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)

Adiponectin, an adipose-derived hormone, exhibits various biological functions, such as increasing insulin sensitivity, protecting hypertension, and suppression of atherosclerosis, liver fibrosis, and tumor growth. Here, we report the role of adiponectin on bone metabolism. C57BL/6J mice were treated with adenovirus expressing lacZ or adiponectin, and their bones were analyzed by three-dimensional microcomputed tomography. Adiponectin-adenovirus treatment increased trabecular bone mass, accompanied by decreased number of osteoclasts and levels of plasma NTx, a bone-resorption marker. In vitro studies showed that adiponectin inhibited M-CSF- and RANKL-induced differentiation of mouse bone marrow macrophages and human CD14-positive mononuclear cells into osteoclasts and also suppressed the bone-resorption activity of osteoclasts. Furthermore, adiponectin enhanced mRNA expression of alkaline phosphatase and mineralization activity of MC3T3-E1 osteoblasts. Our results indicate that adiponectin exerts an activity to increase bone mass by suppressing osteoclastogenesis and by activating osteoblastogenesis, suggesting that adiponectin manipulation could be therapeutically beneficial for patients with osteopenia.
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PMID:Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. 1585 Jul 90

Angiotensin II (AngII) infusion promotes macrophage infiltration into the aortic wall resulting in several forms of vascular pathology. To determine the causal role of macrophages in these vascular diseases, we used osteopetrotic (op) male mice in which a natural mutation ablates production of M-CSF and results in severe depletion of monocytes. AngII infusion into apoE-/- mice resulted in increased atherosclerosis that was attenuated in op mice. AngII infusion in op mice unexpectedly produced grossly discernable thickening of the proximal thoracic aorta characterized by intra-mural hematoma. This pathology was also observed in apoE+/+ x op male mice, and therefore, independent of hyper-lipidemia. No perceptible structural properties of aortas from op mice could be discerned prior to AngII infusion. Regional effects in the contractile response to phenylephrine were noted in aortic rings with enhanced responsivity in the upper thoracic aortas of op mice compared to those from +/+ mice. No differences in contractile response were noted in aortic rings from the lower thorax. In conclusion, deficiency of M-CSF attenuated AngII-induced atherosclerosis but led to an unanticipated pathology of intra-laminar hemorrhage in the upper aortic regions.
Atherosclerosis 2006 Jun
PMID:Angiotensin II infusion induces site-specific intra-laminar hemorrhage in macrophage colony-stimulating factor-deficient mice. 1615 49

Colony-stimulating factor-1 (CSF-1, also known as macrophage-CSF) is the primary regulator of the survival, proliferation, differentiation and function of mononuclear phagocytes. Studies that involve CSF-1-deficient mice demonstrate that there is a variable requirement for CSF-1 in the development of individual mononuclear phagocyte populations. However, these cells uniformly express the CSF-1 receptor, and their morphology, phagocytosis and responsiveness to infectious and non-infectious stimuli is regulated by CSF-1. CSF-1 plays important roles in innate immunity, cancer and inflammatory diseases, including systemic lupus erythematosus, arthritis, atherosclerosis and obesity. In several conditions, activation of macrophages involves a CSF-1 autocrine loop. In addition, secreted and cell-surface isoforms of CSF-1 can have differential effects in inflammation and immunity.
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PMID:Colony-stimulating factor-1 in immunity and inflammation. 1633 66

Myeloperoxidase (MPO) is an oxidant-generating enzyme expressed in macrophages and implicated in atherosclerosis and cholesterol homeostasis. LXRalpha and PPARalpha regulate genes involved in cholesterol metabolism and the inflammatory response in macrophages. Here, we examine the effect of LXR and PPARalpha ligands on MPO expression. LXR and PPARalpha, as heterodimers with RXR, are shown to bind overlapping sites in an Alu receptor response element (AluRRE) in the MPO promoter. The LXR ligand T0901317 suppresses MPO mRNA expression in primary human macrophages, and in bone marrow cells and macrophages from huMPO transgenic mice. The PPARalpha ligand GW9578 downregulates MPO expression in GMCSF-macrophages, while upregulating in MCSF-macrophages. In contrast, the mouse MPO gene, which lacks the primate-specific AluRRE, is not regulated by LXR or PPARalpha ligands. These findings identify human MPO as a novel LXR and PPARalpha target gene, consistent with the role of these receptors in regulation of proinflammatory genes in macrophages.
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PMID:The human myeloperoxidase gene is regulated by LXR and PPARalpha ligands. 1695 79

Intense immunostaining for pregnancy-associated plasma protein-A (PAPP-A), a newly characterized metalloproteinase in the insulin-like growth factor system, colocalizes with activated macrophages in human atherosclerotic plaque. To determine macrophage regulation of PAPP-A expression, we developed two models of human macrophages with basal and activated phenotypes. THP-1 cells and peripheral blood monocytes could be differentiated into macrophages and activated upon specific treatment regimens with phorbol myristate acetate, macrophage colony-stimulating factor, and interleukin-1beta. Activation was assessed by cell secretion of tumor necrosis factor-alpha, which increased 30- to 100-fold with activation. Activated macrophages also secreted matrix metalloproteinase-9. However, no PAPP-A mRNA or PAPP-A antigen could be detected in these cells under any condition. Upon incubation with recombinant PAPP-A, we found that activated macrophages bound and internalized more PAPP-A than unactivated macrophages or monocytes. Internalization accounted for at least 50% of macrophage-associated PAPP-A, as assessed in studies with cytochalasin B. Membrane-bound PAPP-A retained protease activity, whereas internalized PAPP-A had little or no activity. Similar experiments carried out with a mutated variant of PAPP-A, which retains functionality as a protease but is unable to bind surface-associated glycosaminoglycan, showed no macrophage association or internalization. Absence of PAPP-A expression was confirmed in activated macrophages isolated from a hypercholesterolemic rabbit model of atherosclerosis. We therefore conclude that PAPP-A is not synthesized in, but rather is bound and internalized by, macrophages. Our findings likely account for the observed intense immunostaining for PAPP-A colocalizing with activated macrophages and may have physiological significance in the development of vulnerable plaque.
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PMID:Surface association of pregnancy-associated plasma protein-A accounts for its colocalization with activated macrophages. 1704 Sep 68

Two features of advanced atherosclerotic lesions are large numbers of macrophages and a heightened state of inflammation. Some of the macrophages appear to be enriched with free cholesterol (FCMphis), and we have shown that this process induces the synthesis and secretion of inflammatory cytokines, including TNF-alpha and IL-6. However, lesions contain many other macrophages that are not FC-enriched (non-FCMphis). Therefore, we sought to understand how the interaction of these two populations of macrophages would influence the inflammatory response. We show here that non-FCMphis possess a robust ability to deplete TNF-alpha and IL-6 secreted by FCMphis. The mechanism involves enhanced pinocytic uptake and lysosomal degradation of the FCMphi-secreted cytokines by the non-FCMphis. The FCMphis contribute directly to this process by secreting pinocytosis-stimulatory factors that act on non-FCMphis but not on the FCMphis themselves. One of these pinocytosis-stimulatory factors is M-CSF, which is induced by a process involving cholesterol trafficking to the endoplasmic reticulum and signaling through PI-3K and ERK MAPK pathways. However, one or more other FCMphi-secreted factors are also required for stimulating pinocytosis in non-FCMphis. Thus, FCMphis secrete inflammatory cytokines as well as factors that promote the eventual pinocytosis and degradation of these cytokines by neighboring macrophages. This process may normally serve to prevent prolonged or disseminated effects of inflammatory cytokines during inflammation. Moreover, possible perturbation of stimulated pinocytosis during the progression of advanced atherosclerosis may contribute to the heightened inflammatory state of these lesions.
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PMID:The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis. 1706 3

Atherosclerosis is a dynamic chronic inflammatory process, and some inflammatory biomarkers have roles in this process. The levels of C-reactive protein (CRP) in patients with chronic stable coronary heart disease (CHD) have not been investigated well, and the levels of macrophage colony-stimulating factor (M-CSF) and interleukin-3 (IL-3) in patients with chronic stable CHD and the effects of these cytokines on atherogenesis are not known. To determine whether new inflammatory biomarkers have roles in atherosclerosis, the authors measured the levels of CRP, M-CSF, and IL-3 in patients with chronic stable CHD and in healthy controls. They measured plasma CRP concentrations by using a highly sensitive CRP reagent with immunonephelometric method, and plasma M-CSF and IL-3 concentrations with the help of a commercial enzyme-linked immunoassay test in 31 patients with chronic stable CHD documented by coronary angiography and in 22 age-matched healthy control subjects documented by coronary angiography. Mean plasma CRP, M-CSF, and IL-3 concentrations in patients with chronic stable CHD were significantly higher than those in controls (8.2 vs 4.6 mg/L, 195.3 vs 28.9 pg/mL, 173 vs 118 ng/mL, respectively, ppi.05). CRP, M-CSF, and IL-3 were all increased in patients with chronic stable CHD relative to controls. These findings suggest that these are new inflammatory biomarkers that may have important roles in the development of atherosclerotic lesions.
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PMID:Role of novel biomarkers of inflammation in patients with stable coronary heart disease. 1749 62

Monocyte-to-macrophage differentiation and LDL oxidation play a pivotal role in early atherogenesis. We thus questioned possible mechanisms for oxidized LDL (Ox-LDL)-induced monocyte-to-macrophage differentiation in vivo. Mouse peritoneal mononuclear cells, that were isolated 1, 2, or 3 days after Ox-LDL intraperitoneal injection, gradually exhibited the characteristic macrophage morphology, along with the expression of the cell-surface antigen CD11b. Molecular mechanisms involved in Ox-LDL-induced differentiation were further investigated in vitro using the THP-1 monocytic cell line. THP-1 cells incubated with Ox-LDL in the presence of as low as 1 ng/ml of PMA differentiated into macrophages, as evidenced by morphologic, phenotypic, and functional properties. Stimulation of monocyte-to-macrophage differentiation was selective to Ox-LDL (and not native LDL), was dependent on the extent of LDL oxidation, and required Ox-LDL internalization by the cells. These effects of Ox-LDL could be attributed to its major oxysterols, 7-ketocholesterol and 7beta-hydroxycholesterol. Finally, the stimulation of monocyte differentiation to macrophages by Ox-LDL was shown to require the M-CSF-receptor, since blocking the binding to the receptor abolished Ox-LDL/7beta-hydroxycholesterol-induced differentiation. Furthermore, Ox-LDL/7beta-hydroxycholesterol elicited tyrosine phosphorylation and activation of the M-CSF-R. We thus conclude that Ox-LDL induces monocyte differentiation to macrophages in vivo and this phenomenon involves activation of the M-CSF-receptor.
Atherosclerosis 2008 Feb
PMID:Ox-LDL induces monocyte-to-macrophage differentiation in vivo: Possible role for the macrophage colony stimulating factor receptor (M-CSF-R). 1767 37

Research suggests that monocytes differentiate into unique lineage-determined macrophage subpopulations in response to the local cytokine environment. The present study evaluated the atherogenic potential of two divergent lineage-determined human monocyte-derived macrophage subpopulations. Monocytes were differentiated for 7 days in the presence of alternative macrophage development cytokines: granulocyte-macrophage colony-stimulating factor to produce granulocyte-macrophage-CSF macrophages (GM-Mac), or macrophage colony-stimulating factor (M-CSF) to produce M-Mac. Gene chip analyses of three monocyte donors demonstrated differential expression of inflammatory and cholesterol homeostasis genes in the macrophage subpopulations. Quantitative PCR confirmed a fivefold elevation in the expression of genes that promote reverse cholesterol transport (PPAR-gamma, LXR-alpha, and ABCG1) and macrophage emigration from lesions (CCR7) in GM-Mac compared to that in M-Mac. Immunocytochemistry confirmed enhanced expression of the proinflammatory marker CD14 in M-Mac relative to GM-Mac. M-Mac spontaneously accumulated cholesterol when incubated with unmodified low-density lipoprotein whereas GM-Mac only accumulated similar levels of cholesterol after protein kinase C activation. Immunostained human coronary arteries showed that macrophages with similar antigen expression to that of M-Mac (CD68(+)/CD14(+)) were predominant within atherosclerotic lesions whereas macrophages with antigen expression similar to GM-Mac (CD68(+)/CD14(-)) were predominant in areas devoid of disease. The identification of macrophage subpopulations with different gene expression patterns and, thus, different potentials for promoting atherosclerosis has important experimental and clinical implications and could prove to be a valuable finding in developing therapeutic interventions in diseases dependent on macrophage function.
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PMID:Heterogeneity of human macrophages in culture and in atherosclerotic plaques. 1832 97

Current thinking supports the notion that several inflammatory proteins intervene with endothelium and haemostatic factors leading to plaque formation and rupture. Of these, C-reactive protein (CRP), monocyte/macrophage colony-stimulating factor (MCSF) and interleukin-6 (IL-6) promote atherogenesis by inducing monocyte-macrophage activation, foam cell formation, platelet activation, tissue factor expression, release of other procoagulant cytokines or downregulation of atheroprotective cytokines such as interleukin 10 and transforming growth factor b-1 (TGFb-1). CRP, MSCF and IL-6 are interrelated and have been found in increased blood concentrations in CAD. Increased levels of CRP and IL-6 predict a higher cardiovascular event rate in the general population and in addition to high MCSF or low TGFb-1 predict adverse outcome in CAD patients independently of traditional risk factors. Moreover, in CAD patients, the predictive value of MCSF is additive and beyond that of CRP suggesting the need of a "multimarker approach" in assessing cardiovascular risk. Accumulating evidence supports the utility of non-invasive markers of subclinical atherosclerosis, namely carotid intimal media thickness, flow mediated dilatation of the brachial artery, augmentation index or pulse wave velocity, in the prediction of cardiovascular risk particularly in primary prevention settings. The combination of these non-invasive tests has been shown to improve their prognostic accuracy compared to each other alone. Although several therapeutic strategies like vaccination against antigens promoting atherogenesis, cyclooxygenase inhibitors, statins, and ACE inhibitors may reduce the levels of these inflammatory markers and improve the non-invasive markers of subclinical atherosclerosis, the impact on cardiovascular risk resulting from these changes is unknown. The combination of an established inflammatory marker such as CRP or a vascular marker such as IMT with novel biochemical and vascular markers of cardiovascular disease may offer additive prognostic information for adverse outcome.
Atherosclerosis 2008 Jul
PMID:Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease. 1837 39


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