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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a physiological cell death process important for normal development and involved in many pathological conditions. In atherosclerosis, pathological accumulation of cells in the intima has been attributed to the migration and proliferation of smooth muscle cells, macrophages, and lymphocytes. In this report, we explored the possibility that apoptosis may also contribute to the pathogenesis of this disease. We examined 35 human atherosclerotic lesion samples and identified a substantial number of cells undergoing apoptosis in 25 of the samples. Furthermore, in a rat vascular injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptotic cells was demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, nuclear staining with propidium iodide, and electron microscopy. Immunostaining with cell-type-specific markers and subsequent terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling analysis on the same sample revealed that the majority of the apoptotic cells were modulated smooth muscle cells as well as macrophages. These results indicate that apoptosis occurs in cells of the injured blood vessel as well as the advanced atherosclerotic lesion and that physiological cell death may have an important role in determining the course of atherogenesis.
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PMID:Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. 763 21

In the multifunctional pathogens of atherosclerosis, oxidatively modified low density lipoprotein (LDL) plays a central role in atherogenesis. We searched to find out whether oxidized LDL (ox-LDL) could induce apoptosis in smooth muscle cells (SMCs). The induction of apoptosis was demonstrated by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling and DNA fragmentation. Ox-LDL induced apoptosis in a concentration dependent manner in the cells. The structural and biological changes in ox-LDL may be attributed to lysophosphatidylcholine (lyso-PC) accumulation and lipid peroxidation. To determine whether lyso-PC or lipid peroxide is responsible for the biological effect of ox-LDL, we incubated SMCs with lyso-PC or 7-ketocholesterol. Lyso-PC did not induce apoptosis, but 7-ketocholesterol did induce apoptosis. We conclude that ox-LDL induces apoptosis in SMCs and that this apoptosis contributes to lipid peroxidation. This mechanism may be important in determining the course of atherogenesis.
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PMID:Oxidized LDL induces apoptosis in cultured smooth muscle cells: a possible role for 7-ketocholesterol. 867 Feb 95

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

In an attempt to understand the roles of apoptosis in the development of atherosclerosis, we classified lesions developed in the aortas of apo E- and LDL receptor-deficient mice, murine models of atherosclerosis, and determined frequency, spatial distribution and cell types of apoptotic cells in each lesion. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and nuclear staining with propidium iodide were used to demonstrate apoptotic cells. Mean frequencies of TUNEL-positive cells were as follows: 0%, in Type I, 0.3% in Type II, 0.05% in Type III, 0.06% in Type IV and 0.06% in Type V lesions. Most of the TUNEL-positive cells were filled with fat and distributed in close proximity to lipid pools. The TUNEL-positive cells in the intimal side of the lipid cores were macrophages, while some of those in the adventitial side were smooth muscle cells. In conclusion, apoptosis is involved in the active turn-over of foam cells of both macrophage- and smooth muscle cell-lineage especially in the early atherosclerotic lesions of the hyperlipidemic mice.
Atherosclerosis 1997 Dec
PMID:Apoptotic cell death in atherosclerotic plaques of hyperlipidemic knockout mice. 943 Mar 73

1. The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5). 2. The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10(-6)-10(-4) M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10(-6) to 10(-5) M in A7r5 cells. However, the number of viable cells after 10(-4) M curcumin treatment was less than the basal value (2 x 10(5) cells). 3. To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10(-6)-10(-4) M) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation. 4. Following curcumin (10(-6)-10(-4) M) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10(-4) M also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation. 5. The apoptotic effect of 10(-4) M curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10(-4) M) induced cell shrinkage, chromatin condensation, and DNA fragmentation. 6. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10(-5) to 10(-4) M. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10(-4) M curcumin, but unaffected by lower concentrations (10(-6)-10(-5) M). 7. The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10(-5)-10(-4) M) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10(-4) M curcumin. However, the alteration of the p53 mRNA level by curcumin (10(-5)-10(-4) M) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting. 8. Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.
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PMID:Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells. 972 Jul 70

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

The altered coronary vasoactivity detected in experimental hypercholesterolemia before lesion formation is presumably due to an imbalance between vasodilating and vasoconstricting factors. Apoptosis, which has been previously described in advanced atherosclerosis, is modulated by vascular derived peptides with vasoactive properties. We hypothesized that coronary apoptosis occurs in experimental hypercholesterolemia prior to lesion formation. Pigs were sacrificed after being on either a high-cholesterol diet for 10-16 weeks (n = 17) or a normal diet (n = 9). Identification of apoptosis in each layer of coronary arteries and arterioles was performed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL). In additional animals, ligation-mediated polymerase chain reaction (PCR) and transmission electron and confocal microscopy were done. Plasma cholesterol levels were higher in the cholesterol-fed animals (86+/-9 mg/dl versus 342+/-20 mg/dl, P < 0.001). Atheromatous plaques were not evident in the high-cholesterol group. TUNEL was positive in 11 of 17 hypercholesterolemic animals, primarily in the intima (1-2% of cells) and adventitia (3% of cells), but not in control vessels. A similar distribution was detected in arterioles. DNA bands were detected only in experimental animals, as were morphological features of apoptosis by transmission electron and confocal microscopy. In experimental hypercholesterolemia, apoptosis occurred in coronary arteries and arterioles before lesion formation. Apoptosis may be an integral process of early coronary atherosclerosis.
Atherosclerosis 1999 Feb
PMID:Coronary artery apoptosis in experimental hypercholesterolemia. 1003 Mar 83

Oxidized low density lipoproteins (LDLs) play a central role in atherosclerosis, and their toxicity is due, at least in part, to the formation of oxysterols that have been shown to induce apoptosis in various cell types. As 7beta-hydroxycholesterol and 7-ketocholesterol are the major oxysterols found in oxidized LDLs, we have investigated and compared the mode of cell death, apoptosis versus necrosis, that they induce in the cells of the vascular wall, ie, endothelial cells, smooth muscle cells, and fibroblasts. To this end, human vascular endothelial cells from umbilical cord veins (HUVECs), human artery smooth muscle cells, A7R5 rat smooth muscle cells, MRC5 human fibroblasts, and human fibroblasts isolated from umbilical cord veins were taken at confluence and incubated for 48 hours with 7beta-hydroxycholesterol or 7-ketocholesterol (concentration range, 5 to 80 microg/mL). In all cells, both 7beta-hydroxycholesterol and 7-ketocholesterol exhibited toxic effects characterized by a loss of cell adhesion and an increased permeability to propidium iodide. In oxysterol-treated endothelial and smooth muscle cells, typical features of apoptosis were revealed: condensed and/or fragmented nuclei were detected by fluorescence microscopy after staining with Hoechst 33342, oligonucleosomal DNA fragments were visualized in situ in the cell nuclei by the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method, and internucleosomal DNA fragmentation was found on agarose gel. In contrast, in oxysterol-treated fibroblasts, fragmented and/or condensed nuclei were never revealed, and no DNA fragmentation was observed either by the TUNEL method or by DNA analysis on agarose gel, indicating that these oxysterols induced necrosis in these cells but not apoptosis. In addition, acetylated Asp-Glu-Val-L-aspartic acid aldehyde (an inhibitor of Asp-Glu-Val-L-aspartic acid-sensitive caspases) prevented 7beta-hydroxycholesterol- and 7-ketocholesterol-induced cell death in HUVECs and smooth muscle cells but not in fibroblasts. Thus, 7beta-hydroxycholesterol and 7-ketocholesterol have dual cytotoxic effects on the cells of the vascular wall by their ability to induce apoptosis in endothelial and smooth muscle cells and necrosis in fibroblasts.
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PMID:Characterization and comparison of the mode of cell death, apoptosis versus necrosis, induced by 7beta-hydroxycholesterol and 7-ketocholesterol in the cells of the vascular wall. 1032 69

Apoptotic macrophages are regularly found in atherosclerotic plaques indicating programmed cell death as one of their regulatory controls. The objective of this study was to characterize in more detail apoptotic macrophages in atherosclerotic lesions of humans and heritable hyperlipidemic (HHL) rabbits. Macrophages were immunohistochemically analyzed using antibodies directed against alphaMbeta2-integrins (CD11b/CD18), CD44, major histocompatibility complex (MHC) class I and II, inducible nitric oxide synthase (iNOS), manganese superoxide dismutase (MnSOD), tumor necrosis factor alpha (TNFalpha), p53, c-jun/AP-1 and rabbit macrophages (RAM-11) and the TUNEL (TdT-mediated dUTP nick end labeling) technique. Colocalization studies of human atherosclerotic carotid and aortic tissue showed apoptotic plaque macrophages also being MnSOD-, alphaMbeta2-integrin-, CD44-, MHC class I- and II-, iNOS-, TNFalpha- and p53-immunoreactive. Similar results occurred in atherosclerotic aortas of HHL rabbits. Computer-assisted morphometric analyses revealed a positive correlation of the area density of MnSOD-immunoreactive macrophages with those of alphaMbeta2-integrin- and CD44-immunoreactive ones, but not with those of MHC class I- and II- as well as of RAM-11-immunoreactive macrophages. We conclude that apoptotic macrophages located in atherosclerotic vessel wall are activated, antigen-presenting, integrin-expressing and oxidatively stressed cells. Since all these processes have been demonstrated to cause apoptosis of macrophages in vitro, we propose their potency accelerates the susceptibility of the macrophages to programmed cell death in atherosclerotic lesions.
Atherosclerosis 1999 May
PMID:Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits. 1038 Dec 75

There is a type of arteriosclerosis with remodeling of middle-size arteries in which intimal hyperplasia of smooth muscle cells (SMCs) plays the main role, and there are few macrophages, T lymphocytes, and foam cells. It is unknown whether apoptosis and the expression of Bax, an inducer of apoptosis, are increased according to the progression of this type of human arteriosclerosis, which is different from so-called atherosclerosis. Bax heterodimerizes with Bcl-2, an inhibitor of apoptosis, and the ratio of Bax to Bcl-2 determines cellular apoptosis or survival. Thus, we investigated apoptosis and the expressions of Bax, bax mRNA, and Bcl-2 in human arteriovenous (AV) fistulas used for hemodialysis, a representative of arteriosclerosis of the aforementioned type. The material was 20 radial arteries obtained from 20 patients with chronic renal failure undergoing AV shunt surgery. SMCs, macrophages, and T lymphocytes were immunohistochemically identified at the light microscopic (LM) level. Apoptosis was detected by in situ terminal deoxynucleotidyl transferase (TdT)-mediated digoxigenin-dUTP nick end labeling (TUNEL) at both the LM and electron microscopic (EM) level. Cell proliferating activity was estimated by proliferating cell nuclear antigen (PCNA). Bax and Bcl-2 were detected by immunohistochemistry and Western blot analysis. Expression of bax mRNA was detected by in situ hybridization. LM TUNEL-positive cells in both the intima and media were significantly increased according to the percent stenosis of the vessels. EM analysis revealed that ultrastructures of apoptotic SMCs were seen in both synthetic and contractile phenotypes. Their frequency of occurrence in the intima and media were greater in those vessels with >50% stenosis than in those with <50% stenosis (5.2+/-0.7% versus 1.0+/-0.3% in the intima and 2. 1+/-0.5% versus 0.2+/-0.1% in the media). The proportion of apoptotic SMCs with ruptured plasma membranes was greater than that of apoptotic SMCs with intact membranes in the intima of the former (4.1+/-0.6% versus 1.1+/-0.1%). Only those SMCs with apoptotic ultrastructures had TUNEL-positive nuclei with moderate or marked accumulation of immunogold particles at the EM level. However, ultrastructures of oncosis (primary necrosis) were not observed. Immunohistochemical analyses showed significant positive correlations between percent stenosis of vessels and the percentage of either PCNA-positive intimal cells or Bax-positive areas in the intima and media. Bcl-2-positive cells were not observed in the intima but mainly in the outer media. The percentage of Bcl-2-positive medial cells was definitely decreased at an early stage after formation of the AV fistula but did not change according to the duration of hemodialysis or the progression of arteriosclerosis. Western blot analysis of Bax or Bcl-2 and in situ hybridization of bax mRNA confirmed the immunohistochemical data. Thus, regulation of cellularity in intimal hyperplasia of SMCs in human arteriosclerosis with remodeling is mediated by proliferation and apoptosis but not oncosis. The apoptosis is probably induced by an increase in the Bax to Bcl-2 ratio.
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PMID:Apoptosis and overexpression of bax protein and bax mRNA in smooth muscle cells within intimal hyperplasia of human radial arteries : analysis with arteriovenous fistulas used for hemodialysis. 1047 47


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