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)

The atherosclerotic lesion contains large numbers of macrophages and T lymphocytes. This suggests that a cellular immune response may take place in the lesion, and oxidized lipoproteins, heat shock proteins, and micro-organisms have been implied as candidate antigens. However, the effector mechanisms elicited by this response have been largely unclear. We have therefore analyzed endarterectomy specimens by immunohistochemistry and reverse transcription-PCR to detect immune cytokines produced by immunocompetent cells of the advanced human plaque. The pro-inflammatory T cell cytokines, interleukin-2 and interferon-7, were found in a large proportion of plaques (IL-2 in 50% and interferon-gamma in 30% of plaques by immunohistochemistry and mRNA for both cytokines in 70% of plaques by PCR). In contrast, interleukin-4 and interleukin-5 were rarely observed (both cytokines in 10% of plaques by immunohistochemistry, mRNA for interleukin-4 in 10% and for interleukin-5 in 40% by PCR). This demonstrates the presence of a predominantly pro-inflammatory, Th1-type T cell response in atherosclerosis. This conclusion was further supported by the expression of the pro-inflammatory cytokine, interleukin-1 by plaque macrophages and endothelial cells. In addition, the chemokine interleukin-8 and the macrophage differentiation-stimulating cytokine, granulocyte-monocyte colony stimulating factor, were observed in plaque tissues, suggesting that the micro-environment promotes monocyte recruitment and macrophage differentiation. Occasional eosinophils and B cells were, however observed, which is compatible with a microheterogeneity within the lesion. Finally, the anti-inflammatory and fibrogenic cytokines, transforming growth factor-beta1-3 and its carrier protein, latent TGF-beta binding protein, were found in large amounts in all plaques. Together, these results show that a pro-inflammatory, Thl type cellular immune response takes place in the atherosclerotic plaque. The balance between pro-inflammatory and anti-inflammatory cytokines may be decisive for the progression of the lesion.
Atherosclerosis 1999 Jul
PMID:Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. 1042 93

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
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PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17

Multinucleated variant endothelial cells (MVECs) have frequently been observed in the human aorta, and the ratio of MVECs to typical endothelial cells correlates well with the severity of atherosclerosis. MVECs showed no capacity of proliferation in vitro, making their study extremely difficult. We attempted to obtain reproducible MVECs in vitro in order to understand their functional characteristics and their roles in atherosclerosis. This study was designed to derive MVECs from human umbilical cord vein endothelial cells (HUVECs) with different reagents such as Meso-4,4'-(2,3-butanediyl) bis (2,6-piperazinedione) (ICRF-193), low density lipoprotein (LDL), interleukin-4 (IL-4), polyethylene glycol (PG), H2O2, and linoleic acid hydroperoxide (LAHO). We found that 10 microM ICRF-193 was most effective in inducing MVECs. We then investigated the features of aortic endothelial cells (AECs) and ICRF-193 treated HUVECs (I-HUVECs) in the following four aspects: morphology, by light microscopy; cell cycle phase, by uptake of BrdU; expression of endothelial cell (EC) related markers such as von Willebrand Factor (vWF), endothelin-1 (ET-1), prostacyclin (PGI2) and intercellular adhesion molecule CD34 by immunocytochemistry; and biological activity by analyzing their uptake of low density lipoprotein (LDL). Furthermore, we compared aortic MVECs (AMVECs) and other aortic endothelial cells (A-others), as well as A-MVECs and ICRF-193 induced MVECs (I-MVECs) in every parameter examined. We found: 1. Compared with A-others, A-MVECs expressed more vWF (p < 0.01), more ET-1 (p < 0.05) and less CD34 (p < 0.01). In the uptake of LDL, A-MVECs took up more nLDL than A-others; 2. Both A-MVECs and I-MVECs contained multiple nuclei, but the nuclei differed in shape. A-MVECs and I-MVECs were similar in the nuclear incorporation of BrdU, in the uptake of nLDL and oxLDL, and in the expression of vWF, ET-1 and PGI2, but different in the expression of CD34 (p < 0.01). Our findings suggested that A-MVECs may transfer more plasma LDL to the subendothelial space because they took up more LDLs. I-MVECs were similar to A-MVECs morphologically and functionally. Thus, I-MVECs could be considered as substitutes in the study of A-MVECs.
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PMID:Formation of multinucleated variant endothelial cells in vitro and investigation of MVECs' features. 1059 8

It has recently become apparent that the anti-heat shock protein (HSP) antibody plays an important role in the pathogenesis of atherosclerosis. We studied whether immunization with human HSP60 could lead to atherosclerosis in mice. We attempted to induce atherosclerosis in C57BL/6NJcl mice by immunization with human HSP60 under a high-cholesterol diet. The size of fatty streak lesions was significantly enhanced in mice immunized with human HSP60 under a high-cholesterol diet relative to the number in control mice receiving a high-cholesterol diet alone. In addition, these new atherosclerotic model mice showed lesions of inflammation in the periodontal tissue. This new model may thus provide theoretical support for the clinical observation that patients suffering from periodontitis are frequently found to have atherosclerosis. The cytokine ratio of interferon-gamma/interleukin-4 in the high-cholesterol diet group was significantly higher than that in the standard chow group (p<0.05). This suggests the presence of a predominantly Th1-type immune response in atherosclerosis.
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PMID:A new murine model for atherosclerosis with inflammation in the periodontal tissue induced by immunization with heat shock protein 60. 1101 2

Vascular cell adhesion molecule-1 (VCAM-1) is expressed in early stages of atherosclerosis; however, the mechanisms of its upregulation are not fully understood. In the present study, we examined the effects of interleukin-4 (IL-4) on VCAM-1 gene expression and its transcriptional regulatory mechanism in human umbilical vein endothelial cells (HUVEC). Reverse transcription-polymerase chain reaction showed that VCAM-1 mRNA was induced in IL-4-treated HUVEC in a time- and dose-dependent manner. Among known transcription factors that have binding sites in the promoter region of the VCAM-1 gene, IL-4 activated only SP-1. In contrast, nuclear factor- kappa B (NF- kappa B), activator protein-1 (AP-1) and interferon regulatory factor-1 (IRF-1), which also have consensus binding sequences in the 5'-flanking region of the human VCAM-1 gene, were not activated. The role of SP-1 in IL-4-induced VCAM-1 expression was confirmed in HUVEC transfected with a reporter construct of the VCAM-1 promoter with mutated SP-1 binding site. As IL-4 treatment of HUVEC enhanced the intracellular oxidizing potential, as indicated by an increase in 2',7'-dichlorofluorescein (DCF) fluorescence, we studied the effect of antioxidants on IL-4-induced VCAM-1 expression. Pretreatment of HUVEC with pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC) completely prevented IL-4-induced VCAM-1 expression. In addition, PDTC inhibited IL-4-related activation of SP-1. These results suggest that IL-4-induced oxidative stress upregulates the expression of VCAM-1 gene in HUVEC at transcriptional levels via activation of SP-1 transcription factor. In contrast, NF- kappa B, AP-1 or IRF-1 do not appear to be involved in the signal transduction cascade.
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PMID:IL-4-induced oxidative stress upregulates VCAM-1 gene expression in human endothelial cells. 1113 25

We investigated the localization of histidine decarboxylase (HDC), which is the rate-limiting enzyme that generates histamine from histidine, in human aorta/coronary artery. RT-PCR and immunohistochemical staining revealed that the HDC gene was expressed in monocytes/macrophages and T cells in the arterial intima but not in smooth muscle cells in either the arterial intima or the media. A luciferase promoter assay with U937 and Jurkat cells demonstrated that interleukin-4 (IL-4) inhibited the expression of the HDC gene. In contrast, among a scavenger receptor family, IL-4 as well as histamine up-regulated U937 cells to express the LOX-1 gene but not the SR-A gene, which genes encode receptors that scavenge oxidized lipids. These findings suggest that histamine synthesized in the arterial wall participates in the initiation and progression of atherosclerosis and that IL-4 can act as an important inhibitory and/or stimulatory factor in the function of monocytes/macrophages modulated by histamine in relation to the process of atherosclerosis.
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PMID:Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophages in relation to atherosclerosis. 1156 79

Atherosclerosis has many features of a chronic inflammatory disease. To evaluate the role of lipopolysaccharide (LPS), mimicking a systemic infection, we administered the endotoxin to apolipoprotein E (apoE)-deficient mice. LPS injections increase the atherosclerotic lesion size and the titer of plasma autoantibodies directed against oxidized low-density lipoprotein. We found that Th1 and Th2 T cells help the activation of B cells in the autoimmune response. The number of interleukin-4 producing natural killer T cells is highly increased in peripheral blood, liver, spleen and thymus cells, as well as in the atherosclerotic plaque of the LPS-treated mice. Finally, an important adventitial infiltrate of activated lymphocytes, sign of an advanced atherosclerosis, is observed only in the LPS-treated mice. Our results demonstrate that LPS administration aggravates atherosclerosis in apoE-deficient mice. LPS-injected apoE-deficient mice appear to be an excellent animal model to analyze the implementation of new therapeutic approaches in the treatment of atherosclerosis by manipulating immunological effectors.
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PMID:Implication of natural killer T cells in atherosclerosis development during a LPS-induced chronic inflammation. 1202 12

Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) is the third most common cause of community-acquired pneumonia and is probably involved in the development of certain chronic inflammatory diseases, including atherosclerosis and adult-onset asthma. Histamine, synthesized by histidine decarboxylase (HDC) from L-histidine, plays an essential role in allergic and inflammatory processes and in cell differentiation. The effect of C. pneumoniae infection on the expression of HDC has not been examined. In the present study, normal Balb/c mice and HDC knockouts, and control mice with a CD1 background were infected intranasally with C. pneumoniae. On days 1, 3, 7, 16 and 31 after infection, the normal Balb/c mice were sacrificed and divided into three groups. In the homogenized lungs of the first group, C. pneumoniae titres were determined and demonstrated peak levels on day 7. HDC production was revealed by a Western blot assay throughout the observation period of 1-16 days, and cytokine concentrations were determined by ELISA. The interleukin-3 (IL-3) and interleukin-6 (IL-6) levels were highest on day 1 and on days 1-3, respectively; the interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels reached the maximum on day 7, but the quantity of IL-4 was still three times higher than that in the control group 16 days after infection. The lungs of the mice in the second group were processed for the in situ demonstration of HDC activity, while the lungs in the third group were stained for C. pneumoniae antigen. The HDC activity was increased predominantly in the bronchial epithelial cells, while C. pneumoniae antigens were expressed especially in the interstitial macrophages. The HDC knockout mice exhibited a higher survival rate after C. pneumoniae infection than did the control mice. These results point to a strong association between local histamine production and other inflammatory mediators and are novel in demonstrating the role of histamine in the pathomechanism of C. pneumoniae infections.
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PMID:Chlamydophila (Chlamydia) pneumoniae induces histidine decarboxylase production in the mouse lung. 1455 83

Interleukin-4 (IL-4)-mediated pro-oxidative and pro-inflammatory vascular environments have been implicated in the pathogenesis of atherosclerosis. The cellular and molecular regulatory mechanisms underlying this process, however, are not fully understood. In the present study, we employed GeneChip microarray analysis to investigate global gene expression patterns in human vascular endothelial cells after treatment with IL-4. Our results showed that mRNA levels of a total of 106 genes were significantly up-regulated and 41 genes significantly down-regulated with more than a 2-fold change. The majority of these genes are critically involved in the regulation of inflammatory responses, apoptosis, signal transduction, transcription factors, and metabolism; functions of the remaining genes are unknown. The changes in gene expression of selected genes related to inflammatory reactions, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6), were verified by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. IL-4 treatment also significantly increased the adherence of inflammatory cells to endothelial cell monolayers in a dose-dependent manner. These results may help determine the molecular mechanisms of action of IL-4 in human vascular endothelium. In addition, a better understanding of IL-4-induced vascular injury at the level of gene expression could lead to the identification of new therapeutic strategies for atherosclerosis.
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PMID:Gene expression profile in interleukin-4-stimulated human vascular endothelial cells. 1550 79

We report an adolescent girl with a history of angiolymphoid hyperplasia with eosinophilia (ALHE) diagnosed at the age of 10 years. The patient also suffered from chronic persistent multiresistant herpes simplex virus infection. Atherosclerotic occlusive disease of the abdominal aorta and its major branches was observed at the age of 17 years, necessitating vascular surgical intervention 1 year later because of disease progression. Histological examination of the aorta disclosed widespread atherosclerosis and high levels of gene expression of both T-helper cell type (Th) 1- and Th2-derived cytokines. This suggests that a highly stimulated systemic immune response including increased production of both Th1- and Th2-derived cytokines such as interferon-gamma and interleukin-4 may result in severe atherosclerotic lesions at a very young age. In addition, the patient developed a peripheral T-cell lymphoma at the age of 18 years. Neither systemic atherosclerosis nor T-cell lymphoma has been reported in association with ALHE. It is suggested that a highly stimulated dysfunctional immune response may play a key role in persistent inflammatory disease and premature development of atherosclerosis as well as malignant transformation of T cells.
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PMID:Severe atherosclerosis of the aorta and development of peripheral T-cell lymphoma in an adolescent with angiolymphoid hyperplasia with eosinophilia. 1588 66


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