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)

In atherosclerosis and tumor initiation, inducible nitric oxide synthase (iNOS) has been implicated in the damage of vascular walls and DNA, respectively. Moderate consumption of red wine has been ascribed as a preventive for coronary heart disease; however, there has been much debate over whether the beneficial effect is from grape polyphenolic components or ethanol. We studied the interaction of grape compounds on nitric oxide (NO) production by macrophages, mediators of blood vessel damage in atherosclerosis. For the murine macrophage cell line RAW 264.7, stimulation with lipopolysaccharide and interferon-gamma led to expression of the iNOS gene and production of NO. The polyphenols quercetin and resveratrol at a micromolar range suppressed iNOS gene expression and NO production, as determined by reverse transcription-polymerase chain reaction and nitrite assay. The polyphenols were also found to be scavengers of NO in an acellular system using sodium nitroprusside under physiological conditions. Ethanol, at a moderate level, did not produce any appreciable level of reduction of iNOS or NO activity. However, its presence at 0.1 to 0.75% enhanced the effect of grape polyphenols concentration-dependently. Thus, the interaction between these components plays a significant role in the health effects of red wine, especially with respect to their effect on the NO pathway.
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PMID:Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. 1102 Apr 57

A role for interferon-gamma (IFN-gamma) has been implied in the atherogenic process. To determine whether exogenously administered IFN-gamma exerts an effect on the development of atherosclerosis, we intraperitoneally administered either recombinant IFN-gamma (100 U/g body weight) or phosphate buffered saline daily for 30 days to atherosclerosis-susceptible apolipoprotein E-/- mice (16-week-old male mice, n = 11 per group) fed a normal diet. Atherosclerotic lesion size was quantified in the ascending aorta. The number of T lymphocytes and major histocompatibility complex (MHC) class II-positive cells within lesions were also quantified in this region. IFN-gamma administration reduced serum cholesterol concentrations by 15% (P = 0.02). For both groups, the majority of cholesterol was present in very low density lipoproteins, which were modestly reduced in mice receiving IFN-gamma. Despite the decrease in serum cholesterol concentrations, IFN-gamma injections significantly increased lesion size twofold compared to controls (119,980 +/- 18, 536 vs. 59,396 +/- 20,017 micrometer(2); P = 0.038). IFN-gamma also significantly increased the mean number of T lymphocytes (19 +/- 4 vs. 7 +/- 1 cells; P = 0.03) and MHC class II-positive cells (10 +/- 3 vs. 3 +/- 1 cells; P = 0.04) within lesions. These data lend further support to a pro-atherogenic role of IFN-gamma.
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PMID:Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. 1110 54

Cytomegalovirus (CMV) and Chlamydia pneumoniae (CP) possibly contribute to atherosclerosis. Murine CMV (MCMV) and CP increase lesion size in apoE knockout mice. In this study, apoE knockout mice were infected with MCMV and CP to determine whether infection with multiple pathogens increases lesion size to a greater extent than either pathogen alone and whether infection with MCMV changes serum cytokine levels in a manner that could increase lesion development. One group of mice received MCMV at 2 weeks of age, followed by 2 doses of CP at 6 and 8 weeks of age. Additional groups received only MCMV or CP. Animals were killed at 16 weeks of age to determine lesion area. Infection with MCMV alone, CP alone, and both MCMV and CP increased lesion size 84% (P<.001), 70% (P<.0001), and 45% (P<.01), respectively. The MCMV-induced increase in circulating levels of interferon-gamma may have contributed to this increase.
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PMID:Atherosclerosis in apoE knockout mice infected with multiple pathogens. 1112 Sep 28

The formation of atherosclerotic lesions requires the migration of vascular smooth muscle cells from the media into the intima of the artery and their proliferation. These events, which are preceded and accompanied by inflammation, are modulated by integrin receptors linking vascular smooth muscle cells to extracellular matrix molecules. Among them, fibronectin induces vascular smooth muscle cells to acquire the phenotype they show in the atherosclerotic plaque. Here we show that amounts of interleukin-1 beta, tumor necrosis factor alpha and interferon-gamma as possibly released by activated immune cells infiltrating atherosclerotic lesions, upregulate vascular smooth muscle cell expression of the alpha5beta1 integrin, a fibronectin receptor. This improves vascular smooth muscle cell capability of migrating toward soluble or anchored fibronectin and of adhering to immobilized fibronectin. The latter effect, in turn, augments vascular smooth muscle cell proliferative response to mitogens, as suggested by the increase of intracellular pH. Finally, the effects that inflammatory cytokines have on vascular smooth muscle cell locomotion and growth, are specifically blocked by anti-alpha5beta1 antibodies. As fibronectin and alpha5beta1 levels are augmented in vivo in the atherosclerotic plaques, these findings support the use of integrin antagonists as potential adjuvants in atherosclerosis treatment.
Atherosclerosis 2001 Feb 01
PMID:Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing alpha5beta1 integrin expression and function. 1116 70

Even though it is known that apolipoprotein E (apoE) is deeply involved in major age-related disorders such as atherosclerosis or Alzheimer's disease (AD), the control of cell-specific apoE expression is still poorly understood. We compared the apoE secretion as previously described in astrocytic cell17 to hepatic cell apoE secretion. We used the human hepatoma cell line KYN-2 to better delineate the characteristics of apoE secretion and to validate it with respect to the classical human hepatoma cell line HepG2. Interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) significantly inhibited, while IL-2, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were inactive on apoE secretion by KYN-2 as well as HepG2 cells. Cholesterol and 25-OH cholesterol had no effect, while forskolin exerted a significant inhibitory effect, on apoE secretion in KYN-2 cells. Our results suggest that the KYN-2 cell line represents an appropriate cell model, and in any case an alternative model to the HepG2 cell line, to study the control of apoE secretion. The response of KYN-2 cells to both cytokines and cholesterol differs from that found in astrocytoma cells, suggesting that blood variations of apoE concentrations in AD may not reflect the dysregulations taking place in the brain.
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PMID:Control of apolipoprotein E secretion in the human hepatoma cell line KYN-2. 1122 71

Gene transfer with adenoviral vectors is an attractive approach for the treatment of atherosclerosis and restenosis. However, because expression of a therapeutic gene in nontarget tissues may have deleterious effects, artery-specific expression is desirable. Although expression vectors containing transcriptional regulatory elements of genes expressed solely in smooth muscle cells (SMCs) have proved efficient to restrict expression of the transgene, their use in the clinical setting can be limited by their reduced strength. In the present study, we show that low levels of transgene expression are obtained with the smooth muscle (SM)-specific SM22alpha promoter compared with the viral cytomegalovirus (CMV) enhancer/promoter. We have generated chimeric transcriptional cassettes containing either a SM (SM-myosin heavy chain) or a skeletal muscle (creatine kinase) enhancer combined with the SM22alpha promoter. With both constructs we observed significantly stronger expression that remains SM-specific. In vivo, reporter gene expression was restricted to arterial SMCs with no detectable signal at remote sites. Moreover, when interferon-gamma expression was driven by one of these two chimeras, SMC growth was inhibited as efficiently as with the CMV promoter. Finally, we demonstrate that neointima formation in the rat carotid balloon injury model was reduced to the same extent by adenoviral gene transfer of interferon-gamma driven either by the SM-myosin heavy chain enhancer/SM22alpha promoter or the CMV promoter. These results indicate that such vectors can be useful for the treatment of hyperproliferative vascular disorders.
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PMID:Chimeric smooth muscle-specific enhancer/promoters: valuable tools for adenovirus-mediated cardiovascular gene therapy. 1124 69

In the early atherosclerotic lesion, monocytes accumulate at sites of inflammation and endothelial injury. Platelet-derived growth factor (PDGF), produced for example by macrophages, is a chemoattractant for smooth muscle cells and possibly also for macrophages. During early differentiation into macrophages, human monocytes (early hMDM) showed lower expression of PDGF alpha-receptor (PDGF-Ralpha) than beta-receptor (PDGF-Rbeta) mRNA. Early hMDM showed increased random motility (chemokinesis) in the presence of PDGF of the long (BB(L)) but not short (BB(S)) B-chain homodimer. Neither PDGF-AA(S) nor PDGF-AA(L) affected early hMDM motility. Since increased cytokine levels accompany inflammation, the influence of interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) on PDGF-R expression and migratory response were studied. Only PDGF-Ralpha mRNA was highly upregulated by IFN-gamma. TGF-beta only had minor effects on receptor mRNAs. Upregulation of PDGF-Ralpha levels by IFN-gamma was accompanied by significantly increased migration (chemotaxis) towards PDGF-AA(L) only. Consequently, IFN-gamma modulates PDGF-Rs expression in early hMDM and, subsequently, the chemotactic activity of PDGF-AA(L) on IFN-gamma-stimulated early hMDM. This suggests that PDGF-AA(L) may be involved in attracting activated monocytes to sites of inflammation and injury.
Atherosclerosis 2001 Jun
PMID:Expression of PDGF receptors and ligand-induced migration of partially differentiated human monocyte-derived macrophages. Influence of IFN-gamma and TGF-beta. 1139 22

Although the concept that inflammation plays a role in the biology of atherosclerosis is now well accepted, the basic feature of the arterial lesion remains the accumulation of clusters of foam cells. These clusters are the consequence of the enhanced recruitment of monocytes in the vessel wall induced by the hyperlipidemia and of the disproportionate accumulation of lipids in the cytoplasm of macrophages deriving from monocytes. Ultimately, every molecular force and pathway with modulating activity over the developing lesion will have to act on a convergence point with factors regulating cholesterol balance in the macrophage. Consistent with this view is the recent report that cytokines, such as tumor necrosis factor-alpha, can influence the expression of the scavenger receptor, whereas interferon-gamma can inhibit adenosine triphosphate-binding cassette transporter-1, the main effector of cholesterol efflux in the peripheral cell. Conversely, recent data have shown that primary alterations in macrophage cholesterol balance, such as those produced by the total absence of acylcoenzyme A:cholesterol acyltransferase-1, may determine local changes compatible with the activation of inflammatory pathways. In this brief review, we discuss some of the convergence points between inflammation and cholesterol balance, and we highlight the additional therapeutic targets suggested by these new developments in vascular biology.
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PMID:The inflamed plaque: cytokine production and cellular cholesterol balance in the vessel wall. 1147 38

Tumor necrosis factor (TNF) receptor superfamily 14 (TNFRSF14) is the cellular receptor for TNF superfamily 14 (LIGHT). Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high level of expression of the TNFRSF14 in regions rich in macrophages/foam cells. To investigate the role of TNFRSF14 in the functioning of monocytes in relation to atherogenesis, we have analyzed TNFRSF14 expression levels and cellular events after stimulation of TNFRSF14 in peripheral blood monocytes or the human macrophage-like cell line, THP-1. A high level of expression of TNFRSF14 was detected in activated monocytes, in macrophages derived from monocytes, and in THP-1 cells. Concomitant activation of THP-1 cells with interferon-gamma and immobilized anti-TNFRSF14 monoclonal antibody resulted in synergistic induction of proatherogenic cytokines, such as TNF-alpha and interleukin-8. Activation of THP-1 cells with immobilized anti-TNFRSF14 monoclonal antibody induced expression of matrix metalloproteinase (MMP)-1, MMP-9, MMP-13, and tissue inhibitors of metalloproteinase-1 and -2. Furthermore, immunohistochemical staining of atherosclerotic plaques with severe infiltration of foam cells revealed that the expression patterns of TNFRSF14 and MMP-1, -9, and -13 overlapped. Treatment of THP-1 cells with soluble LIGHT also caused induction of MMP-9 and interleukin-8. These data suggest that TNFRSF14 is involved in atherosclerosis via the induction of proatherogenic cytokines and decreasing plaque stability by inducing extracellular matrix-degrading enzymes.
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PMID:Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. 1174 58

Given the significance of CD40-CD40 ligand interactions in chronic inflammatory diseases including atherosclerosis, the transcriptional regulation of CD40 expression as a potential therapeutic target was investigated in human umbilical vein cultured endothelial cells. Exposure to interferon-gamma (IFN-gamma) plus tumor necrosis factor-alpha resulted in a marked synergistic de novo expression of CD40, which, according to electrophoretic mobility shift analysis, was attributable to activation of the transcription factors nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription-1 (STAT-1), and interferon regulatory factor-1 (IRF-1). Subsequent time-course studies revealed that de novo synthesis of IRF-1 preceded that of CD40. Decoy oligodeoxynucleotide (ODN) neutralization of STAT-1 or IRF-1, but not of NF-kappaB, inhibited cytokine-stimulated CD40 expression by 60% at both the mRNA and protein levels, and this effect was mimicked by antisense ODN blockade of IRF-1 synthesis. In contrast, CD40 expression in response to IFN-gamma stimulation was sensitive to neutralization of STAT-1 only. These findings suggest that depending on the cytokine composition, CD40 expression in human endothelial cells under proinflammatory conditions is governed by STAT-1 either directly or indirectly through de novo synthesis of IRF-1. Moreover, decoy ODN neutralization of these transcription factors may provide a novel therapeutic option for interfering with CD40-CD40 ligand-mediated inflammatory responses in vivo.
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PMID:Cytokine-inducible CD40 expression in human endothelial cells is mediated by interferon regulatory factor-1. 1178 Dec 33


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