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)

Oxidized derivatives of cholesterol, the oxysterols, have been implicated in the development of atherosclerosis. We have found that the oxysterol, 25-hydroxycholesterol (25OHC), is a potent stimulator of eicosanoid production in endothelial cells. Confluent monolayers of bovine coronary artery endothelial cells (BCAECs) were treated with 25OHC (10 micrograms/ml) or interleukin-1 beta (IL-1 beta, 1 ng/ml), a known prostaglandin G/H synthase-2 (PGHS-2) inducer, for 48 h at 37 degrees C. Following incubation with [14C]arachidonic acid, the 14C-labeled metabolites of arachidonic acid were extracted and resolved using both normal and reverse phase high-performance liquid chromatography (HPLC) systems. 25OHC-treated cells had a five-fold increase in their prostaglandin production when compared to untreated cells. Eicosanoid production in IL-1 beta treated cells was not as pronounced. The major component in both sets of cells comigrated with 6-ketoPGF1 alpha. Other PGHS metabolites, 15- and 11-hydroxyeicosatetraenoic acids (HETEs) and 12-hydroxyheptadecatrienoic acid (HHT) were also identified and increased following 25OHC treatment. Epoxyeicosatrienoic acids, metabolites of cytochrome P450, were not effected. Enhanced production of 6-ketoPGF1 alpha, 15-HETE, 11-HETE and HHT were inhibited by indomethacin. Thus, all eicosanoids induced by 25OHC treatment were PGHS products. Western immunoblot analysis of lysates from 25OHC, IL-1 beta, or vehicle treated cells using anti-PGHS-1 and -2 antibodies revealed a significant increase in PGHS-2, but not PGHS-1, in both 25OHC and IL-1 beta treated cells. The notion that oxysterols can modulate vascular eicosanoid production through enzyme induction may be important in ultimately understanding their role in the pathogenesis of atherosclerosis.
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PMID:25-Hydroxycholesterol enhances eicosanoid production in cultured bovine coronary artery endothelial cells by increasing prostaglandin G/H synthase-2. 908 8

The plasma level of fibrinogen is associated with the risk of ischaemic heart disease (IHD) and the severity of atherosclerosis. It has been suggested that an increased plasma level of fibrinogen is a coronary risk indicator because it reflects the inflammatory condition of the vascular wall. An inflamed vascular wall may increase the production of the cytokines interleukin 6 (IL6), interleukin 1-beta (IL1-beta), and tumour necrosis factor alpha(TNF-alpha), which have a major role in the regulation of synthesis in the liver of acute phase proteins, including fibrinogen. Smoking has also been reported to increase the levels of fibrinogen and C-reactive protein (CRP). This may indicate that smoking induces an inflammatory reaction, probably of the pulmonary bronchi and alveolae. Therefore, we anticipated that with both types of inflammation the levels of acute phase proteins and cytokines would be related. We have investigated the contribution of inflammation to the plasma levels of fibrinogen in 34 patients with severe coronary artery disease (CAD) and 30 healthy controls comparable for age and smoking habits. We did not find a parallel in the effects of smoking and ischaemic heart disease on the plasma levels of fibrinogen, CRP, IL6, IL1-beta and TNF-alpha. Cardiovascular disease had its most important effect on the plasma fibrinogen level, while smoking appeared to increase the CRP levels, while both CAD and smoking seemed to affect the IL6 levels. Our results indicate that both smoking and CAD induce an inflammatory condition but that the increase of plasma levels of different inflammatory markers is complex. Although the acute phase reaction is the main regulatory mechanism of fibrinogen, the increase of fibrinogen in our group of CAD patients could not be fully explained by increased inflammation.
Atherosclerosis 1996 Apr 05
PMID:Association of plasma fibrinogen levels with coronary artery disease, smoking and inflammatory markers. 912 93

Intimal thickening caused by accumulation of cells, lipids, and connective tissue characterizes atherosclerosis, an arterial disease that leads to cardiac and cerebral infarction. Apoptosis, or genetically programmed cell death, is important for the development and morphogenesis of organs and tissues. As in other tissues, cells of cardiovascular tissues can undergo apoptosis. Increased apoptosis has been found in both human and animal atherosclerotic lesions, mediating tissue turnover and lesion development. In addition to vascular cells, many activated immune cells, mainly macrophages and T cells, are present in atherosclerotic lesions, where these cells produce biologically active substances such as the proinflammatory cytokines tumor necrosis factor, interleukin-1 (IL-1), and interferon-gamma. Simultaneous exposure to these cytokines may trigger apoptosis of vascular smooth muscle cells. The products of death-regulating genes including Fas/Fas ligand, members of IL-1 beta cysteinyl protease (caspase) family, the tumor suppressive gene p53, and the protooncogene c-myc have been found in vascular cells and may participate in the regulation of vascular apoptosis during the development of atherosclerosis. Abnormal occurrence of apoptosis may take place in atherosclerotic lesions, including attenuation or acceleration of the apoptotic death process. The former may cause an increase in the cellularity of the lesions, and the latter can reduce cellular components important for maintaining the integrity and stability of the plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of patients with atherosclerosis and its major complications, heart attack and stroke.
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PMID:Regulation of programmed cell death or apoptosis in atherosclerosis. 947 49

Leukocyte-endothelial cell interactions, which are mediated by various adhesion molecules, are a crucial event in inflammatory reactions including atherosclerosis. alpha-tocopherol (alpha-Toc) has been used for therapy of vascular diseases because of its antioxidant activity. However, the effect of alpha-Toc on inflammatory reactions has not been investigated very well. In the present study, we examined the effect of alpha-Toc on expression of adhesion molecules on human neutrophils and human umbilical vein endothelial cells (HUVEC). Expression of CD11a, CD11b and CD18 on neutrophils was assessed by immunofluorescence flow cytometry 30 min after the stimulation of neutrophils with 10(-7) M platelet-activating factor (PAF). Surface expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on HUVEC was evaluated by enzyme immunoassay 8 h after the incubation of HUVEC with IL-1 beta (20 U/ml). PAF induced upregulation of CD11b and CD18 on neutrophils and IL-1 beta increased surface expression of ICAM-1 and VCAM-1 on HUVEC. Coincubation of neutrophils with alpha-Toc and pretreatment of HUVEC with alpha-Toc significantly reduced PAF-induced CD11b/CD18 expression and IL-1 beta-induced upregulation of ICAM-1 and VCAM-1, respectively. These findings indicate that alpha-Toc may work as an anti-inflammatory agent through inhibiting neutrophil-endothelial cell adhesive reactions.
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PMID:alpha-Tocopherol protects against expression of adhesion molecules on neutrophils and endothelial cells. 952 24

By extrapolation from the responses of cultured human umbilical vein endothelial cells (EC) and bovine aortic EC to short-term cytokine stimulation, EC activation is postulated as a likely component of the host response in acute allograft rejection and cardiac transplant-associated accelerated arteriosclerosis. To investigate the extent to which EC activation occurs in vivo in humans and to identify potential targets for therapeutic interventions, we compared the phenotypic characteristics of vascular EC as seen during clinicopathologically significant vs non-significant acute cardiac allograft rejection. We used monoclonal and monospecific polyclonal antibodies to coagulation molecules [tissue factor, thrombomodulin (TM), antithrombin III (AT-III), fibrinogen/fibrin, cross-linked fibrin and von Willebrand factor (vWF)], adhesion molecules (P-selectin, ICAM-1) and major histocompatibility complex (MHC) class I and II molecules. In addition we sought evidence of local cytokine production (IL-1, IL-2R, IL-4, IL-6, IL-7, IL-8, TNF-alpha, PDGF-AA, PDGF-BB), which might mediate alterations in expression of these proteins. We found that in clinically significant grades of cardiac allograft rejection requiring increased immunosuppression, in contrast to lesser grades of rejection not requiring clinical intervention, there was increased microvascular EC activation and differential expression of cytokines. EC changes associated with more extensive cardiac allograft rejection requiring treatment included: (i) disruption of the normal anticoagulant state with downregulation of TM and AT-III, upregulation of tissue factor and vWF expression, and associated extensive fibrin deposition; (ii) upregulation of MHC class I antigens, which are potential targets for host cytotoxic T lymphocytes; (iii) increased expression of the leucocyte adhesion molecules P-selectin and ICAM-1; (iv) expression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha; and (v) increased expression of PDGF-AA and BB, which are known to promote migration and proliferation of intimal cells, and hence may contribute to development of transplant-associated atherosclerosis. Collectively these findings suggest that immune events resulting in EC surface changes and/or production of key cytokines play a role in the pathogenesis of acute transplant rejection and may contribute to the long-term complication of accelerated arteriosclerosis in allograft coronary arteries.
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PMID:Endothelial activation and cytokine expression in human acute cardiac allograft rejection. 953 4

JE is a member of the family of "immediate early" genes induced by growth factors and cytokines. JE encodes a low molecular weight secretory glycoprotein analogous to the human monocyte chemoattractant protein, MCP-1. JE and MCP-1 proteins are thought to play an important role in inflammation and in the recruitment of monocyte/macrophages to the vessel wall during the development of atherosclerosis. We have previously reported that the induction of JE in rat aortic smooth muscle cells (SMC) was specific to platelet-derived growth factor (PDGF) and was not seen with other growth agonists. Using a luciferase reporter system and transient transfection assays of rat aortic SMC, we now report the identification of a region in the proximal rat JE promoter that is responsive to PDGF but not to other growth factors (angiotensin II and alpha-thrombin) or cytokines (interleukin 1-beta and tumor necrosis factor-alpha). The full response to PDGF (approximately 6-fold) requires the cooperative activity of two potentially novel cis-acting elements, at positions -146 to -128 and -84 to -59. While each element produces a different pattern in electrophoretic mobility shift assays, they appear to bind the same PDGF-responsive species. Further analysis of these regions should provide important insights into PDGF-specific responses in vascular SMC.
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PMID:Platelet-derived growth factor-specific regulation of the JE promoter in rat aortic smooth muscle cells. 973

Cardiovascular disease is the leading cause of morbidity and mortality in westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. Recently, we showed that supplementation with AT resulted in significant decreases in monocyte superoxide anion release, lipid oxidation, interleukin-1 beta (IL-1 beta) release, and adhesion to endothelium. The reduction in superoxide and lipid oxidation by AT seemed to be mediated by inhibition of protein kinase C. The aim of this study was to investigate the mechanism(s) by which AT inhibits IL-1 beta release. Potential mechanisms examined included its effect as an antioxidant and its inhibitory effects on protein kinase C and the cyclooxygenase-lipoxygenase pathways. Although AT decreased superoxide release from activated monocytes, superoxide dismutase and catalase had no effect on IL-1 beta release. Also, a similar antioxidant, beta-tocopherol, had no effect on IL-1 beta release. The protein kinase C inhibitor, bisindolylmaleimide, did not inhibit IL-1 beta release from activated monocytes, in spite of AT decreasing protein kinase C activity. Leukotriene B4, a major product of 5-lipoxygenase, has been shown to augment IL-1beta release. In the presence of AT, a significant reduction in leukotriene B4 and IL-1 beta levels was observed, which was reversed by the addition of leukotriene B4. Similar observations were seen with specific inhibitors of 5-lipoxygenase. The product of cyclooxygenase, prostaglandin E2, has been shown to inhibit IL-1 beta activity in some systems. However, AT had no significant effect on prostaglandin E2 levels in activated monocytes. In the presence of indomethacin, a cyclooxygenase inhibitor, AT inhibited IL-1 beta activity. Also, AT had no effect on IL-1 beta mRNA levels or stability, suggesting a posttranscriptional effect. Thus, in activated human monocytes, AT exerts a novel biological effect of inhibiting the release of the proinflammatory cytokine, IL-1 beta, via inhibition of the 5-lipoxygenase pathway.
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PMID:Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase. 1019 45

In the diabetic vascular complication, biochemical and mechanical injuries to endothelial cells are involved not only in the process of microangiopathy, but also in diabetic atherosclerosis (or arteriosclerosis) which is so-called macroangiopathy. In the presence of diabetes or persistent hyperglycemia, many cytokines including growth factors such as PDGF, HB-EGF, IL-1 beta and TNF alpha are upregulated in intimal cells of the arterial or aortic wall. These changes alter the cytokine network in the common mechanism of atherosclerosis, "Response-to-injury hypothesis", and further accelerate the formation of atherosclerotic lesion. In addition, diabetes causes abnormal responsibility to HB-EGF, PDGF and TGF-beta in medial smooth muscle cells leading to the elevated activity to their proliferation and migration into the intima. Thus, all cell types consisting arterial or aortic wall are involved in the process of diabetic atherosclerosis.
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PMID:[Mechanism of atherosclerosis in diabetes: altered cytokine network in the vascular wall]. 1019 40

Endothelial cells (ECs) and smooth muscle cells (SMCs), which are the major component cells of blood vessels, produce various bioactive substances and communicate with each other through them. Although several studies of the interaction between ECs and SMCs have been reported, the effect of coculture with SMCs on ECs is still obscure. To clarify the interaction of ECs and SMCs, we examined the effect of coculture with SMCs on the proliferation, the IL-1 beta secretion, the PDGF production and tube formation of ECs, using the coculture model: transferable wells and collagen gel. IL-1 and PDGF are considered to be related to progression of atherosclerosis. Proliferation and tube formation of ECs are associated with repair of vessels. In the transferable well system coculture with SMCs stimulated the proliferation of ECs, and enhanced the IL-1 beta secretion of ECs and in the collagen gel system coculture with SMCs induced the tube formation of ECs, and appeared to enhance the PDGF production of ECs. In conclusion, the effect of coculture with SMCs on ECs has two conflicting aspects: progression of atheroscleosis and angiogenesis. These results suggest that an imbalance of their effects may lead to pathological events.
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PMID:The effect of coculture with human smooth muscle cells on the proliferation, the IL-1 beta secretion, the PDGF production and tube formation of human aortic endothelial cells. 1037 58

Inflammatory mechanisms play a central role in the pathology of a variety of conditions ranging from atherosclerosis, arthritis, cancer and Alzheimer's disease. Under normal conditions the inflammatory response initiates protective actions, but triggers tissue damage under pathological conditions. Acute or chronic inflammation is mediated by nascent expression of a host of proteins such as the cytokines interleukins (IL), tumor necrosis factor (TNF), and interferons. Currently available in vitro or in vivo methods do not offer the specificity to probe the complex inflammatory cascade. We developed an animal model in which a single injection of the proinflammatory cytokines TNF-alpha and IL-1 beta in live rodents initiates a rapid inflammatory reaction which can be monitored by video microscopy and electron microscopy. This model exhibits the characteristic feature of inflammatory reaction such as adhesion and transmigration of leukocytes, and activation and degranulation of platelets and mast cells. This model is applicable to inflammatory processes in the peripheral and cerebral vasculature including the blood-brain barrier disruption in Alzheimer's disease. The animal model of inflammation reported here may prove to be a valuable tool in investigating the pathophysiology of a number of inflammatory diseases and identifying potential targets as well as agents for therapy.
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PMID:Animal model of vascular inflammation. 1062 99


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