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)

Increased expression of cell adhesion molecules is an important pathological event during the development of atherosclerosis. The smooth muscle cell (SMC) is one of the cell types present in the atherosclerotic lesion. To evaluate the regulation of adhesion molecules in human vascular SMCs and its possible role, we studied the expression of adhesion molecules in SMCs stimulated with interleukin 1-beta (IL-1 beta), a pleiotropic cytokine that is involved in the pathological development of vascular diseases including atherosclerosis and restenosis. Our data demonstrated that IL-1 beta markedly induced the adhesiveness of human vascular SMCs for monocytes and neutrophils in a concentration (10 pM - 10 nM)- and time (0.5-24 h)-dependent manner. The maximal induced adhesion by IL-1 beta (1 nM) was reached at 4 h, with 4.6-fold and 3.3-fold for monocytes and neutrophils, respectively. This induction was dose-dependently inhibited by the IL-1 receptor antagonist (IL-1 ra). The IL-1 beta-induced expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin 1 (ELAM-1) on SMCs was examined by reverse transcription/polymerase chain reaction (RT/PCR). Unstimulated, serum-deprived SMCs expressed a low or undetectable level of mRNA for these adhesion molecules. The expression of ICAM-1 and VCAM-1 but not ELAM-1 mRNA was significantly induced with IL-1 beta in a concentration (1 fM - 1 nM)- and time (0.5 - 24 h)-dependent manner. The maximal increase in ICAM-1 and VCAM-1 mRNAs was reached at 4 h after IL-1 beta stimulation. The IL-1 beta-induced adhesion of SMCs for monocytes was partially inhibited by monoclonal anti-human ICAM-1 and anti-human VCAM-1 antibody, but not by anti-human ELAM-1 antibody. Pretreatment of monocytes with anti-human integrin beta 2 antibody significantly reduced the adhesion of monocytes to IL-1 beta-stimulated SMCs. These results suggest that IL-1 beta is a potent inducer for ICAM-1 and VCAM-1 expression in human vascular SMC, and could play a role in the pathogenesis of atherosclerosis by recruitment and retention of inflammatory cells such as monocytes and neutrophils in the lesions.
Atherosclerosis 1995 May
PMID:Interleukin-1 beta induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. 754 98

Vascular cells, including smooth muscle cells (VSMC), may release interleukin 1 (IL-1) and transcribe its genes for both isoforms. Previous studies have shown that cysteinyl-leukotrienes can modulate cytokine production by monocytes and a cytokine-eicosanoid network has been suggested during atherosclerosis. In this study the effects of cysteinyl-leukotriene D4 (LTD4) on IL-1 beta production and IL-1 beta mRNA expression were tested on rat VSMC. LTD4 showed a significant dose-dependent (from basal production of 55 +/- 15 pg/ml to maximal production of 177 +/- 14 pg/ml) and time-dependent (peaking at 24 h 16 +/- 54 pg/ml) increase of IL-1 beta immunoreactivity in the supernatants of conditioned medium and cell lysates. Furthermore, LTD4 induced an increased mRNA expression which began at 1 h and peaked at 12 h incubation time. The production of IL-1 beta was inhibited by MK-571 (from 145 +/- 12 to 60 +/- 10 pg/ml), a specific receptor antagonist of LTD4 and partially reduced by IL-1 receptor antagonist (IL-1 ra) (from 160 +/- 12 to 85 +/- 5 pg/ml). These experiments suggest that cysteinyl-leukotrienes, potentially produced in the vascular wall by leukocytes or by transcellular metabolism, may be involved in local IL-1 production.
Atherosclerosis 1995 Jun
PMID:Cysteinyl-leukotriene D4 induced IL-1 beta expression and release in rat vascular smooth muscle cells. 766 77

Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1 beta (IL-1 beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNF alpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNF alpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNF alpha but not to LPS, IL-1 beta, or PIC. TNF alpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappa B-like DNA enhancer elements and associated NF-kappa B-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-1 gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.
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PMID:Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. 769 89

Monocyte chemoattractant protein-1 (MCP-1, or monocyte chemotactic and activating factor) plays important roles in the recruitment of monocytes and thus in the development of atherosclerosis. In this study, we determined whether MCP-1 synthesis was induced by the cellular interaction between monocytes and endothelial cells during the process of transendothelial migration. We found that when human peripheral blood monocytes (2.5 x 10(6) cells) and umbilical vein endothelial cells (HUVECs; 5.0 x 10(5) cells) were cocultured for 5 hours, 7.9 ng/mL MCP-1 was secreted into the medium, whereas when the two were cultured separately, MCP-1 levels were 1.0 and 0.9 ng/mL, respectively. Furthermore, the use of interleukin-1 beta (IL-1 beta)-pretreated HUVECs in cocultures induced twice the levels of MCP-1 as in unstimulated HUVEC culture. Conditioned medium had transendothelial chemotactic activity for monocytes, and this activity was completely abolished by addition of anti-MCP-1 antibody. Although MCP-1 mRNA levels were very low or undetectable in HUVECs or monocytes alone, message could be detected after 2 hours of coculture in total mRNA preparations from both monocytes and HUVECs. mRNA levels increased by 4 hours and had declined slightly by 24 hours. The rapid induction of message suggests that cell contact between monocytes and HUVECs induces the de novo synthesis of MCP-1 protein. Anti-interleukin (IL)-1 alpha/beta and anti-tumor necrosis factor-alpha antibodies, or anti-lymphocyte function-associated antigen-1 and very late antigen-4 antibodies, had little or no inhibitory effects on MCP-1 secretion by cocultures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of monocyte chemoattractant protein-1 synthesis in human monocytes during transendothelial migration in vitro. 772 91

To elucidate physiological functions of adrenomedullin (AM) secreted from vascular smooth muscle cells (VSMCs), we examined the effect of cytokines, growth factors and related substances on AM production in cultured rat VSMC. Among them, interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta, as well as lipopolysaccharide (LPS), markedly augmented production and gene expression of AM. Although maximal stimulation levels of these substances were not greatly different, ED50 values of IL-1s (0.3 ng/ml) were about 1/10 that of TNFs and LPS. AM mRNA levels maximized at 3-6 h after stimulation with IL-1 beta and LPS, while TNF-alpha increased the AM mRNA level up to 48 h. Furthermore, IL-1 alpha, TNF-alpha and LPS additively increased AM production in VSMC. AM production was slightly augmented by fibroblast, epidermal and platelet derived growth factors. These results suggest that AM secreted from VSMC actually exerts a vasorelaxant effect under physiological conditions such as endotoxin shock, atherosclerosis and inflammation.
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PMID:Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. 785 73

Monokines, such as interleukin-1, have been implicated in the pathogenesis of several pathologic processes, including the initiation and progression of atherosclerosis. Since estrogen has been identified as a modulator of atherosclerosis progression, we sought to examine the effect of estrogen on the inducible expression of interleukin-1 beta (IL-1 beta) and interleukin-1 alpha (IL-1 alpha) mRNA in the monocytic cell line, THP-1. Cells were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) (50 ng/ml) for 48 or 96 h to induce differentiation. Some cells were treated with lipopolysaccharide (LPS) (10 micrograms/ml) in the last 3 h and/or 10(-9) M ethinyl estradiol (estrogen) in the last 20 h. Total cellular RNA was isolated, and cDNA was synthesized and amplified using the polymerase chain reaction (PCR) using two sets (pairs) of 32P-labeled primers, one for IL-1 beta (product size 388 bp) and the second for the internal control, beta-actin (1126 bp), or to detect another cytokine mRNA, a set of primers for IL-1 alpha (product size 420 bp) and beta-actin. The PCR products were separated on a 3.0% agarose gel and the ratio of radioactivity incorporated into cytokine PCR products and beta-actin products was determined to assess the relative changes in the relative levels of cytokine to beta-actin mRNA abundance in response to various inducers. Treatment with TPA for 48 h induced expression of IL-1 beta mRNA, an effect that was enhanced two fold by LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The inducible expression of THP-1 cell interleukin-1 mRNA: effects of estrogen on differential response to phorbol ester and lipopolysaccharide. 818 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

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

We examined the effects of dietary n-3 polyunsaturated and saturated fatty acids on the development of the atherogenic process in mice and on the macrophage ability to secrete several effector molecules that may be involved in the atherogenic process. The secretion of inflammatory proteins such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) and the production of lipoprotein lipase (LPL), nitrogen oxide (NO2), and prostaglandin E2 (PGE2) were evaluated in peritoneal macrophages isolated from atherosclerosis-susceptible C57BL/6J mice. The mice were assigned at random to three experimental groups: the first group was fed a semi-defined control diet (control diet); the second group was maintained on the control diet supplemented with 10% menhaden oil (menhaden diet); and the third group received the control diet supplemented with 10% palm oil plus 2% cholesterol (saturated fat diet). Macrophages derived from mice fed the menhaden diet showed a suppression of their basal TNF-alpha mRNA expression and production. They also presented a dramatically decreased ability to express TNF-alpha and IL-1 beta mRNAs in response to exposure to lipopolysaccharide (LPS) compared with the macrophages from the control group. LPL mRNA and protein expression were downregulated after 6 and 15 weeks of menhaden-diet feeding. Significantly higher NO2 production in response to interferon gamma was found, both after 6 and 15 weeks of diet feeding, in the menhaden group compared with the control group. In addition, prostaglandin production and macrophage tumoricidal activity in response to LPS were decreased in this group compared with the control group. Macrophages derived from the saturated fat group did not show any significant alterations in TNF-alpha, LPL, NO2, or PGE2 secretion compared with controls. Interestingly, we observed a progressive increase of the LPS-induced IL-1 beta gene expression and secretion among macrophages harvested from mice receiving the dietary supplement of saturated fatty acids. At 6 and 15 weeks histologic examination of the atherosclerotic lesions did not reveal any important lesions in the control and menhaden groups, whereas a gradual development of fatty streaks was observed in the menhaden experimental diets for 10 additional weeks resulted in a major development of lesions in the control group, whereas only slight lesions were observed in the menhaden group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dietary n-3 polyunsaturated fatty acids prevent the development of atherosclerotic lesions in mice. Modulation of macrophage secretory activities. 839 89

The development of the atheromatous plaque is largely dependent on vascular smooth muscle cell proliferation and production of biologically active compounds such as cytokines and growth factors. Cytokines such as IL-1 derived from blood vessel wall may contribute to regional defense or pathology. Neutralization of the effects mediated by IL-1 by a receptor antagonist specific for IL-1 alpha and IL-1 beta has been shown to reduce the possible pathologic consequences induced by IL-1 in the regional environment. The effect of human recombinant interleukin-1 receptor antagonist (hrIL-1ra), a new member of the IL-1 family, has been assessed on modulating vascular smooth muscle cell (VSMC) proliferation in the rat. A significant dose- and time-dependent reduction of DNA synthesis was observed when hrIL-1ra was added to the cell cultures. The maximum inhibitory effect was seen using IL-1ra at a concentration of 250 ng/ml and after 48 h incubation with cultured vascular smooth muscle cells. Furthermore, hrIL-1ra inhibited VSMC growth in the presence of exogenous mitogenic doses of IL-1 alpha. The addition of indomethacin to the cultures did not modify the inhibitory events. These data suggest a possible pharmacologic role for IL-1ra in inhibiting VSMC proliferation by possibly interfering with the autocrine regulatory pathway of IL-1.
Atherosclerosis 1993 Feb
PMID:Effect of interleukin-1 receptor antagonist on vascular smooth muscle cell proliferation. 846 Oct 62


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