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)

Emerging experimental data supports a circulating precursor origin for some smooth muscle cells that participate in vasculogenesis but uncertainty exists on the precise phenotype and lineage of these vascular precursors. We determined the lineage of human smooth muscle outgrowth cells (SOC) derived from circulating blood mononuclear cells and smooth muscle-like cells present in regions of vasculogenesis in diseased arteries. Immunophenotypic characterization of SOC was performed using FACS and immunofluorescence (IF). An SOC hierarchy was determined based on in vitro clonogenic and proliferative potential. Lineage of smooth muscle-like cells in vasculogenic regions in vivo was also determined by dual IF for myeloid and smooth muscle specific markers combined with FISH for the X and Y chromosome in diseased vessel of human subjects who had undergone gender mismatched cardiac transplantation. We show here that primary high proliferative potential smooth muscle outgrowth cells (HPP-SOC) expanded in culture from human peripheral blood mononuclear cells (PBMC) and recipient-derived chimeric smooth muscle cells participating in vasculogenesis in vivo share a myeloid phenotype (CD68 and CD14 positivity). Moreover, HPP-SOC in vitro are distinct in being negative for several myeloid markers such as CD11b, CD13 and CD33, and CD45 surface antigens and chimeric SMC in vivo show no evidence of cell fusion propensity. This study provides evidence of a possible myeloid subpopulation origin for smooth muscle outgrowth cells in blood and vasculogenic smooth muscle-like cells in the intima and adventitial microvasculature of diseased arteries. These data have significant implications for understanding the role myeloid cells play in smooth muscle cell biology and vascular remodelling.
Atherosclerosis 2008 May
PMID:Myeloid lineage of high proliferative potential human smooth muscle outgrowth cells circulating in blood and vasculogenic smooth muscle-like cells in vivo. 1796 71

ORP8 is a previously unexplored member of the family of oxysterol-binding protein-related proteins (ORP). We now report the expression pattern, the subcellular distribution, and data on the ligand binding properties and the physiological function of ORP8. ORP8 is localized in the endoplasmic reticulum (ER) via its C-terminal transmembrane span and binds 25-hydroxycholesterol, identifying it as a new ER oxysterol-binding protein. ORP8 is expressed at highest levels in macrophages, liver, spleen, kidney, and brain. Immunohistochemical analysis revealed ORP8 in the shoulder regions of human coronary atherosclerotic lesions, where it is present in CD68(+) macrophages. In advanced lesions the ORP8 mRNA was up-regulated 2.7-fold as compared with healthy coronary artery wall. Silencing of ORP8 by RNA interference in THP-1 macrophages increased the expression of ATP binding cassette transporter A1 (ABCA1) and concomitantly cholesterol efflux to lipid-free apolipoprotein A-I but had no significant effect on ABCG1 expression or cholesterol efflux to spherical high density lipoprotein HDL(2). Experiments employing an ABCA1 promoter-luciferase reporter confirmed that ORP8 silencing enhances ABCA1 transcription. The silencing effect was partially attenuated by mutation of the DR4 element in the ABCA1 promoter and synergized with that of the liver X receptor agonist T0901317. Furthermore, inactivation of the E-box in the promoter synergized with ORP8 silencing, suggesting that the suppressive effect of ORP8 involves both the liver X receptor and the E-box functions. Our data identify ORP8 as a negative regulator of ABCA1 expression and macrophage cholesterol efflux. ORP8 may, thus, modulate the development of atherosclerosis.
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PMID:OSBP-related protein 8 (ORP8) suppresses ABCA1 expression and cholesterol efflux from macrophages. 1799 39

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

Inflammation in atherosclerotic plaques makes them unstable and can cause thrombosis. Therefore, it is important to detect macrophage activity for clinical management of atherosclerosis. Peripheral benzodiazepine receptor (PBR) is expressed in various tissue and organs including macrophages. In this study, we tested whether inflammation characterized by macrophage infiltration can be detected by PBR binding. Six patients diagnosed as carotid atherosclerosis underwent endarterectomy. Using the fresh frozen sections, presence of PBRs and macrophages was examined by in vitro autoradiography using [(3)H]PK 11195 and immunohistochemical staining of CD68, respectively. All sections showed specific binding of [(3)H]PK 11195, and the staining with CD68 indicating macrophage infiltration. Density and distribution of PBR detected by [(3)H]PK 11195 autoradiography were consistent with those of the immunohistochemical staining. In conclusion, this study demonstrated that macrophage and inflammatory activity in atherosclerotic plaque can be imaged specifically by the binding of PBR indicating future application of PET imaging for PBR.
Atherosclerosis 2008 Nov
PMID:Increased peripheral benzodiazepine receptors in arterial plaque of patients with atherosclerosis: an autoradiographic study with [(3)H]PK 11195. 1843 54

This paper presents a simple and reliable method of triple immunofluorescence staining that allows simultaneous detection of various cell types present in atherosclerotic plaque of apolipoprotein E and LDL receptor-double knockout (apoE/LDLR -/-) mice. We used combined direct and indirect procedures applying commercially available primary antibodies raised in different species to detect smooth muscle cells (Cy3-conjugated mouse anti-smooth muscle actin, SMA), macrophages (rat anti-CD68) and T lymphocytes (rabbit anti-CD3). Fixation of the material in acetone and modified incubation protocol employing nonfat dry milk in preincubation and incubation media significantly increased the intensity of labeling and effectively quenched the background. Our method offers an efficient way to detect qualitative as well as quantitative changes of macrophages, T lymphocytes and smooth muscle cells in atherosclerotic plaque of apoE/LDLR -/- mice during atherosclerosis development or in response to pharmacological treatment.
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PMID:Triple immunofluorescence labeling of atherosclerotic plaque components in apoE/LDLR -/- mice. 1851 29

Secretory phospholipase A2 (sPLA2) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA2 inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE(-/-) mice were investigated. Male apoE(-/-) mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti-alpha actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by approximately 75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA2 inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture.
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PMID:The synergistic inhibition of atherogenesis in apoE-/- mice between pravastatin and the sPLA2 inhibitor varespladib (A-002). 1902 66

We recently showed that poly(ADP-ribose) polymerase (PARP) is activated within atherosclerotic plaques in an animal model of atherosclerosis. Pharmacological inhibition of PARP or reduced expression in heterozygous animals interferes with atherogenesis and may promote factors of plaque stability, possibly reflecting changes in inflammatory and cellular factors consistent with plaque stability. The current study addresses the hypothesis that pharmacological inhibition of PARP promotes atherosclerotic plaque regression. Using a high-fat diet-induced atherosclerosis apolipoprotein E(-/-) mouse model, we demonstrate that administration of the potent PARP inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), when combined with a regular diet regimen during treatment, induced regression of established plaques. Plaque regression was associated with a reduction in total cholesterol and low-density lipoproteins. Furthermore, plaques of TIQ-A-treated mice were highly enriched with collagen and smooth muscle cells, displayed thick fibrous caps, and exhibited a marked reduction in CD68-positive macrophage recruitment and associated foam cell presence. These changes correlated with a significant decrease in expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1, potentially as a result of a robust reduction in tumor necrosis factor expression. The PARP inhibitor appeared to affect cholesterol metabolism by affecting acyl-coenzymeA/cholesterol acyltransferase-1 expression but exerted no effect on cholesterol influx or efflux as assessed by an examination of the ATP-binding cassette transporter-1 and the scavenger receptor-A expression levels in the different experimental groups. In accordance, PARP inhibition may prove beneficial not only in preventing atherogenesis but also in promoting regression of preexisting plaques.
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PMID:Thieno[2,3-c]isoquinolin-5-one, a potent poly(ADP-ribose) polymerase inhibitor, promotes atherosclerotic plaque regression in high-fat diet-fed apolipoprotein E-deficient mice: effects on inflammatory markers and lipid content. 1912 46

Increased circulating adhesion molecules in patients with obesity play an important role in the development of endothelial dysfunction/atherosclerosis. The aim of this study was to assess the contribution of various fat depots to the production of adhesion molecules in obesity. 12 women with first and second degree of obesity, 13 women with third degree of obesity and 14 lean age-matched women were included into study. Circulating levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were measured by Luminex kits. mRNA expression of ICAM-1, VCAM-1, E-selectin, monocyte chemoattractant protein-1 (MCP-1), and CD68 in subcutaneous (SAT) and visceral adipose tissue (VAT) was measured by RT-PCR; ICAM-1 and VCAM-1 protein levels by Luminex kits, normalized to protein content. Obesity increased ICAM-1 and VCAM-1 mRNA expression and protein levels and CD68 mRNA expression in VAT. Expression of E-selectin and MCP-1 did not significantly differ between groups. Expression of ICAM-1 and VCAM-1 positively correlated with expression of CD68 in both adipose depots. In VAT, ICAM-1 and VCAM-1 expression and protein levels positively correlated with BMI. Obesity was associated with increased adhesion molecules mRNA expression and protein levels in VAT, but not in SAT. Increased adhesion molecules production in visceral fat may provide a novel direct link between visceral adiposity and increased risk of cardiovascular complications.
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PMID:The influence of obesity and different fat depots on adipose tissue gene expression and protein levels of cell adhesion molecules. 1924 17

It is not clear if 18FDG-PET can be useful for detection of inflammation in low to moderate carotid stenosis. We studied 15 patients scheduled for endarterectomy with contralateral carotids with less than 50% stenosis. 18-FDG-PET was performed prior to CEA and 3 months following surgery. FDG-uptake values were calculated based on maximum standardized uptake value (SUV) and corresponding uptake ratios. We confirmed by CD68 macrophage staining that FDG accumulation corresponds to active inflammation (R=0.8 p less than 0.005). We found significant correlation between the FDG-uptake in the carotids scheduled for CEA and contralateral carotids with low to moderate stenosis (R=0.9 p less than 0.001). The FDG uptake ratio in the contralateral arteries remained stable on the follow-up imaging (1.15+/-0.2 vs. 1.14+/-0.1, R=0.7 p=0.006). We did not find correlation between FDG uptake and symptomatic or asymptomatic patients, degree of carotid stenosis and vascular risk factors. This is a prospective, preliminary in vivo study demonstrating that low to moderate carotid atherosclerosis can be detected using 18-FDG-PET imaging and highlights the truly systemic nature of atherosclerosis.
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PMID:Imaging of early inflammation in low-to-moderate carotid stenosis by 18-FDG-PET. 1927 79

Nicotinamide N-methyltrasferase (NMMT) catalyzes the conversion of nicotinamide (NA) to 1-methylnicotinamide (MNA). Recent studies have reported that exogenous MNA exerts anti-thrombotic and anti-inflammatory activity, suggesting that endogenous NMMT-derived MNA may play a biological role in the cardiovascular system. In the present study, we assayed changes in hepatic NNMT activity and MNA plasma levels along the progression of atherosclerosis in apoE/LDLR(-/-) mice, as compared to age-matched wild-type mice. Atherosclerosis progression in apoE/LDLR(-/-) mice was quantified in aortic root, while hepatic NNMT activity and MNA plasma concentrations were concomitantly measured in 2-, 3-, 4-, and 6-month-old mice. In apoE/LDLR(-/-) mice, atherosclerotic plaques developed in the aortic roots beginning at the age of 3 months and gradually increased in size, macrophage content, and inflammation intensity over time, as detected by Oil-Red O staining, CD68 immunostaining, and in situ zymography (MMP2/MMP9 activity). Hepatic NNMT activity was upregulated approximately two-fold in apoE/LDLR(-/-) mice by the age of 2 months, as compared to wild-type mice (1.03 +/- 0.14 vs. 0.64 +/- 0.23 pmol/min/mg, respectively). MNA plasma concentrations were also elevated approximately two-fold (0.30 +/- 0.13 vs. 0.17 +/- 0.04 micromol/l, respectively). As atherosclerosis progressed, hepatic NMMTactivity and MNA plasma concentrations increased five-fold in 6-month-old apoE/LDLR(-/-) mice at the stage of advanced atherosclerotic plaques (NMMT activity: 2.29 +/- 0.34 pmol/min/mg, MNA concentration: 1.083 +/- 0.33 micromol/l). In summary, the present study demonstrated that the progression of vascular inflammation and atherosclerosis was associated with the upregulation of hepatic NNMT activity and subsequent increase in endogenous MNA plasma levels. Given the anti-thrombotic and anti-inflammatory properties of exogenous MNA, robust activation of an endogenous NA-MNA pathway in atherosclerosis may play an important compensatory role.
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PMID:Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis. 1930 95


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