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)

Immunological mechanisms play an important role in the pathogenesis of atherosclerosis and atherosclerotic abdominal aortic aneurysms (AAA). Inflammatory leukocytes invade the vessel wall and produce cytokines which perpetuate the immune events underlying these diseases. Interleukin (IL)-1 beta, IL-8, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1, among others, may play a role in the generation by AAA. The aim of this study was to investigate the possible pathogenetic role of other proinflammatory cytokines, namely IL-2, IL-4, IL-6, and interferon (IFN)-gamma. Enzyme-linked immunosorbent assay of human explant culture supernatants revealed a significant increase in IFN-gamma production by AAA compared to occlusive (atherosclerotic) or normal (NL) aortic explants. IL-6 production was also increased in AAA compared to NL aortic explant supernatants. Neither AAA nor NL aortic tissues produced IL-2 or IL-4 in the same culture system. These results suggest that IL-6, a cytokine involved in T and B lymphocyte activation during inflammation, and IFN-gamma, which stimulates T and B lymphocytes, macrophages, endothelial cells and fibroblasts, may play a role in the pathogenesis of various vascular inflammatory diseases such as AAA.
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PMID:Human atherosclerotic abdominal aortic aneurysms produce interleukin (IL)-6 and interferon-gamma but not IL-2 and IL-4: the possible role for IL-6 and interferon-gamma in vascular inflammation. 787 3

The intercellular adhesion of circulating leukocytes to vascular endothelium is a prerequisite for leukocyte emigration from the blood to extravascular tissues. This process is facilitated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Both cultures contained similar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectively). Adhesion molecule expression was up-regulated by interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were more sensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expression were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke.
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PMID:Adhesion molecules on normotensive and hypertensive rat brain endothelial cells. 790 12

Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion molecules, enhances cytokine production, and induces tissue factor procoagulant activity. In the present study, we have examined the relative roles of the two cell surface receptors for TNF-alpha (p55 and p75) on endothelial cells, using antibodies with both agonistic and antagonistic activities. We report that anti-p55 receptor agonistic antibody Htr-9 induces the expression of tissue factor antigen and the release of interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In contrast, there is very little or no activation of endothelial cell responses by an anti-p75 agonist. TNF-alpha-induced expression of tissue factor and adhesion molecules, and release of IL-8 and GM-CSF, are decreased by antibodies with antagonistic activities for either receptor, although the effect of anti-p55 antibodies is markedly greater than that of anti-p75 antibodies. The responses of endothelial cells to lymphotoxin/TNF-beta are significantly decreased by anti-p55 antagonists alone. Our data suggest that endothelial cell responses to TNF-alpha, such as expression of tissue factor and adhesion molecules for mononuclear cells, which may be important in the pathogenesis of atherosclerosis, are mediated predominantly, but not exclusively, by the p55 TNF receptor.
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PMID:Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells. 791 75

Atherosclerosis is characterized by cholesterol accumulation, inflammation, and fibrous tissue formation. We have analyzed inflammatory components of atherosclerotic plaques and obtained evidence for T lymphocyte activation and cytokine secretion. A molecular genetical characterization of T cell clones obtained from atherosclerotic lesions revealed that the cells are heterogeneous with regard to antigen receptor gene organization. This indicates that they are derived from several progenitors and respond to different antigenic epitopes. The latter are not yet known, and it is also unclear to what extent the lymphocytic infiltrate in plaques represent a local immune response. Vascular effects of cytokines produced by plaque macrophages and lymphocytes were studied in cell culture and animal experiments. It was found that the T cell cytokine, interferon-gamma, inhibits cholesterol accumulation and foam cell formation by down-regulating the scavenger receptor on macrophages. It also inhibits smooth muscle proliferation in culture and the formation of arterial restenosis after angioplasty in experimental animals. Together, these studies emphasize the importance of vascular-immune interactions in the pathogenesis of atherosclerosis.
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PMID:Immunological control mechanisms in plaque formation. 794 75

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.
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PMID:Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. 796 80

We previously reported that follistatin, an activin-binding protein, is produced in arteriosclerotic lesions. Here, the expression of activin-A which promotes the growth of vascular smooth muscle cells was examined in arteriosclerotic lesions of WHHL (Watanabe heritable hyperlipidemic) rabbits. Activin-A mRNA was detected in normal aorta by reverse transcriptase-polymerase chain reaction using specific primers for activin-A cDNA and was increased remarkably in arteriosclerotic lesions. In addition, using the cloned rabbit activin-A cDNA, RNA probe was prepared and in situ hybridization histochemistry was performed. Activin-A transcripts were detected abundantly in neointima of the diseased artery. Furthermore, immunohistochemistry also detected activin-A at the protein level. These observations suggest that activin-A is a cytokine expressed in arteriosclerotic lesions and might be involved in the pathogenesis of atherosclerosis.
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PMID:Demonstration of activin-A in arteriosclerotic lesions. 799 62

Mounting evidence suggests that oxidative processes contribute to the pathogenesis of atherosclerosis and that antioxidants may represent a strategy to complement the lowering of lipids in the therapy of this disease. Although multiple molecular events have been identified in vitro and although it is tempting to ascribe multiple atherogenic properties to oxidized LDL, our understanding of this process remains incomplete. Further research is warranted in several areas. First, it will be important to selectively inhibit different aspects of the process to determine the relative contribution of various biological targets. In this regard pharmacological inhibition of 15-lipoxygenase in vivo in relevant animal models is required to address the question of the contribution of this enzyme to significant oxidative events. The lack of specific inhibitors has made this task more difficult. It will also be important to define the biologically active moiety of oxidized LDL to begin to determine the mechanisms through which it exerts its atherogenic effects. It is likely that alternate protein targets can be identified both downstream and upstream of the oxidative process. Research is only now beginning to elucidate the inflammatory mechanisms that account for the cellular response. Further research into adhesion events, cytokine profiles, and downstream effector molecules of the oxidative process are likely to identify alternate targets for therapeutic intervention.
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PMID:Oxidation, lipoxygenase, and atherogenesis. 801 70

Direct gene transfer has been used to develop molecular genetic interventions for acquired diseases in several animal models. Through the use of intravascular catheters or anatomically localized injection of DNA liposome complexes, specific tissues can be transduced with recombinant genes. Several promising applications of this method for the study of vascular biology have been demonstrated by direct gene transfer into arteries in vivo. Delivery, via catheter, of genes that modulate the thrombogenic or proliferative properties of vascular cells may someday provide therapy for stenotic lesions of atherosclerosis or following angioplasty. Cancer is another acquired disorder in which direct gene transfer may improve the efficacy of treatment. Introduction of class I MHC or cytokine genes with antitumor or immunostimulatory effects have demonstrated promise in animal models. Direct transfer of an allogeneic class I MHC gene into tumors in vivo induces a CD8+ CTL response against weak antigens on poorly immunogenic tumors. The efficacy of this antitumor response can be augmented to induce regression of actively growing established tumors. Additional strategies, such as intratumoral delivery of combinations of multiple cytokine and MHC genes, may serve to improve the antitumor response. A clinical gene therapy protocol is underway to analyze the safety and efficacy of DNA liposome-mediated gene transfer in humans. Development of improved gene delivery systems and introduction of recombinant genes into visceral tumors by intravascular catheter will extend the application of direct gene transfer to immunotherapy of malignancies. These clinical trials of direct gene transfer will help to develop new treatment strategies for human diseases.
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PMID:Direct gene transfer for the understanding and treatment of human disease. 802 91

Research in recent years has resulted in an increased understanding of the molecular mechanisms in the development of inflammatory processes. In atherosclerosis, focal expression of key adhesion molecules has been detected which may mediate the recruitment of mononuclear cells to the plaque. Local cytokine production could account for further cell migration and proliferation. The presence of substantial numbers of T lymphocytes in the plaque and local and circulating autoantibodies to modified lipoproteins suggest that T and B lymphocyte responses may play important roles in these processes.
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PMID:Immune mechanisms in atherogenesis. 807 32

The vascular endothelium plays an active role in physiological processes such as hemostasis, regulation of vessel tone and vascular permeability. Cell injury, or any event which disrupts endothelial integrity and thus endothelial permeability properties, may be involved in the early events leading to atherosclerotic lesion formation. Because of its constant exposure to blood components, including prooxidants, diet-derived fats and their derivatives, the endothelium is susceptible to oxidative stress and to injury mediated by blood lipid components. It is likely that these events potentiate the overall inflammatory response to injury by increasing cytokine release in proximity to the endothelium, which then could further disrupt endothelial barrier function. Even though mechanisms associated with lipid/cytokine-mediated endothelial cell dysfunction are unclear, our data suggest that they may be both oxidative and non-oxidative in nature. We suggest that dietary fats, rich in certain unsaturated fatty acids are atherogenic by enhancing the formation of reactive oxygen intermediates. These intermediates can activate oxidative stress-responsive transcription factors, such as NF-kappa B, which in turn may promote cytokine production, adhesion molecule expression and ultimately endothelial barrier dysfunction. The resulting disturbances in endothelial integrity possibly allow increased penetration of cholesterol-rich lipoprotein remnants into the arterial wall, a critical event in the etiology of atherosclerosis. Data suggest that certain nutrients, which have antioxidant and/or membrane stabilizing properties, protect endothelial cells by interfering with the above proposed mechanisms of endothelial cell dysfunction.
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PMID:Influence of nutrients and cytokines on endothelial cell metabolism. 807 69


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