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

Colony stimulating factors belong to a family of cytokines that regulate proliferation in macrophages and other vascular cell types. They have been implicated in the inflammatory-fibroproliferative response of atherosclerosis. The present study was undertaken to assess the effect of granulocyte-macrophage and macrophage colony stimulating factors on the transcription of type VIII collagen by vascular smooth muscle cells and their potential relevance for the expression of collagen in atherosclerotic lesions. The influence of colony stimulating factors was studied in relation to transforming growth factor beta1, the factor exhibiting the most potent effect on collagen metabolism. Northern blot experiments showed that treatment with both colony stimulating factors and transforming growth factor beta1 transiently stimulated the transcription of type VIII collagen mRNA. Maximal levels were reached after 2 h and 100 pg/ml granulocyte macrophage colony stimulating factor (4-fold), 1 U/ml macrophage colony stimulating factor (4.6-fold) and 1 ng/ml transforming growth factor beta1 (1.6-fold). While overnight treatment with colony stimulating factors stimulated the expression of transforming growth factor beta1 mRNA, short incubations did not influence or downregulate the transcription. In turn, treatment with transforming growth factor beta1 reduced the expression of granulocyte-macrophage and macrophage colony stimulating factor mRNA. The in vitro mRNA expression patterns were directly reflected in the distribution patterns found in intimal thickenings and advanced atherosclerotic lesions. This study demonstrates that colony stimulating factors and transforming growth factor beta1 modulate the transcription of type VIII collagen in vitro. Our data indicate a direct mechanism and exclude a pathway, which is mediated via the stimulation of transforming growth factor beta1 transcription. Our studies further support the hypothesis that colony stimulating factors in concert with transforming growth factor beta1 affect the collagenous composition of the extracellular vascular matrix.
Atherosclerosis 1999 May
PMID:Colony stimulating factors modulate the transcription of type VIII collagen in vascular smooth muscle cells. 1038 Dec 74

Glucocorticoid, an anti-inflammatory agent, inhibits the development of atherosclerosis in various experimental animal models. This is partially explained by its ability to inhibit smooth muscle cell migration and proliferation in the intima and to reduce chemotaxis of circulating monocytes and leukocytes into the subendothelial spaces. We have recently demonstrated that oxidized LDL (Ox-LDL) has a mitogenic activity for macrophages in vitro in which Ox-LDL-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) production plays an important role. Proliferation of cellular components is one of the characteristic events in the development and progression of atherosclerotic lesions. In the present study, we investigated the effects of glucocorticoids on Ox-LDL-induced macrophage growth. Dexamethasone, prednisolone, and cortisol inhibited Ox-LDL-induced thymidine incorporation into macrophages by 85%, 70%, and 50%, respectively. Ox-LDL induced a significant production of GM-CSF by macrophages, which was effectively inhibited by dexamethasone, prednisolone, and cortisol by 80%, 65%, and 50%, respectively. Dexamethasone-mediated inhibition of Ox-LDL-induced GM-CSF mRNA expression and macrophage growth was significantly abrogated by RU-486, a glucocorticoid receptor antagonist. Our results suggest that the inhibitory effects of glucocorticoids on macrophage growth may be due to the inhibition of Ox-LDL-induced GM-CSF production through transactivation of the glucocorticoid receptor.
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PMID:Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor. 1039 91

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

Free radicals which are produced constantly in the human body have a significant role in the development of atherosclerosis. The responsibility of leukocytes for vascular disease has been proved in several ways. Hormonally active women are protected much more against myocardial infarction than men, which fact can be explained partly by endocrinological reasons, too. The authors have set the aim to investigate whether estrogen therapy effects on the one hand the intracellular activity of the granulocyte-enzyme, myeloperoxidase (MPO), which takes place in free radical reactions and on the other hand the amount of MPO released from neutrophils. In the case of women having menopause and being treated with hormone replacement (n = 11) the intracellular activity and the amount of MPO-release increased significantly as compared to the level at the time of starting taking the medicine (p < 0.001). Based on the results it can be supposed that the vasoprotective effect of estrogens is fulfilled through their influence on the MPO enzyme, too. Besides the fact that intensified MPO activity through enhanced consumption might induce the decreased accumulation of H2O2 (a reactive oxygen species, substrate of MPO), MPO also has a role in the termination of the whole process of free radical production in granulocytes by the inactivation of the NADPH-oxidase system. This means that the growing intracellular MPO activity and the increased amount of enzyme released induce the decrease of the amount of free radicals produced during the "respiratory burst" and this is advantageous from the point of view of vasoprotection. The increased MPO activity and the NADPH-oxidase inactivation supposed to be elicited by it, might have further positive consequences since MPO has an effect on HDL-metabolism and the outflow of cholesterol from "foam cells", NADPH-oxidase has a suspected role in LDL-oxidation and NADPH is one of the cofactors of NO-synthase (NOS). The decreased superoxide anion level on the other hand may mitigate the chance of the neutralizing of nitric oxide (NO) by it. The superoxide anion is a potent vasoconstrictor and therefore, its diminished production may be beneficial, i.e. decreases the risk of coronary spasm. The new conceptual synthesis worked out by the authors may provide a possible explanation of the increased susceptibility to infections during steroid treatment, too.
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PMID:[Changes in the myeloperoxidase activity of human neutrophilic granulocytes and the amount of enzyme deriving from them under the effect of estrogen]. 1044 40

Inflammatory process plays an important role in the development and progression of atherosclerotic lesions. Recently, group-II phospholipase A(2) (PLA(2)), an inflammatory mediator, was reported to exist in human atherosclerotic lesions and to enhance the development of murine atherosclerotic lesions. Oxidized low density lipoprotein (Ox-LDL) stimulates the growth of several types of macrophages in vitro. Since proliferation of macrophages occurs in atherosclerotic lesions, it is possible to assume that the Ox-LDL-induced macrophage proliferation might be involved in the progression of atherosclerosis. In this study, the role of group-II PLA(2) in the Ox-LDL-induced macrophage growth was investigated using thioglycollate-elicited mouse peritoneal macrophages. Thioglycollate-elicited macrophages significantly expressed group-II PLA(2) and released it into the culture medium. The Ox-LDL-induced thymidine incorporation into thioglycollate-elicited macrophages was three times higher than that into resident macrophages, whereas under the same conditions, granulocyte/macrophage colony-stimulating factor (GM-CSF) equally induced thymidine incorporation into both types of macrophages. Moreover, the Ox-LDL-induced GM-CSF release from thioglycollate-elicited macrophages was significantly higher than that from resident macrophages. In addition, the Ox-LDL-induced thymidine incorporation into macrophages obtained from human group-II PLA(2) transgenic mice and the GM-CSF release from these cells were significantly higher than those from their negative littermates, and the Ox-LDL-induced thymidine incorporation into human group-II PLA(2) transgenic macrophages was significantly inhibited by a polyclonal anti-human group-II PLA(2) antibody. These results suggest that the expression of group-II PLA(2) in thioglycollate-elicited macrophages may play an enhancing role in the Ox-LDL-induced macrophage growth through the enhancement of the GM-CSF release.
Atherosclerosis 2000 Nov
PMID:Group-II phospholipase A(2) enhances oxidized low density lipoprotein-induced macrophage growth through enhancement of GM-CSF release. 1105 98

Inflammation and oxidative stress contribute to the pathogenesis of many human diseases including atherosclerosis. Advanced human atheroma contains high levels of the enzyme myeloperoxidase that produces the pro-oxidant species, hypochlorous acid (HOCl). This study documents increased numbers of myeloperoxidase-expressing macrophages in eroded or ruptured plaques causing acute coronary syndromes. In contrast, macrophages in human fatty streaks contain little or no myeloperoxidase. Granulocyte macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, selectively regulates the ability of macrophages to express myeloperoxidase and produce HOCl in vitro. Moreover, myeloperoxidase-positive macrophages in plaques co-localized with granulocyte macrophage colony-stimulating factor. Pro-inflammatory stimuli known to be present in human atherosclerotic plaque, including CD40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of myeloperoxidase from HOCl production by macrophages in vitro. HOCl-modified proteins accumulated at ruptured or eroded sites of human coronary atheroma. These results identify granulocyte macrophage colony-stimulating factor as an endogenous regulator of macrophage myeloperoxidase expression in human atherosclerosis and support a particular role for the myeloperoxidase-expressing macrophages in atheroma complication and the acute coronary syndromes.
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PMID:Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. 1123 37

We and other groups have recently demonstrated that oxidized low density lipoprotein (Ox-LDL) induces proliferation of macrophages in vitro. Since previous immunohistochemical studies demonstrated that macrophages and macrophage derived foam cells proliferated in situ in atherosclerotic lesions, it seems reasonable to expect that the Ox-LDL-induced macrophage proliferation might be linked to the development of atherosclerotic lesions. Thus, clarification of the molecular cascades of Ox-LDL-induced macrophage proliferation is expected to enhance our knowledge of the pathogenesis of atherosclerosis. Recently, we demonstrated that the activation of PKC leads to release into the culture medium of granulocyte/macrophage colony-stimulating factor (GM-CSF) which plays an important role in Ox-LDL-induced macrophage proliferation. In this review article, we mainly show the role of GM-CSF in the Ox-LDL-induced macrophage proliferation. Moreover, based on our recent findings, we summarize the Ox-LDL-induced signaling pathway for macrophage proliferation.
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PMID:Granulocyte/macrophage colony-stimulating factor plays an essential role in oxidized low density lipoprotein-induced macrophage proliferation. 1142 39

It is recognized that macrophages in peripheral tissues often proliferate under pathological conditions such as tumors, inflammation and atherosclerosis. Because the growth state of macrophages is believed to be a factor regulating the pathological process of the diseases, substances that regulate macrophage growth or survival may be useful for disease control. In this paper, we identified the activity inhibiting macrophage growth in a hot water extract of roots of Securidaca inappendiculata. The extract markedly inhibited macrophage colony-stimulating factor (M-CSF/CSF-1)-induced growth of macrophages, whereas it exerted a less potent effect on growth of Concanavalin A (Con A)-stimulated thymocytes or M-CSF-stimulated bone marrow cells. The inhibition of macrophage growth was caused by a cytotoxic effect rather than a cytostatic effect. Cell death was due to the induction of apoptosis, as judged by staining with terminal deoxynucleotidyl transferase-mediated d-UTP nick end labelling (TUNEL). The cytotoxic activity seemed to be specific to peripheral macrophages; it showed a weak effect on the growth and survival of tumor cell lines including a macrophage-like cell line, J-774.1. Moreover, the saponin fraction induced apoptotic cell death of macrophages only when they were stimulated by M-CSF; it did not affect the viability of macrophages cultured without M-CSF or with granulocyte/macrophage-CSF. We determined the structures of the two active triterpene saponin compounds in the fraction, named securioside A and securioside B having a 3,4-dimethoxycinnamic group which is essential for the cell death-inducing activity. They are believed to be the primary compounds of new drugs for the treatment of pathological states in which macrophage proliferation occurs.
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PMID:Macrophage-oriented cytotoxic activity of novel triterpene saponins extracted from roots of Securidaca inappendiculata. 1160 30

Neutrophil granulocytes are involved in the pathogenesis of atherosclerosis also through their free radical generation. The aim of the study was to test how extracellular levels of myeloperoxidase (MPO; a granulocyte enzyme playing role in free radical production) change by age and what effect this change has on the production of the free radical superoxide anion by neutrophils. We also wanted to examine whether the antioxidant effect of different steroid hormones is realized through the MPO. Plasma myeloperoxidase concentrations of healthy blood donors were quantified by ELISA. Superoxide anion production was measured by photometry. Myeloperoxidase concentration was significantly lower in plasmas obtained from older women and men than in those from younger subjects. Adding the MPO inhibitors 4-aminobenzoic acid hydrazide (ABAH) and indomethacin to the granulocytes, the generation of superoxide anion increased and the decreasing effect of the steroids on superoxide production was inhibited. Incubating the neutrophils with the product of the reaction catalyzed by MPO itself (hypochlorite anion), we found significant decrease in superoxide generation. According to our results MPO seems to diminish the production of superoxide anion and so probably has an antioxidant ability. Therefore, its lower plasma levels may contribute to the increasing incidence of atherosclerosis and other free radical mediated disorders in old people. Thus, after further studies MPO might become one of the indicators of cardiovascular risk and the scavenger capacity in general.
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PMID:Plasma concentration of myeloperoxidase enzyme in pre- and post-climacterial people: related superoxide anion generation. 1173 54

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free radicals and adhesion molecules were implicated in the pathogenesis of atherosclerosis leading to cardiovascular disorders. Therefore, we investigated the link between CD15, CD11c, CD11b, and CD64 expression on leukocytes and their ability to generate reactive oxygen species (ROS) in patients with OSA and control volunteers. We also studied the effects of hypoxia in vitro on monocytes from control subjects and the ability of monocytes from both groups to adhere to human endothelial cells in culture. The effect of nasal continuous positive airway pressure (nCPAP) treatment was studied as well. We found that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, increased intracellular ROS production in some monocyte and granulocyte subpopulations, and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects. Furthermore, nCPAP treatment was associated with downregulation of CD15 and CD11c monocyte expression and decreased basal ROS production in CD11c+ monocytes. Monocyte adherence to endothelial cells decreased as well. Our findings provide one of the possible mechanisms for explaining the high rate of cardiovascular morbidity in patients with sleep apnea.
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PMID:Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. 1193 9


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