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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The balance between prostaglandin (PG)I2, a potent vasodilator and inhibitor of platelet aggregation mainly produced by endothelial cells, and thromboxane (TX)A2, a vasoconstrictor and inducer of platelet aggregation and adhesion synthesized predominantly by platelets, seems to be relevant for the regulation of vessel tone and platelet aggregation. PGE2 has vasodilating properties, too. Thus, substances affecting the biosynthesis of PG and TX may have prophylactic and therapeutic, but also detrimental effects with regard to hypertension and atherosclerosis. A mechanism of action which is related to the PG system is discussed for a number of antihypertensive agents, e.g. propranolol, angiotensin converting enzyme inhibitors, furosemide and cicletanine. The vasoprotective effect of inhibition of platelet cyclooxygenase by acetylsalicylic acid is well known. Calcium antagonists, dipyridamole, estradiol, aprotinin and interferon have also been reported to possibly exert beneficial effects on PG/TX levels, while cyclosporin A and streptokinase have shown undesirable interactions with the PG system.
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PMID:[Vasoactive drugs with an effect on the prostaglandin system]. 141 11

Biosynthesis of apolipoprotein (apo) E has been previously demonstrated to be regulated in macrophages by intracellular free cholesterol levels as well as by macrophage activating factors. In this report, the regulation of apo E secretion by cytokines detected within atherosclerotic lesions has been investigated. Granulocyte macrophage-colony stimulating factor (GM-CSF) stimulated macrophages had a 3-5-fold reduction in apo E secretion, comparable to that observed for gamma interferon (IFN gamma), while tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) resulted in a 2-fold decrease. In contrast to the reduction in apo E secretion by these cytokines, transforming growth factor beta (TGF-beta) stimulated macrophages secreted 3-fold greater amounts of apo E than controls. The reduced secretion of apo E by GM-CSF was reversible, heat labile, dose dependent, maximal 48 h after cytokine exposure and was coincident with an increase in fibronectin secretion. The opposing effects of GM-CSF and TGF-beta on apo E secretion were consistent with similar changes detected in apo E mRNA levels. Cytokine effects on apo E secretion in cholesterol loaded macrophages were also investigated and found to be similar to the non-loaded cells with GM-CSF decreasing and TGF-beta increasing apo E secretion. The observed differences in apo E secretion did not correlate with any significant changes in either cellular cholesterol distribution in the non-cholesterol loaded macrophages or in basal ACAT activity. In addition to changes in apo E secretion, cytokine treated macrophages pulsed with [14C]oleate and acetylated LDL for 2-6 h had a 2-fold increase (GM-CSF) or decrease (TGF-beta) in cholesterol esterification. Therefore, GM-CSF and TGF-beta mediated changes in apo E secretion may occur through a mechanism independent of changes in cellular free cholesterol levels. These results suggest that cytokines expressed within an atheroma may play an important role in the modulation of macrophage mediated reverse cholesterol transport.
Atherosclerosis 1992 Oct
PMID:Cytokine regulation of macrophage apo E secretion: opposing effects of GM-CSF and TGF-beta. 146 52

Cardiac allograft vasculopathy (accelerated transplant atherosclerosis) is considered by most to involve a chronic allogeneic immune response to one or more constituents in the coronary vascular wall. Recent evidence suggests that there is an association between cytomegalovirus infection and the development of cardiac allograft vasculopathy (CAV). To determine whether CMV directly infects and/or potentially influences immunogenicity of vascular tissue, human umbilical vein (HU-VECs) or human aortic (HAECs) endothelial cells and human aortic smooth muscle cells (HASMCs) were isolated, cultured, and infected with CMV strain AD 169. Infection was detected using an immunoperoxidase-labeled monoclonal antibody to CMV immediate-early antigen (L-14). The presence and relative quantity of MHC class I and II antigens were determined flow cytometrically using monoclonal antibodies to monomorphic class I and class II HLA determinants. Gamma interferon was used as a positive control stimulant for the upregulation of MHC determinants. Both pooled HUVECs as well as 2 cell lines of HAECs served as targets for CMV infection though less than 10% of the cells were infected despite inocula of 10 pfu/cell. Infection of the pooled HUVECs resulted in no significant changes in the cell surface density of either MHC class I or II determinants. In contrast, HASMCs were excellent targets for CMV infection with virtually 100% of cells infected. CMV infection of 2 distinct HASMC cultures resulted in an increase of 254 +/- 158 relative fluorescence units (RFUs) in MHC class I antigen expression, as assessed by fluorescence intensity, in a variable portion of the HASMCs. A second population of cells exhibited a decrease of 73 +/- 16 RFUs in MHC class I antigen expression. No significant change in MHC class II antigen expression was noted. These results demonstrate that while HUVECs and HAECs are targets of CMV infection, human aortic smooth muscle cells can more readily be infected by CMV. Furthermore, CMV can regulate smooth muscle cell MHC class I expression, hence potentially altering immunogenicity. A pathophysiologic link between cardiac allograft vasculopathy and CMV disease can therefore be hypothesized.
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PMID:Cytomegalovirus-induced regulation of major histocompatibility complex class I antigen expression in human aortic smooth muscle cells. 165 93

The effectiveness of rabbit interferon in suppressing atherosclerosis was evaluated in rabbits fed a diet containing 1% cholesterol. Ten male New Zealand White rabbits received intramuscular injections of 1 million units of interferon twice a week, while a control group of 10 rabbits received injections of buffer. Both groups had average serum cholesterol levels of over 2000 mg/dl during the 8-week experimental period. Interferon treatment resulted in no significant hypolipidemic effect or changes in lipoprotein composition. Atherosclerotic lesions in aortas were quantified both macroscopically and microscopically. Interferon treatment decreased the grossly visible lesion area significantly from 25 +/- 4% to 8 +/- 1% (mean +/- SEM, p less than 0.005) compared to the untreated group. Microscopic analysis of serial cross-sections of aortic segments revealed significant (p less than 0.01) reductions in both lesion size and frequency in the interferon-treated group. Electron microscopy also showed that interferon treatment reduced the pathological effects of cholesterol feeding. Tissue analysis showed that total aortic cholesterol was reduced by 28% by interferon treatment, while the aortic phospholipid concentration was increased by 25%. The possibility exists that the interferon preparation used contained other biological response modifiers and that the observed effects may be totally unrelated with interferon. These results suggest that the mechanism of atherosclerosis suppression in these cholesterol-fed rabbits is not related to the lowering of serum cholesterol but may be associated with inhibition of lesion initiation.
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PMID:Suppression of aortic atherosclerosis in cholesterol-fed rabbits by purified rabbit interferon. 169 May 36

Cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and gamma-interferon (IF) are produced by activated hematopoietic cells. They possess antiviral activity and have other biological activities such as induction of cell proliferation and hemorrhagic necrosis of tumors. Since herpes simplex virus (HSV) infection of human vascular cells is known to produce a biochemical and cytopathological effect virtually indistinguishable from atherosclerosis, we hypothesized that these cytokines many prevent cholesteryl ester (CE) accumulation in arterial smooth muscle cells (SMC) that is seen with herpesvirus infection. We now report that TNF and IL-1 but not gamma-IF prevent CE accumulation in HSV-infected arterial SMC by induction of cyclic AMP-dependent CE hydrolysis. This effect is mediated through the arachidonate 12-lipoxygenase pathway via 12-HETE since pretreatment of cells with several lipoxygenase inhibitors abolishes the antiviral effect and 12-HETE is the major (greater than 99%) lipoxygenase metabolite produced by these cells. This conclusion is further based on our observations that TNF and IL-1 enhance 12-HETE production in SMC and that 12-HETE significantly increases both intracellular cyclic AMP and lysosomal CE hydrolysis. Moreover, dibutyryl cyclic AMP restored a normal phenotype in these virally infected cells. Collectively, these findings identify for the first time a biochemical mechanism involved in the reduction of lipid accumulation in virally infected arterial SMC by these potent cytokines.
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PMID:Evidence for cytokine regulation of cholesterol metabolism in herpesvirus-infected arterial cells by the lipoxygenase pathway. 210 32

Macrophages are important cells in the pathogenesis of atherosclerosis because of their tendency to accumulate lipid and become transformed into foam cells. Cultured human monocyte-derived macrophages spontaneously secrete lipoprotein lipase (LPL), and LPL has been linked to increased lipid uptake by these cells. Because secretion of various macrophage products depends on activation by lymphokines, we studied the effects of immunoregulatory lymphokines on LPL secretion by cultured human macrophages. After culturing cells in RPMI 1640 medium with 20% fetal calf serum, recombinant human gamma-interferon (gamma-INF), interleukin-1 (IL-1), and interleukin-2 (IL-2) were added to the medium and LPL secretion was assessed by measuring LPL activity and/or LPL mass in the medium. Gamma-INF suppressed LPL production both when added to freshly plated cultures of human blood monocytes, as well as when added to monocyte/macrophages from mature cultures (day 6) that were producing large amounts of LPL. IL-1 inhibited medium LPL when added to freshly plated cultures, but not when added to mature cultures. On the other hand, IL-2 did not inhibit LPL in freshly plated cultures, but produced a dose-dependent suppression of LPL from mature cultures. None of the cytokines were cytotoxic to macrophages, and cells that were cultured in gamma-INF demonstrated partial recovery from LPL-suppressive doses of the cytokine. After exposure of cells to 50 U/ml of gamma-INF and 50 U/ml of IL-2 for 3 days, LPL mRNA levels, when expressed as LPL/gamma-actin ratios, were 42% and 53% of controls, respectively. Thus, activation of human macrophages in vitro by gamma-INF resulted in a suppression of LPL production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of cytokines on the production of lipoprotein lipase in cultured human macrophages. 212 74

There is evidence that fatty streaks in arteries can transform into atherosclerotic plaques. Mononuclear cells, including both monocytes and lymphocytes, are among the first cells participating in the development of atherosclerosis of experimental animals. To investigate the roles of different cell types in human atherosclerosis, we enumerated and compared the cellular compositions of normal intima, the transition zone (the area between the normal intima and the core of fatty streaks), fatty streaks, and plaques in young (age 16-30 years) and aged (over 60 years) human specimens using double-staining immunofluorescence with a series of monoclonal and polyclonal antibodies. T lymphocytes, both T helper/inducer (70% of T cells) and T suppressor/cytotoxic (30%) phenotypes, were found in every stage of atherosclerosis, constituting 30 to 40% of total cells in fatty streaks and transition zones of young subjects, and occasionally even in normal intima. Seventy percent of these T cells were HLA-DR positive, which indicated that most of them were activated. Macrophages were most frequent in fatty streaks and around the necrotic core of plaques. Smooth muscle cells, increasing from 5 to 30% with lesion progression, were HLA-DR positive where activated T helper cells occurred in the vicinity. The intracellular presence of the invariant gamma chain confirmed that HLA-DR was actually synthesized by these smooth muscle cells. Endothelial cells were HLA-DR positive above those regions of the lesions where HLA-DR-positive cells had accumulated, but not in normal intima, again suggesting induction of HLA-DR expression by T-cell-derived gamma-interferon. Furthermore, most HLA-DR-positive cells were also identified as HLA-DP and HLA-DQ positive. This aberrant major histocompatibility complex class II antigen expression in smooth muscle and endothelial cells may participate in the perpetuation of the atherogenetic autoimmune reaction.
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PMID:Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. 220 32

Monocytes and endothelial cell interactions play a key role in the development of vascular lesion, inflammation and atherosclerosis. Leukocyte adhesion is mediated through specific molecules CD11/CD18 complexes on the leukocyte side and the ELAM (Leukocyte Adhesion Molecule) ICAM (Intercellular Adhesion Molecule) on the endothelium cell surface. Several monocyte products damage endothelial cells such as free radicals, oxygen peroxides, proteases, hydrolases, lipases... Various monokines alter endothelial cell function and proliferation. Interleukin 1, gamma interferon, alpha tumor necrosis factor increase ELAM, further more they induce the synthesis of procoagulant activity by endothelial cells. Monocyte derived growth factor stimulates endothelial cells proliferation while transforming growth factors, beta (TGF beta) and TNF alpha inhibit endothelial cell growth. Lipid products of monocyte origins such as leukotrienes induce an activation of endothelial cells which results in a production of prostacyclin. Monocytes may also participate in the coagulation process by producing thromboplastin and coagulation factors and facilitating the tenase (activation of factor X) complex formation. On the other hand, monocyte also synthesize tissue plasminogen activator and inhibitor. The numerous factor produced by monocytes may affect in different ways the endothelial cell behavior.
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PMID:[Monocyte-endothelium relations]. 265 10

The effects of two chemically different interferon inducers on the suppression of atherosclerosis were studied in rabbits fed an atherogenic chow diet. One group (10 rabbits per group) was fed normal rabbit chow, and three groups were fed an atherogenic chow. One of the latter groups received the atherogenic feeding alone; the other two were treated with either polyinosinic-polycytidylic acid (poly I:C) or 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP). Neither of the drugs reduced significantly the hypercholesterolemia induced by the feeding. However, both poly I:C and ABPP treatment significantly reduced the percent area of the aortic intimal surface lesions, stained for lipid with Sudan IV, compared with that in untreated rabbits fed atherogenic chow. Microscopic sections of typical aortic plaques showed that both drug treatments significantly reduced the size and number of intimal lipid deposits compared with those observed in the aortas of untreated animals. Chemical analysis for cholesterol and collagen content revealed that interferon-inducing agents significantly reduced cholesterol deposits in the aorta, with little effect on fibrous protein deposition. The results indicate that two unrelated interferon-inducing drugs suppressed atherogenesis without reducing serum cholesterol and low density lipoprotein levels. Whether the protection against atherosclerosis is exerted by endogenous interferon production remains to be determined.
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PMID:Suppression of experimental atherosclerosis in rabbits by interferon-inducing agents. 619 32

Atherosclerotic lesions in the coronary arteries of transplanted mouse hearts manifest high expression of ICAM-1 (CD54), especially on endothelial surfaces, and of LFA-1 (CD11a) on migratory mononuclear cells. The possible participation of cellular adhesion systems in the evolution of these complex lesions was suggested by the increased expression of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1 (LFA-1) and also by our previous studies with this experimental system. In our studies, we have found that administration of a monoclonal antibody (mAb) to gamma-interferon will greatly suppress coronary changes, and gamma-interferon is known to stimulate the formation of these adhesion molecules. The present experiments were to evaluate how administration to murine heart transplant recipients of mAbs against ICAM-1, LFA-1, or both affected the development of coronary atherosclerosis. It was found that treatment with either mAb alone did not alter the severity of coronary atherosclerosis, but that both mAbs given together can significantly suppress lesion formation at 30 days compared with controls (P < 0.044). Continuing treatment was even more effective when extended to 60 days (P < 0.003). The mAbs to ICAM-1 and LFA-1 bound their targets in vivo (primarily endothelium and mononuclear cells, respectively), but complete, long-term saturation of combining sites was not attained, even with very high doses. No appreciable reduction in arterial endothelial ICAM-1 expression was evident. It is concluded that the ICAM-1/LFA-1 system is of central importance in the evolution of accelerated coronary atherosclerosis.
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PMID:Coronary atherosclerosis in transplanted mouse hearts. IV Effects of treatment with monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte function-associated antigen-1. 757 Sep 84


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