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)

Sections of human atherosclerotic lesions of different stages show that, in early lesions, the acellular lipid core is usually immediately adjacent to the deepest edge of a collection of macrophage foam cells. Advanced lesions with a large lipid core have variable numbers of macrophage foam cells, close to the lateral edges, or shoulders, of the core. In both early and advanced lesions, some of the macrophages nearest the core appear to be dying. Lipid cores contain two materials which in earlier lesions are found only in macrophages, namely ceroid and CD68 antigen, but do not contain recognisable smooth muscle cell actin. It is concluded that death of macrophage foam cells contributes to the origin and slow enlargement of the lipid core. The cause of macrophage death is not yet certain, but is under investigation.
Atherosclerosis 1995 Apr 07
PMID:Evidence that the death of macrophage foam cells contributes to the lipid core of atheroma. 760 75

Inflammatory cytokines associated with atherosclerosis may be capable of stimulating the synthesis and activity of inducible nitric oxide synthase (iNOS), which could further influence the pathologic features associated with the disease. Although there is a certain amount of indirect evidence to support the presence of iNOS in atherosclerosis, there has been no definitive study to confirm this. This study has assessed the localization of iNOS within human normal and atherosclerotic vessels by immunocytochemistry, Western blotting, and in situ hybridization. Further, activity of NO synthase has been assessed by detection of nitrotyrosine, which is a marker indicative of the formation and activity of the nitric oxide-derived oxidant, peroxynitrite. In Western blots of crude homogenates of atherosclerotic aorta, the iNOS antiserum reacted with a band of approximately 130 kd (the known molecular weight for iNOS), but no such band was seen in normal aorta. Immunostaining and in situ hybridization confirmed the presence of iNOS in atherosclerotic vessels, in which it was specifically localized to (CD68-positive) macrophages, foam cells, and the vascular smooth muscle. The antiserum to nitrotyrosine reacted with a wide range of protein bands (approximately 180 to 30 kd) in Western blots of atherosclerotic aorta. The distribution of immunostaining for nitrotyrosine was virtually identical to that seen for iNOS and was present in macrophages, foam cells, and the vascular smooth muscle. In conclusion, these studies have demonstrated that stimulated expression of iNOS is associated with atherosclerosis and that the activity of this enzyme under such conditions preferentially promotes the formation and activity of peroxynitrite. This may be important in the pathology of atherosclerosis, which contributes to lipid peroxidation and to vascular damage.
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PMID:Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. 868 42

Coronary plaque inflammation may promote plaque rupture and thrombosis. To test this hypothesis, 351 coronary plaques from 83 patients were formalin-fixed and stained with haematoxylin and eosin. There were six groups: (1) ruptured plaques; (2) intact plaques from recently infarcted hearts; (3) plaques from hearts with severe coronary atherosclerosis without identifiable thrombosis; (4) native explanted hearts with severe coronary atherosclerosis; (5) cardiac transplant atherosclerosis; and (6) fatalities unrelated to coronary atherosclerosis. Selected arteries were immunostained for leukocyte markers and serially sectioned to identify plaque rupture. There were infiltrates of CD68-positive macrophages and CD3- and CD8-positive T cells adjacent to all plaque ruptures. Labelling with HLA-DR and CD30 indicated inflammatory cell activation. Plaque rupture was strongly statistically associated with the severity and frequency of superficial plaque inflammation but not that of deep plaque inflammation. Although atherosclerotic inflammation has been identified adjacent to rupture, this is its first comparison with control plaques. These results support the concept that inflammation in the fibrous cap is particularly associated with plaque rupture.
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PMID:Association of coronary plaque rupture and atherosclerotic inflammation. 907 9

Secretory nonpancreatic type II phospholipase A2 (snpPLA2) hydrolyzes fatty acids at the sn-2 position in phospholipids releasing free fatty acids (FFAs) and lysophospholipids. These products may act as intracellular second messengers or can be further metabolized into proinflammatory lipid mediators. The presence of snpPLA2 in extracellular fluids and serum during inflammation has suggested a role of the enzyme in this process. However, the presence of snpPLA2 in a variety of normal tissues suggests that snpPLA2 may also have physiological functions. Atherosclerosis appears to have an inflammatory component. Here we report on the snpPLA2 localization in normal and atherosclerotic lesions and on the properties of the isolated enzyme. A strong snpPLA2 immunoreactivity was observed in the arterial media that was colocalized with alpha-actin-positive vascular smooth muscle cells (SMCs) in both normal and atherosclerotic vessels. In aortic atherosclerotic lesions, snpPLA2 was observed colocalized with CD68-positive macrophages and HHF-35-positive SMCs and extracellularly in the lipid core. snpPLA2 was isolated from human normal arteries and from aorta with lesions. The enzyme was isolated by acid extraction of normal arterial tissues followed by immunoaffinity chromatography. The purified snpPLA2 had an expected molecular weight of 14 kD by polyacrylamide gel electrophoresis and appeared as a single band in immunoblotting. The enzymatic activity was followed by measuring release of fatty acids from phospholipid liposomes or LDL as substrates. The enzymatic activity was inhibited with two specific inhibitors for human snpPLA2: (1) monoclonal antibody 187 and (2) LY311727, a synthetic selective inhibitor. The mRNA for snpPLA2 was detected with reverse transcriptase polymerase chain reaction. These results indicate that snpPLA2 is present in human arteries and that it is able to hydrolyze phospholipids in LDL. The results support the hypothesis that snpPLA2 can release proinflammatory lipids at places of LDL deposition in the arterial wall.
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PMID:Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries. Activity of the isolated enzyme on low-density lipoproteins. 908 85

The overgrowth of cells of the vessel wall, especially of the smooth muscle cells (SMCs), contributes to the pathogenesis of coronary atherosclerosis and wound repair after coronary angioplasty. However, the association between cellular proliferation in coronary lesions and clinical pathophysiology remains to be clarified in humans. Thus, we investigated proliferative activity in coronary tissues obtained from patients with coronary ischemia. The proliferative activity in tissues obtained by using directional coronary atherectomy (DCA) from 87 coronary lesions was assessed by immunohistochemical staining for the proliferating cell nuclear antigen (PCNA). The lesions were divided into 34 primary lesions and 53 postangioplasty lesions. The 34 primary tissue samples were obtained from 9 patients with stable angina pectoris (SAP) and 25 patients with acute coronary syndromes (ACS). Collectively, the 53 postangioplasty tissue samples were obtained from 37 patients with SAP and 16 patients with ACS. The PCNA labeling index (LI) was quantified as the mean percentage of PCNA-positive cells in the 3 most positive high-power fields (x 200). The mean LIs were high in the primary ACS samples [8.9 +/- 2.1% (p = 0.01)] and postangioplasty samples [2.3 +/- 0.8% (p = 0.08) in SAP cases and 4.1 +/- 2.4% (p = 0.06) in ACS cases] compared with the primary SAP samples (0.2 +/- 0.2%). Intimal hyperplasia, a random proliferation of SMCs (alpha-actin positive) was marked in the primary ACS samples (76%) as well as in the postangioplasty SAP (92%) and ACS (81%) samples, as compared with the primary SAP samples (33%) (p < 0.01). PCNA expression was mainly evident in the nucleus of the SMCs and CD68-positive macrophages. Many PCNA-positive cells were localized in plaque areas, as follows: intimal hyperplasia, neovascularized lesions, lesions with macrophage clusters, and lesions near areas of disrupted internal elastic lamina. The levels of PCNA expression in coronary lesions were not associated with the subsequent development of restenosis after DCA. Our findings suggest that the excessive proliferation of vascular wall cells, especially SMCs, is involved in the pathogenesis of ACS and in the process of wound repair after angioplasty in humans.
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PMID:Comparison of proliferative activity in coronary plaques from patients with coronary ischemia. Histopathological and immunohistochemical analysis. 911 65

Oxidation of low density lipoproteins (LDL) has been implicated as a causal factor in the pathogenesis of atherosclerosis. Oxidized LDL has been found to exhibit numerous potentially atherogenic properties in vitro, including receptor-mediated uptake by macrophages. Oxidized LDL is a ligand for the class A scavenger receptor type I/II (SR-AI/II), but cross-competition studies with cultured macrophages suggested that there is an additional receptor(s) that is specific for oxidized LDL and that does not interact with acetyl LDL or other chemically modified LDL. A number of macrophage membrane proteins, including CD36, FcgammaRII-B2, scavenger receptor BI, and macrosialin/CD68, have been found to bind to oxidized LDL in vitro and have been proposed as candidate oxidized LDL receptors. However, because of overlapping ligand specificity with the SR-AI/II, it has been difficult to evaluate the relative importance of these proteins in the uptake of oxidized LDL by macrophages. In the present report, we have studied the uptake and degradation of oxidized LDL by macrophages from mice in which the SR-AI/II gene had been disrupted. The uptake of acetyl LDL was reduced by more than 80% in macrophages from scavenger receptor knockout mice, confirming that most of the uptake of acetyl LDL by macrophages can be attributed to this receptor. In contrast, the uptake of extensively oxidized LDL was reduced by only 30% and showed high affinity, saturable uptake with apparent Km of about 5 microg/ml, similar to that of the SR-AI/II. This indicates that about 70% of the uptake of oxidized LDL in macrophages is attributable to an alternate oxidized LDL receptor(s). In contrast to findings reported with CD36, mildly oxidized LDL was internalized much more slowly than extensively oxidized LDL. Unlabeled oxidized LDL, polyinosinic acid, phosphatidylserine-rich liposomes, and LDL or bovine albumin modified by fatty acid oxidation products were effective competitors for the uptake of radioiodinated oxidized LDL by macrophages from knockout mice, whereas acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors. This ligand specificity differs from that of CD36-related (class B) scavenger receptors but is similar to the reported specificity of macrosialin/CD68 in ligand blots. However, the rate of uptake of oxidized LDL by knockout macrophages was not increased by phorbol ester or in thioglycollate-elicited macrophages, both of which are expected to increase the amount of macrosialin on the cell surface. In macrophages from SR-AI/II knockout mice, ligand blots of membrane proteins with iodinated, oxidized, or acetylated LDL revealed several bands, with apparent molecular size on SDS-polyacrylamide gel electrophoresis of 60, 94, 124, and 210 kDa, but none of the bands were specific for oxidized LDL. These results provide direct evidence that a receptor other than SR-AI/II is responsible for most of the uptake of oxidized LDL in murine macrophages, but further studies are needed to identify the receptor(s) involved.
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PMID:High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger receptor class A type I/II. 914 99

The possibility that Fas/APO 1 is involved in the apoptosis of advanced human coronary atherosclerosis was examined in the present study. Coronary arteries with atherosclerosis were obtained from human hearts with chronic ischemic heart disease at cardiac transplantation. Normal vessels were used as controls. Fas/APO 1 was detected by immunohistochemistry with a monoclonal antibody. Apoptotic cells were stained in situ by terminal deoxynucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) and DNA fragmentation into oligonucleosomes was checked by gel electrophoresis. Bcl-2, an antiapoptotic oncoprotein, was detected by immunohistochemistry and Western blot. Apoptotic cells were present in the neointima in all stages of atherosclerosis, and in intraplaque small vessels. In initial lesions, only a few cells were undergoing apoptosis. By contrast, in advanced lesions, many cells were found to undergo apoptosis. Apoptosis was further confirmed by genomic DNA analysis using gel electrophoresis. Apoptotic cells were either smooth muscle cells or macrophages, but also endothelial and blood borne cells. Fas/APO 1 was present in foam cells. Most of the Fas/APO 1 positive cells were stained for the macrophage marker CD68 and for alpha-smooth muscle actin in serial sections. Several anti-Fas/APO 1 positive foam cells were revealed to undergo apoptosis by double staining. Bcl-2 was detected in Fas/APO 1 expressing plaques. A number of CD3-positive T-lymphocytes were found around foam cells expressing Fas/APO 1. This data suggests that Fas/APO 1 regulated apoptosis is involved in the development of advanced human atherosclerotic lesions and that it probably determines the amount of tissue mass in the diseased vessels.
Atherosclerosis 1997 Jun
PMID:The role of Fas/APO 1 and apoptosis in the development of human atherosclerotic lesions. 919 70

Atherosclerotic plaques contain inflammation, composed largely of macrophages and lymphocytes. A proportion of lymphocytes shows signs of activation, but the question arises whether they are activated in an antigen specific way. The expression of costimulatory molecules-receptors that provide accessory signals during antigen-specific activation is a prerequisite for such a condition. This aspect of inflammation in atherosclerotic lesions has not been investigated. Human arterial segments with diffuse intimal thickening, fatty streaks and atherosclerotic plaques were studied with immuno-single and double staining methods. Macrophages and T lymphocytes were stained with CD68 and CD3, respectively, and pan-B cell markers CD19 and CD22 were also used. Costimulatory molecules B7-1 and B7-2, together with their common ligand CD28, and CD27 with its ligand CD70, were stained with specific monoclonal antibodies. The results show that most T lymphocytes were CD27 positive and that only a subpopulation of these (5-15%) was positive also for B7-1, CD28 and CD70. Macrophages expressed B7-1, B7-2, CD28 and CD70, while macrophages positive for CD28 and CD70 have not been reported yet. The expression of costimulatory molecules was most pronounced in the superficial layers at the fibrous cap, but decreased towards the lipid core. This study shows, therefore, that atherosclerotic plaques provide costimulatory signals generally accepted as a prerequisite for adequate T cell stimulation. In addition, this study reveals that only approximately 5-15% of the lymphocytes appears actively involved in the inflammatory reaction.
Atherosclerosis 1997 Sep
PMID:Costimulatory molecules in human atherosclerotic plaques: an indication of antigen specific T lymphocyte activation. 929 83

Inducible nitric oxide synthase (iNOS) is a high-output isoform of NOS that produces nitric oxide (NO), a nonspecific immune effector molecule. In some animal models of autoimmunity, the induction of iNOS has been shown to lead to inflammation and tissue damage, and it has been suggested that iNOS is an immune mediator in humans as well. Using in situ hybridization and immunohistochemical techniques, we demonstrate that iNOS mRNA and protein are present in the coronary arteries of transplanted human hearts with accelerated graft arteriosclerosis (AGA). iNOS is expressed in cells morphologically consistent with macrophages in the neointima of 7 of 10 of the transplanted vessels with AGA that were examined. In serial sections, these same cells express the macrophage marker CD68. In contrast, iNOS is absent from five native coronary arteries with atherosclerosis and absent from two normal coronary arteries. Although iNOS is expressed in macrophages in AGA, its role in the pathogenesis of AGA is unknown.
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PMID:Inducible nitric oxide synthase expression in coronary arteries of transplanted human hearts with accelerated graft arteriosclerosis. 932 24

F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.
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PMID:Localization of distinct F2-isoprostanes in human atherosclerotic lesions. 932 67


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