF-alpha production as observed with TxB2. Risk factors such as SDS-cholesterol, fibrinogen and factor VII were the same in men and women, whereas total cholesterol was higher in women than in men (P < 0.05). Since TxA2 is known to be a mediator of atherosclerotic-induced lesions and TNF-alpha is a well-established indicator of inflammatory reactions, we propose that the reduced production of TxB2 and TNF-alpha in women in our model system may partially explain the lower incidence of atherosclerosis in women as compared with men, and the phenomenon of increased incidence of this disease after menopause.
Atherosclerosis 1993 Aug
PMID:Thromboxane production in the blood of women increases after menopause whereas tumor necrosis factor is reduced in women compared with men. 825 57

The production of cytokines during aging, except interleukin (IL)-2, has been neglected in humans. We measured the in vitro production of IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and IL-1 beta by peripheral mononuclear cells from selected healthy young (mean age 26.8 years) and aged (mean age 80.2 years) subjects. Significant increases of IL-6, TNF-alpha and IL-1 beta levels were found in mitogen-stimulated cultures from aged donors, occurring at 24 to 72 h after stimulation. No significant differences were observed for IFN-gamma production. Proliferative capability of cells stimulated with PHA was not impaired in aged subjects. Since the amounts of all cytokines studied were similar in unstimulated cultures from young and aged subjects, and also serum levels of TNF-alpha did not differ, these data indicate that the cellular machinery for the production of these cytokines is well preserved in aging, and also that cells from old people are able to up-regulate their production in response to appropriate stimuli. The increases in cytokine synthesis were not dependent on changes in the number of monocytes, nor were they related to the significant rise of CD45RO+, and the concomitant decrease of CD45RA+, occurring in both CD4+ and CD8+ lymphocytes from aged subjects. The increased production of pro-inflammatory cytokines by stimulated mononuclear cells of healthy aged subjects may be relevant to several aspects of age-associated pathological events, including atherosclerosis, osteoporosis, fibrosis and dementia.
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PMID:Increased cytokine production in mononuclear cells of healthy elderly people. 837 Apr 15

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-alpha promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-1 alpha-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-gamma. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.
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PMID:Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis. 844 15

Modified lipoproteins, particularly different forms of oxidized LDL (ox-LDL), have been reported to elicit humoral immune responses both in experimental animals and humans. In diabetes, glycation and oxidation processes coexist and lead to the formation of glycoxidation products. Ox-LDL has been demonstrated in atheromatous lesions, anti-ox-LDL antibodies have been detected in circulation and in atheromatous plaques, and immune complexes (ICs) formed with LDL and anti-LDL (LDL-IC) have been isolated from the serum of patients with manifestations of atherosclerosis. In addition, in vitro formed LDL-ICs and ICs isolated from patients have been demonstrated to cause intracellular accumulation of cholesteryl esters (CEs) in human macrophages and fibroblasts. The accumulation of CEs in macrophages exposed to LDL-ICs is unique to this type of IC and is associated with paradoxical overexpression of LDL receptor and with increased synthesis and release of interleukin 1 beta and tumor necrosis factor (TNF) alpha. The overexpression of LDL receptors is higher in LDL-IC-stimulated macrophages that release markedly high amounts of TNF-alpha than in macrophages that release low amounts of TNF-alpha into the medium. The release of cytokines in the subendothelial space may have a significant role in promoting the interaction of endothelial cells with mononuclear cells, causing endothelial cell damage directly or indirectly, and also in inducing smooth muscle cell proliferation. Thus, in view of the above data, it can be concluded that humoral autoimmunity may play a significant role in the pathogenesis of atherosclerosis in diabetes.
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PMID:Cytokines, modified lipoproteins, and arteriosclerosis in diabetes. 867 88


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