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)

Cells bearing a smooth muscle cell marker--alpha-actin and a macrophage marker--CD68 antigen were immunocytochemically identified on 'en face' preparations of human aortic intima. Cells, expressing smooth muscle alpha-actin, macrophage CD68 antigen and both markers, i.e. smooth muscle cells possessing the macrophage antigen, were identified both in grossly normal aortic areas and in atherosclerotic lesions (fatty streaks and atherosclerotic plaques). CD68-positive smooth muscle cells were most common in the lipid-rich areas: fatty streaks and atherosclerotic plaque shoulders. Cells expressing smooth muscle alpha-actin and CD68 were also revealed in primary cultures prepared from grossly normal and atherosclerotic intima. Cells expressing both antigens were found in all examined cultures. The proportion of these cells in cultures from grossly normal areas and atherosclerotic plaques was similar: 14.5 +/- 4.1 and 14.6 +/- 4.8%, respectively. Cultures from fatty streaks had a higher content of cells expressing both antigens: 25.1 +/- 7.0%. Modified low density lipoprotein-induced intracellular lipid accumulation in cells cultured from grossly normal intima led to a three-fold increase in the number of cells sharing alpha-actin and CD68 antigen. Accumulation of latex beads by phagocytosis had a similar effect. It was suggested that in atherosclerotic lesions intracellular lipid accumulation and other stimulators of phagocytosis may provoke the expression of macrophage-associated antigen CD68 in settled cells of the subendothelial intima of human aorta.
Atherosclerosis 1997 Nov
PMID:Subendothelial smooth muscle cells of human aorta express macrophage antigen in situ and in vitro. 939 69

The objective of the current study was to characterize the influence of high density lipoproteins (HDL) on processes related to the vascular recruitment of human monocytes, which may contribute to the anti-atherogenic properties of these lipoproteins. We show that HDL(3) and apo AI inhibit the following processes in primary human monocytes: (1) M-CSF induced cell spreading; (2) M-CSF stimulated expression of surface molecules involved in adhesion, migration, and scavenging; (3) fMLP induced chemotaxis. These processes are obviously modulated by the regulation of cellular cholesterol pools as indicated by the following findings. In Tangier monocytes with defective apo AI induced cholesterol efflux, apo AI had no influence on the spreading response. In control cells, stimulation of cholesterol efflux by p-cyclodextrin mimicked the effect of apo AI and HDL(3) on spreading and chemotaxis, whereas cholesterol loading with enzymatically modified LDL (E-LDL) showed the opposite effect. Finally, a similar inverse regulation by E-LDL and apo AI/HDL(3) was also observed in regard to the surface expression of beta(1)- and beta(2)-integrins as well as the hemoglobin/haptoglobin scavenger receptor CD163 and the Fcgamma-IIIaR CD16. CDC42 was identified as a potential downstream target linking changes in cellular cholesterol content to monocyte spreading and chemotaxis. Thus, CDC42 antisense markedly reduced spreading and, in parallel with their influence on monocyte spreading, HDL(3), apo AI and p-cyclodextrin down-regulated CDC42 expression while E-LDL had the inverse effect. The apo AI induced decrease of CDC42 protein expression was paralleled by the reduction of active GTP-bound CDC42. In summary, we provide evidence that HDL(3) and apo AI are able to inhibit processes in primary human monocytes, which are related to the recruitment of monocytes into the vessel wall and probably involve regulation of cellular cholesterol pools and CDC42 function.
Atherosclerosis 2001 Dec
PMID:Apolipoprotein AI and HDL(3) inhibit spreading of primary human monocytes through a mechanism that involves cholesterol depletion and regulation of CDC42. 1173 Aug 11

Although haptoglobin polymorphism has been shown to be a genetic risk factor in coronary artery disease, its mechanisms of action are incompletely defined. Recently, a macrophage scavenger receptor for the uptake of haptoglobin-hemoglobin (Hp-Hb) complexes was cloned and designated CD163. Macrophage expression of CD163 is increased by glucocorticoids, IL-10 and IL-6. To better understand the in vivo response of CD163 to an inflammatory stimulus and glucocorticoid treatment, we studied 18 patients who underwent elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). We report a rapid increase in plasma levels of soluble CD163 by 1 h post-declamping the aorta during CABG surgery with CPB. Furthermore, we demonstrate significant increases in monocyte CD163 on post-operative day 1; 14-fold for patients pre-treated with methylprednisolone and 3-fold for those who did not receive exogenous glucocorticoids. These findings show CD163 to be rapidly mobilized in response to systemic inflammatory stimuli and to be affected significantly by glucocorticoids in vivo. The proposed role of CD163 as a Hp-Hb scavenger and anti-inflammatory molecule, in conjunction with the results of this study, make CD163 an intriguing target for potential manipulation of the acute response to inflammation.
Atherosclerosis 2003 Oct
PMID:Increase in plasma and surface CD163 levels in patients undergoing coronary artery bypass graft surgery. 1461 14

Highly efficient systems remove the toxic and proinflammatory haemoglobin from the circulation and local sites of tissue damage. Macrophages are major haemoglobin-clearing cells; CD163 was recently recognized as the specific haemoglobin scavenger receptor (HbSR). It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection and inflammation. Haemoglobin functions as a double-edged sword. In moderate quantities and bound to haptoglobin, it forms a ligand for haemoglobin scavenger receptor CD163/HbSR, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. CD163/HbSR plays a crucial role in the control of inflammatory processes, probably in part through its effects on both ferritin induction and subsequent induction of antiinflammatory pathways through interleukin-10 and haem oxygenase. Besides the observation that the haemoglobin scavenger receptor provides a promising target for new treatment possibilities, it offers a novel view on the aetiology of diverse physiological as well as pathophysiological processes. In addition, monocyte CD163/HbSR and soluble CD163/HbSR are potential diagnostic tools in a variety of disease states, such as inflammation, atherosclerosis, transplant rejection, and carcinoma.
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PMID:Haemoglobin scavenger receptor: function in relation to disease. 1677 Apr 44

The haptoglobin genotype has been demonstrated to be an independent risk factor for CVD in multiple epidemiological studies. The primary function of haptoglobin is to mitigate the deleterious effects of extracorpuscular hemoglobin. We sought to determine if the protein products of the two haptoglobin alleles differed in their ability to modulate the cytokine profile produced by macrophages in response to hemoglobin. Peripheral blood mononuclear cells were isolated from normal human volunteers and cultured in the presence of complexes formed by the protein products of the two different haptoglobin alleles with hemoglobin. The release of specific cytokines in the conditioned media of these cells was assessed by ELISA. We found that the haptoglobin 1 allele protein product-hemoglobin complex stimulated the secretion of significantly more Il-6 and Il-10 than the haptoglobin 2 allele protein product-hemoglobin complex. We demonstrate that the release of these cytokines is dependent on the liganding of the haptoglobin-hemoglobin complex to the CD163 receptor and the activity of casein kinase II. Haptoglobin genotype modulates the balance of inflammatory (Th1) and anti-inflammatory (Th2) cytokines produced by macrophages exposed to free hemoglobin. This may have implications in understanding inter-individual differences in the inflammatory response to hemorrhage.
Atherosclerosis 2007 Mar
PMID:Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin. 1682 Jan 50

Heme toxicity contributes to the pathogenesis of chronic inflammatory diseases, atherosclerosis, and hemolysis associated vasculopathy. Macrophage clearance of cell free hemoglobin (Hb) is thus an essential homeostatic function of these cells. We examined the transcriptional response of human PBMC derived macrophages to Hb by gene array analysis. The observed noninflammatory macrophage response was characterized by induction of an antioxidative and antiinflammatory gene expression pattern with most prominent induction of the inducible heme oxygenase (HO-1). The metabolically active Hb-CD163-HO-1 pathway resulted in synthesis of ferritin-1 of the antioxidative and antiinflammatory end products linked to heme breakdown by HO-1. This response was mediated by the Hb scavenger receptor CD163 and heme and was not related to Hb mediated depletion of reduced glutathione. In contrast to other cellular responses induced by CD163, there was no role of protein phosphorylation dependent CD163 signaling in the protective macrophage response to Hb. Instead, CD163 acted as an Hb transporter, which undergoes constitutive and ligand independent internalization and recycling between the cell surface and early endosomes. The expression of CD163 and HO-1 in macrophages of neovascularized atherosclerotic lesions suggests that the pathway described herein is active in vivo. Noninflammatory Hb clearance and intimately linked HO-1 expression may provide the long sought-after explanation for the antiinflammatory activity associated with CD163-positive macrophages.
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PMID:Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. 1706 96

Hemoglobin (Hb) released during hemolysis is a potent oxidant. Extracorpuscular Hb may enter the vessel wall and mediate low-density lipoprotein oxidation, thereby promoting the development and progression of atherosclerosis. Haptoglobin (Hp) is an antioxidant protein as a result of its ability to bind Hb and block Hb-induced oxidative damage. Hp also facilitates the removal of Hb from the extravascular compartment via the CD163 macrophage scavenger receptor. In man, there are two common alleles for Hp denoted 1 and 2, and correspondingly, three different possible genotypes: Hp1-1, Hp2-1, and Hp2-2. We have recently demonstrated in several longitudinal studies that Hp genotype is an independent risk factor for diabetic vascular complications. Specifically, we have shown that diabetic individuals with Hp2-2 are more likely to develop nephropathy, retinopathy, and cardiovascular disease as compared with those with Hp2-1 or Hp1-1. Mechanistically, we have found significant Hp type differences in the antioxidant and CD163-mediated scavenging and activation functions of the different Hp protein types. Furthermore, we have demonstrated that these functions are modified in the diabetic state. In this review, we focus on the clinical studies associating the Hp polymorphism and diabetic vascular complications, and the molecular basis behind this interaction.
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PMID:In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. 1731 95

Intraplaque hemorrhage accelerates atherosclerosis via oxidant stress and contributes to lesion development and destabilization. Normally, macrophages scavenge hemoglobin-haptoglobin (HbHp) complexes via CD163, and this process provokes the secretion of the anti-inflammatory atheroprotective cytokine interleukin (IL)-10. We therefore tested the hypothesis that HbHp complexes may drive monocyte differentiation to an atheroprotective phenotype. Examination of the macrophage phenotype in hemorrhaged atherosclerotic plaques revealed a novel hemorrhage-associated macrophage population (HA-mac), defined by high levels of CD163, but low levels of human leukocyte antigen-DR. HA-mac contained more iron, a pro-oxidant catalyst, but paradoxically had less oxidative injury, measured by 8-oxo-guanosine content. Differentiating monocytes with HbHp complexes reproduced the CD163(high) human leukocyte antigen-DR(low) HA-mac phenotype in vitro. These in vitro HA-mac cells cleared Hb more quickly, and consistently showed less hydrogen peroxide release, highly reactive oxygen species and oxidant stress, and increased survival. Differentiation to HA-mac was prevented by neutralizing IL-10 antibodies, indicating that IL-10 mediates an autocrine feedback mechanism in this system. Nonlinear dynamic modeling showed that an IL-10/CD163-positive feedback loop drove a discrete HA-mac lineage. Simulations further indicated an all-or-none switch to HA-mac at threshold levels of HbHp, and this conversion was experimentally verified. These data demonstrate the creation of a novel atheroprotective (HA-mac) macrophage subpopulation in response to intraplaque hemorrhage and raise the possibility that therapeutically reproducing this macrophage phenotype may be cardio-protective in cases of atherosclerosis.
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PMID:Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. 1923 37

Hemoglobin is a highly reactive molecule, and besides its oxygen-carrying capacity, it has multiple enzymatic and ligand-binding activities that have only recently been explored as fundamental pathophysiologic mechanisms. Nitric oxide neutralization, generation of potentially toxic radical species, and heme-mediated inflammation are among the most extensively studied mechanisms of Hb-mediated pathology. Extracellular Hb has an established role in sickle cell disease and other hemolytic disorders. However, extracellular Hb seems also to have relevant disease-modifying activities in many other important pathologic conditions, such as malaria and atherosclerosis. In this Forum, we summarize the current knowledge of mechanisms of Hb toxicity. Special emphasis is given to the highly efficient endogenous scavenger and detoxification pathways, such as alpha-hemoglobin stabilizing protein (AHSP), haptoglobin, hemopexin, CD163, and heme oxygenase. Systemic and local activity of these pathways finally determines the impact of extracellular Hb on physiology and tissue homeostasis.
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PMID:Clearance and control mechanisms of hemoglobin from cradle to grave. 1978 93

Patients with systemic lupus erythematosus (SLE) have a high risk of developing cardiovascular disease; however, the mechanisms involved in the early onset of atherosclerosis in these patients are not clear. Scavenger receptors, CD36 and CD163 are expressed by mononuclear phagocytes and participate in the binding and uptake of oxidized low-density lipoproteins (Ox-LDL), contributing to foam-cells formation and atherosclerosis development. The aim of the present study was to evaluate CD36(+) and CD163(+) expression and Ox-LDL removal by monocytes from SLE and atherosclerotic patients, compared to similar age-range healthy controls. Healthy controls, SLE, and atherosclerotic patients were evaluated for carotid intima media thickness (CIMT), lipid profile, and native LDL (N-LDL) and Ox-LDL binding/endocytosis. SLE patients presented decreased high-density lipoproteins (HDL) and increased Triglyceride levels, and half of the SLE patients had increased CIMT, compared to their healthy controls (HC(SLE)). The number of CD14(+)CD163(+) cells was increased in atherosclerosis healthy controls (HC(Atheros)) compared to HC(SLE), but there were no differences between SLE or atherosclerotic patients and their respective healthy controls. Clearance assays revealed a similar capacity to bind/endocytose Ox-LDL by monocytes from SLE patients and HC(SLE), and an increased binding and endocytosis of Ox-LDL by monocytes from atherosclerotic patients, compared to HC(Atheros). The decreased CD36 and CD163 expression observed in atherosclerotic and SLE patients, respectively, suggest that these inflammatory conditions modulate these receptors differentially. The increased CIMT observed in SLE patients cannot be explained by Ox-LDL binding/endocytosis, which was comparable to their controls.
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PMID:Atherosclerosis development in SLE patients is not determined by monocytes ability to bind/endocytose Ox-LDL. 2123 94


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