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)

We examined 164 endomyocardial biopsy specimens from 29 patients who received an orthotopic heart transplant since 1984. Rejection was graded according to the Hannover classification. Non-isotopic in situ DNA hybridization was conducted on cryostat sections with biotinylated probes for herpes simplex virus, Epstein-Barr virus, and cytomegalovirus. Serial sections of 126 biopsies were investigated immunohistochemically for the presence of activated T lymphocytes and proliferating cells, with monoclonal antibodies against interleukin 2 receptors (CD 25) and Ki-67 antigen. Relations between rejection grades, presence of proliferating cells, and presence of herpesvirus DNA were determined for the total number of biopsies. For some patients correlation of these parameters was studied over time. Herpesviral nucleic acids were detected in 25% of all biopsies: 37% of biopsies with relevant rejection (grades A 2 or A 3; 39% of all biopsies) compared to 18% of biopsies graded A 0, A 1, or A 5 (61% of all samples) (P less than 0.01). 56% of the biopsies with infection showed relevant rejection as compared with only 33% of the uninfected. Ki-67 expression was found in 41% of all biopsies, mainly in infiltrating cells: 69% of biopsies with relevant rejection compared with 23% of cases of minor/no rejection (P much less than 0.001). Ki-67 expression was also associated with herpesvirus infection: 66% of infected biopsies contained Ki-67 positive cells compared with 33% of uninfected biopsies (P less than 0.001). Herpesvirus infection was usually observed within the interstitial cell population, which, in many cases, displayed a considerable Ki-67 expression, too. In few cases only, hybridization was unequivocally found in vascular wall cells or myocytes. Viral myocarditis does not only mimic graft rejection morphologically, but it may also affect the course of rejection, via induction of antigenic changes or direct injury of cardiac tissues. Virus infections may also elicit or aggravate obliterative coronary artery disease, and thus contribute to accelerated graft atherosclerosis.
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PMID:Rejection, herpesvirus infection, and Ki-67 expression in endomyocardial biopsy specimens from heart transplant recipients. 131 59

During repair of 12 atherosclerotic abdominal aortic aneurysms, fresh samples of aneurysm wall were obtained. Histology confirmed the presence of advanced atherosclerosis associated with medial thinning and a variable aortic adventitial chronic inflammatory cell infiltrate. Monoclonal antibodies were used to identify the inflammatory cells throughout the aortic wall. The majority of lymphocytes in the aortic adventitia were B-cells. B-cells were not present in atheromatous plaques. T-cells, predominantly T-helper cells, were found in atheromatous plaques and in aortic adventitia. The majority of lymphocytes and macrophages in aortic adventitia and most vascular endothelial cells were HLA-DR positive. Ki-67 staining was found in B-cells and T-helper cells, indicating that these cells were proliferating. Occasional lymphocytes were BerH2 positive, indicating that some lymphocytes were activated. These findings suggest that chronic periaortitis is an active, immunologically mediated, local complication of advanced human atherosclerosis.
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PMID:Immunohistochemical characterization of inflammatory cells associated with advanced atherosclerosis. 207 87

Seven cases of inflammatory abdominal aortic aneurysms (IAs) were studied by light microscopy, transmission electron microscopy (TEM) and immunohistochemistry. Microscopically, atherosclerosis coexisted with adventitial fibrosis and inflammation. The inflammatory component showed a follicular and a diffuse pattern. Fibrous entrapment of fatty tissue, adventitial vasculitis, neuritis were also common findings. By TEM, sparse smooth muscle cells having dilated cisternae of rough endoplasmic reticulum, large bundles of collagen fibres and oedematous, amorphous fibrillary elastin were observed. By immunohistochemistry, the follicles mostly contained CD22+ B-cells. T4- (CD2+/CD4+/CD8-), T8-(CD2+/CD4-/CD8+) cells as well as macrophages (CD4+/CD11c+) and follicular dendritic reticulum cells (DRC1+) were also detected. The monoclonal antibody Ki-67 reacted with 2-48% of germinal center cells. In the fibrous extrafollicular adventitia, actively synthesizing plasma cells prevailed over T4-cells, and macrophages. Some of the macrophages were also activated (CD4+/CD11c+/CD25+/CD30-). IgM, IgG and C3c deposits were detected in the fibrous zone, in the germinal centers, within adventitial vessels and nerves. HLA-DR antigen was diffusely expressed in cells populating both the fibrous and the follicular zones as well as in endothelial and Schwann cells. These findings suggest that IAs could develop in some individuals affected by advanced atherosclerosis of the abdominal aorta through a pathogenic B-cell response to locally presented antigens.
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PMID:An immunohistochemical study of inflammatory abdominal aortic aneurysms. 809 31

Atherosclerosis is a fibroproliferative disease of the arterial intima. It was recently found that wild-type p53 (wt p53) accumulates in human atherosclerotic tissue. Wt p53 is a cell cycle regulator involved in DNA repair, DNA synthesis, cell differentiation, and apoptosis and might therefore make an important contribution to the cellularity of atherosclerotic plaques. The product of the MDM2 gene is a nuclear protein which forms a complex with p53, thereby inhibiting the negative regulatory effects of wt p53 on cell cycle progression. In order to address a potential role of the interaction of p53 with MDM2 for the regulation of cellularity in atherosclerotic tissue, 22 carotid atheromatous plaques from patients undergoing endarterectomy were studied to determine the presence of p53 immunoreactivity (IR), MDM2 IR, cell proliferation as evidenced by MIB1/Ki-67 IR and DNA fragmentation by in situ terminal transferase-mediated dUTP 3' end labelling (TUNEL), as a marker for apoptosis. p53 IR localized to areas with evidence of chronic inflammation (22/22) and was observed in virtually all cell types in 68.79 +/- 7.51 per cent of the nuclei. p53 staining in the control tissue from human internal mammary arteries was present in 0.2 +/- 0.29 per cent of the cells (P < or = 0.002). MDM2 IR was present in all cases (22/22) in macrophages and smooth muscle cells (SMCs) in 60.53 +/- 8.32 per cent of the nuclei (controls: 0.8 +/- 0.65 per cent, P < or = 0.002) and co-localized with p53 IR as shown by examination of adjacent sections and by double immunofluorescence labelling. Importantly, co-immunoprecipitation and western blot analysis revealed that p53 and MDM2 were physically associated, indicating that MDM2-p53 complex formation takes place in vivo in human atherosclerotic tissue. Positive TUNEL staining and MIB1/Ki-67 IR present in 3.01 +/- 1.27 per cent of the nuclei (controls: 0 per cent, P < or = 0.002) localized to the same plaque compartments as p53 IR and MDM2 IR. Thus, the fate of cells with p53 accumulation may depend on the interaction and the stoichiometry of the p53 and MDM2 proteins. Cells were indeed found with strong p53 accumulation and nuclear morphology typical for apoptosis and there were a few MIB1/Ki-67-positive cells with co-expression of MDM2, indicating a possible role for MDM2 in reversing the negative regulatory effects of p53 for cell cycle progression. The nuclear co-localization of p53 IR with MDM2 IR and the co-immunoprecipitation assay indicate the presence of p53-MDM2 complex formation in vivo in human atherosclerotic tissue. The destiny of individual p53 and MDM2-co-expressing cells either to undergo p53-dependent apoptosis or to re-enter the cycle of cell proliferation may depend on the relative ratios of the two proteins. p53 and MDM2 may therefore play an important role in regulating cellularity and inflammatory activity in human atherosclerotic plaques.
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PMID:Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. 977 85

Because of their possible beneficial effects on atherosclerosis and cancer risk, soy-derived isoflavone phytoestrogens may be useful as a dietary alternative or supplement to postmenopausal hormone replacement therapy. We examined this possibility in a well-characterized primate model of postmenopause. Adult, surgically postmenopausal female macaques (Macaca fascicularis) were treated continuously with either estradiol (E2), an isoflavone-rich soy protein isolate (SPI), or both (E2+SPI). Doses were equivalent on an energy basis to 1 and 148 mg/d per woman for E2 and SPI, respectively. After 6 mo, histopathologic, morphometric, and immunohistochemical measurements of the endometrium and mammary glands were taken. Increases in endometrial thickness, gland area, and epithelial proliferation were induced by E2 and E2+SPI. Morphometric changes were accompanied by increased epithelial staining of the proliferation marker Ki-67 in the E2-treated group. The effects of E2 were partially antagonized by SPI (manifested as decreased Ki-67 staining). Mammary gland proliferation was induced by E2 and E2+SPI. The effects of E2 were also antagonized by SPI in the mammary gland. Morphometric and immunohistochemical measures of proliferation were in agreement in endometrium. In this nonhuman primate model, treatment with SPI did not induce proliferation in endometrial and mammary tissue. SPI may have antiproliferative effects in the endometrium and mammary gland when given along with exogenous estrogen.
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PMID:Effects of mammalian and plant estrogens on mammary glands and uteri of macaques. 984 9

We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.
Atherosclerosis 2000 Jun
PMID:Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. 1085 25

The aim of the present study was to investigate anti-proliferative and anti-atherogenic properties of 17beta-estradiol in balloon injured female and male rabbit aortae. Thirty-two female and 32 male New Zealand White rabbits where gonadectomised. Vascular injury was performed with a balloon catheter in the lower abdominal aorta. Male and female rabbits were randomised into four groups of eight animals each. Only two of four groups received a 0.5% cholesterol-enriched diet. One cholesterol-diet group and one normal-diet group received intramuscular injections of estradiol valerate (1 mg/kg body weight/week). After 28 days, the denuded part of the abdominal aorta was excised and analysed by morphometry and immunohistochemistry. Estrogen treatment did not show an inhibitory effect on neointimal proliferation in normo-cholesterolemic male or female rabbits. A gender independent inhibitory effect of 17beta-estradiol was seen on atheroma development in cholesterol-fed female and male rabbits, while plasma total cholesterol levels were significantly reduced in male rabbits only. The 17beta-estradiol treatment was associated with a significantly decreased number of luminal endothelial cells in normo and hyper-cholesterolemic female rabbits, as evaluated by immunohistochemical staining for 'von Willebrand factor'. Staining for Ki-67-positive proliferating cells after 28 days showed a statistically significant increased proliferative activity in the neointima of hyper-cholesterolemic female rabbits. The neointimal content of macrophages increased significantly in all hyper-cholesterolemic rabbits. Under 17beta-estradiol treatment, the number of macrophages was increased in female and decreased in male rabbits by tendency. Additionally, the 'classical' vascular estrogen receptor was present in both female and male rabbit aortae without statistically significant differences. In conclusion, 17beta-estradiol did not reduce post-injury neointima formation in normo-cholesterolemic rabbits. However, in hyper-cholesterolemic rabbits, 17beta-estradiol reduced atheroma development gender independently. This effect cannot be explained by lowering of plasma cholesterol levels or endothelium-mediated pathways, and requires further investigation on, for example, antioxidative, antiproliferative or estrogen receptor mediated effects.
Atherosclerosis 2001 Jan
PMID:17beta-estradiol, gender independently, reduces atheroma development but not neointimal proliferation after balloon injury in the rabbit aorta. 1113 81

Advanced atherosclerotic lesions often contain adventitial lymphoid infiltrates, which occasionally contain nodular aggregates resembling lymphoid follicles. The structural organization suggests that local maturation of B cells may take place at these sites, as described for the mucosa-associated lymphoid tissue (MALT). This concept was evaluated by studying the micro-anatomy and cellular composition of adventitial infiltrates associated with advanced atherosclerosis of the aorta. Sections of 22 atherosclerotic aortas were stained immunohistochemically for cellular markers characteristic for lymphoid follicles, such as HECA-452-positive endothelial cells, CD20-positive B cells, CD21-positive follicular dendritic cells, and CD68-positive macrophages. Ki-67 was used as a proliferation marker. The TUNEL technique was used to study the presence of apoptotic cells. Specimens containing MALT served as comparison and positive controls. Seven of the 22 atherosclerotic aortas contained adventitial infiltrates resembling lymphoid follicles. The organized nodular centres were composed of CD45RA+ B cells, follicular dendritic cells (CD21+), a few T lymphocytes (CD3+) and 'tingible body' macrophages (CD68+). A large number of cells were Ki-67-positive; apoptotic bodies were numerous and phagocytosed by macrophages. The parafollicular area contained CD45RO-positive T cells and HECA-452-positive vessels. Vessels elsewhere were always HECA-452-negative. Specimens with MALT showed similar features. This study reveals a close resemblance between adventitial lymphoid infiltrates in advanced atherosclerotic aortic disease and MALT, suggesting local generation of a humoral immune response, likely to be initiated by antigens released during a process of long-standing tissue injury and inflammation as part of advanced atherosclerosis.
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PMID:Adventitial infiltrates associated with advanced atherosclerotic plaques: structural organization suggests generation of local humoral immune responses. 1118 Jan 75

CAP37, a neutrophil-derived protein, originally identified for its antimicrobial activity is now known to have strong immunoregulatory effects on host cells. Recently, we described its expression and localization within the vascular endothelium associated with atherosclerotic plaques. Since CAP37 is a potent activator of endothelial cells and monocytes, two of the key cellular components of the atherosclerotic plaque, this study was undertaken to determine whether CAP37 had functional effects on smooth muscle cells another important cellular participant in atherosclerosis. Sections from atherosclerotic lesions were stained for the presence of CAP37 and smooth muscle cell alpha actin. The effect of CAP37 on aorta smooth muscle cell migration and proliferation was investigated and the upregulation of adhesion molecules was determined. Immunocytochemistry indicated that CAP37 was present in a subset of smooth muscle cells within atherosclerotic lesions, but was absent in normal vessels. Flow cytometry using double labeling for the proliferation marker Ki-67 and CAP37 demonstrates that CAP37 is mainly expressed in proliferating smooth muscle cells. We show that CAP37 supports migration and proliferation of smooth muscle cells in vitro. Furthermore, CAP37-treated smooth muscle cells expressed higher levels of the cell adhesion molecule ICAM-1 when compared with untreated cells. We suggest that due to its localization to atherosclerotic plaques and its ability to modulate smooth muscle cells, CAP37 may play a role in the progression of this disease.
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PMID:Functional modulation of smooth muscle cells by the inflammatory mediator CAP37. 1502 Feb 8

In response to biological and mechanical injury, or in vitro culturing, vascular smooth muscle cells (VSMCs) undergo phenotypic modulation from a differentiated "contractile" phenotype to a dedifferentiated "synthetic" one. This results in the capacity to proliferate, migrate, and produce extracellular matrix proteins, thus contributing to neointimal formation. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP or cGMP, are critical in the homeostasis of cyclic nucleotides that regulate VSMC growth. Here, we demonstrate that PDE1A, a Ca2+-calmodulin-stimulated PDE preferentially hydrolyzing cGMP, is predominantly cytoplasmic in medial "contractile" VSMCs but is nuclear in neointimal "synthetic" VSMCs. Using primary VSMCs, we show that cytoplasmic and nuclear PDE1A were associated with a contractile marker (SM-calponin) and a growth marker (Ki-67), respectively. This suggests that cytoplasmic PDE1A is associated with the "contractile" phenotype, whereas nuclear PDE1A is with the "synthetic" phenotype. To determine the role of nuclear PDE1A, we examined the effects loss-of-PDE1A function on subcultured VSMC growth and survival using PDE1A RNA interference and pharmacological inhibition. Reducing PDE1A function significantly attenuated VSMC growth by decreasing proliferation via G1 arrest and inducing apoptosis. Inhibiting PDE1A also led to intracellular cGMP elevation, p27Kip1 upregulation, cyclin D1 downregulation, and p53 activation. We further demonstrated that in subcultured VSMCs redifferentiated by growth on collagen gels, cytoplasmic PDE1A regulates myosin light chain phosphorylation with little effect on apoptosis, whereas inhibiting nuclear PDE1A has the opposite effects. These suggest that nuclear PDE1A is important in VSMC growth and survival and may contribute to the neointima formation in atherosclerosis and restenosis.
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PMID:Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. 1657 12


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