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

We have investigated the toxicity of the cholesterol oxidation products (oxysterols), 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol and 26-hydroxycholesterol to human monocyte-macrophages in vitro. The 7-position derivatives are present in low density lipoprotein (LDL) oxidised with copper (II) sulphate and macrophages, and in extracts of human atherosclerotic lesions, which also contain 26-hydroxycholesterol. We have also assessed 25-hydroxycholesterol for toxicity because it has often been used in studies of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition and LDL receptor down-regulation. Measurement of radioactivity release from monocyte-macrophages preloaded with tritiated adenine, as a means of assessing cytotoxicity that all the oxysterols showed time- and concentration-dependent toxicity. The cytotoxic potency of 26-hydroxycholesterol was the greatest. The 7-position derivatives also produced marked cell damage, though at higher concentrations than for 26-hydroxycholesterol. Of the oxysterols assessed, the toxicity of 25-hydroxycholesterol was the least. The cytotoxicity of 7 beta-hydroxycholesterol and 26-hydroxycholesterol was also shown using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) dye reduction assay which confirmed that 26-hydroxycholesterol was more toxic than 7 beta-hydroxycholesterol. Incubation of monocyte-macrophages with cholesterol added to the different oxysterols gave varying results. Cholesterol, which was not itself toxic, inhibited the toxicity of 25-hydroxycholesterol and 26-hydroxycholesterol, but the toxicity of the 7-position derivatives was not affected. The possible relevance of these molecules to the death of macrophages seen in atherosclerosis is discussed.
Atherosclerosis 1995 Nov
PMID:Toxicity of oxysterols to human monocyte-macrophages. 857 33

The inhibition of experimental atherosclerosis by antioxidants and the presence of oxidized LDL (oxLDL) in atherosclerotic lesions indicate that oxLDL may play what is perhaps a primary role in atherogenesis. LDL promotes the growth of arterial smooth muscle cells (SMCs), and oxLDL has cytotoxic effects. Since excessive intimal growth alternating with necrosis is typical of atherosclerotic lesions, we wondered whether these extreme changes in the lesions could be related to the extreme effects of LDL and oxLDL on cells. We therefore examined the effects of increasing LDL oxidation on its capacity to induce cell growth or cell death and whether the latter could be due to apoptosis. Cells of the types present in the atherosclerotic artery used, ie, SMCs (human arterial), macrophages (human macrophage-like cell line THP-1), and human fibroblasts. Growth was evaluated by measuring the synthesis of DNA and culture size (MTT method) and apoptosis by using the in situ labeling of internucleosomally degraded DNA and, in the case of SMCs, the appearance of chromatin condensation. The oxidation of LDL was by UV or Fe ions. Shortly oxidized LDL had a markedly increased growth-promoting effect on all cell types. With prolonged exposure to UV, but not to Fe, LDL became increasingly cytotoxic, and this toxicity was paralleled by the appearance of apoptosis in all cell types. After prolonged UV treatment, low-molecular-weight material from the partially degraded LDL was responsible for the induction of apoptosis. The dual effect of oxLDL, ie, its strong growth-promoting effect or the induction of cell death by apoptosis, depending on the degree of change by oxidation, is compatible with the notion that oxLDL plays a role not only in atherogenesis but also more extensively in the development of the structure typical of the atherosclerotic lesion, with focal excessive growth alternating with necrosis.
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PMID:Contrary effects of lightly and strongly oxidized LDL with potent promotion of growth versus apoptosis on arterial smooth muscle cells, macrophages, and fibroblasts. 863 Jun 68

Mesenchymal cell migration and replication are central biologic events involved in atherosclerosis and lung and hepatic fibrosis. Tissue repair and fibrosis are thought to be regulated by growth regulatory molecules, comprising both stimulators and inhibitors of mesenchymal cell functions, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), fibroblast growth factors, and several neuropeptides such as substance P. Secretoneurin (SN), a novel 33-amino acid neuropeptide derived from secretogranin II (chromogranin C), is widely distributed in the central and peripheral nervous and neuroendocrine systems, including afferent C-fibers, and can be released in the periphery by capsaicin. Recently, we reported that SN triggers the selective migration of human monocytes and fibroblasts in vitro, implicating its involvement in inflammatory responses. We report herein that SN stimulates specific migration (maximal response at 10(-10) M) of cultured arterial smooth muscle cells (SMCs), originating from rat thoracic aorta, and initiates DNA synthesis and SMC growth (BrdU incorporation, MTT test) with a maximum at 10(-8) M SN to a similar extent as observed by PDGF. Both functional activities of SN were inhibited by specific anti-SN immunoglobulins (dilution, 1:1000), and furthermore, a trypsinized SN peptide (10(-8) M) was unable to provoke biologic effects. Our studies suggest that SN functions as a regulatory peptide to modulate SMC migration and proliferation, which in conjunction with other factors could serve to aggravate and accelerate the development of atherosclerotic or restenotic lesions at sites of vascular injury.
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PMID:Response of vascular smooth muscle cells to the neuropeptide secretoneurin. A functional role for migration and proliferation in vitro. 935 68

Allylamine (AA, 3-aminopropene) is a specific cardiovascular toxin used experimentally to model myocardial necrosis and atherosclerosis. In these physiologic experiments, 10-day AA exposure (100 mg . kg-1 . day-1 by gavage) produced severe myocardial necrosis and increased heart rate but did not affect systolic blood pressure in rats. Mid-thoracic aortic ring segments were removed, and reactivity to contractile and relaxant agonists was tested. Aortic rings (approximately 3 mm) from AA-treated rats were contracted significantly more by high potassium (100 mM) and slightly more by norepinephrine (NE, 10 microM) than anatomically matched control aortic rings. No difference in aortic ring NE sensitivity or percentage relaxation in response to acetylcholine (1 microM) or sodium nitroprusside (100 microM) was detected between control and AA-treated rat aortic rings. Allylamine (1 microM-1 mM) induced modest, concentration-dependent contractions and tension oscillations in aortic rings from both control and AA-treated rats. Aortic rings from AA-treated rats, however, were more sensitive to AA. Vascular smooth muscle cells derived from control and AA-treated rat aortas had similar toxic sensitivity to AA in vitro using the MTT viability assay. The mechanisms by which AA exposure increased heart rate in vivo and contractility of aortic rings are unknown. These experiments support the previously proposed concept that AA-induced acute myocardial necrosis is due to coronary vasospasm and myocardial ischemia and cell injury.
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PMID:Allylamine cardiovascular toxicity: evidence for aberrant vasoreactivity in rats. 947 32

Oxygen radical injury and lipid peroxidation have been suggested as major causes of cancer, atherosclerosis and the aging process. We examined in vitro the effect of garlic on H2O2-induced oxidant injury in bovine pulmonary artery endothelial cells (PAEC). After overnight preincubation with Aged Garlic Extract (AGE, from Wakunaga Pharmaceutical Co., Ltd., Japan) or S-allyl cysteine (SAC), PAEC monolayers were exposed to H2O2 for 3 h. Cell viability (MTT assay), lactate dehydrogenase (LDH) release, and lipid peroxidation (TBA-RS) were measured to assess oxidant injury. AGE (1-4 mg/ml) pretreatment significantly reduced the loss of cell viability induced by 50-100 microM of H2O2. AGE and SAC exhibited dose dependent inhibition of both LDH release and TBA-RS production induced by 50 microM of H2O2. The results show that AGE and SAC can protect vascular endothelial cells from oxidant injury. Numerous garlic compounds could be involved in the antioxidant properties of garlic, while there could be some prooxidant compounds derived from garlic. It is important to keep an array of antioxidant compounds to develop good herbal preparation, like AGE.
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PMID:[Garlic compounds protect vascular endothelial cells from oxidant injury]. 950 21

To clarify the mechanism of cellular injury through the nonenzymatic reaction of glucose with proteins, we studied the cytotoxic effect of glycated bovine serum albumin on cultured smooth muscle cells in the presence of cupric ion. Glycated proteins were prepared by incubating bovine serum albumin with 0.5 M D-glucose in 0.3 M sodium phosphate buffer at 37 degrees C for 2, 4 and 16 weeks (g-BSA-2, g-BSA-4 and g-BSA-16, respectively). Early glycation products, such as fructosamine, were formed more than two weeks after incubation. However, the immunoreactivity of glycated proteins to anti-AGE antibody was 12-fold higher in g-BSA-16 than in g-BSA-2. Both g-BSA-2 and g-BSA-16 showed a concentration-dependent cytotoxicity in smooth muscle cells in the presence of 80 microM cupric ion by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) dye reduction assay and dye exclusion test. Flow cytometry and spectrofluorophotometry using dihydrorhodamine 123 showed that the extracellular generation of oxidants was dose-dependently enhanced with increasing concentrations of g-BSA-2 or g-BSA-16 in the presence of cupric ion. However, no difference was observed in the intracellular generation of oxidants between the presence and absence of glycated proteins by flow cytometry using 2', 7'-dichlorofluorescein diacetate. Cytotoxicity and oxidant generation were prevented by catalase and tiron, but not by superoxide dismutase or mannitol, a hydroxyl radical scavenger. These results indicate that smooth muscle cells may be damaged by reactive oxygen species which are produced extracellularly by the interaction with the early glycation products and cupric ion, and suggest that hydrogen peroxide may be a candidate for reactive oxygen species which contribute to such oxidative damage of smooth muscle cells.
Atherosclerosis 1998 Feb
PMID:Oxidative damage of vascular smooth muscle cells by the glycated protein-cupric ion system. 954 97

Oxidized low-density lipoprotein (oxLDL) plays a key role in the development of atherogenesis, partly by causing injury to vascular cells. However, different preparations of LDL, methods of oxidation, and/or active components often produce cellular effects of various degrees. To explore the quantitative relationship between dose and level of oxidation of the oxLDL utilized, we employed combinations of different levels of oxidation and concentrations of oxLDL to induce cell death in cultured vascular smooth muscle cells (VSMC). We also examined the effect of lysophosphatidylcholine (lysoPC), a putative active component of oxLDL, on VSMCs by determining, in parallel with a cytotoxicity test (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay), DNA fragmentation ([3H]thymidine release), and flow cytometric analyses. We found that oxLDL caused cytotoxicity in an oxidative level- and dose-dependent manner, lysoPC also caused dose-dependent cytotoxicity with or without serum. Fragmentation of DNA was observed in both oxLDL- and lysoPC-treated VSMCs. Furthermore, lysoPC-induced DNA ladder was also demonstrated by gel electrophoresis at a concentration of 25 micromol/l or higher. Flow cytometric analysis yielded similar results for oxLDL- and lysoPC-treated VSMC; namely, an accumulation in the fraction of cells in G(0)/G(1) phase with a reciprocal change in S-phase fraction. Membrane phosphatidylserine exposure, detected by annexin V staining, provided additional evidence that lysoPC induced significant apoptosis in VSMC. Taken together, the degree of oxLDL-induced cytotoxicity/apoptosis of VSMC depended on combined effects of oxLDL concentration and oxidative level. Moreover, lysoPC also elicited a dose-dependent apoptosis in addition to cytotoxicity.
Atherosclerosis 2000 Aug
PMID:Lysophosphatidylcholine induces apoptotic and non-apoptotic death in vascular smooth muscle cells: in comparison with oxidized LDL. 1092 25

The aim of this study was to evaluate the effects of advanced glycation end-products (AGEs) on the proliferative activity and fibronectin production of smooth muscle cells (SMCs). AGE-bovine serum albumin (AGE-BSA) was prepared by incubation with D-glucose at 37 degrees C for 60 days. Cultured SMCs were obtained from explants isolated from porcine abdominal aorta and used between passages 3 and 10. The proliferative activity of SMCs was examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and by incorporation of 3H-thymidine into DNA. Fibronectin production was assessed by competitive ELISA assay for both fibronectin secreted into the culture medium (M-FN) and cell-associated fibronectin (C-FN), i.e., both intra- and peri-cellular fibronectin. Theassay revealed that AGE-BSA did not produce any change in optical density (A570) of SMCs at concentrations of up to 20 microg/ml, but decreased that of SMCs at a concentration of 40 microg/ml. The addition of PDGF (5 ng/ml) induced an increase in 3H-thymidine incorporation into DNA of quiescent SMCs, while the addition of AGE-BSA (20 microg/ml) had no effect. In contrast, AGE-BSA significantly increased C-FN of SMCs (30.8+/-8.58 ng/microg TP), compared to unmodified BSA (16.5+/-4.19 ng/microg TP). However, no difference in M-FN levels was observed between cells treated with AGE-BSA and unmodified BSA. The addition of anti-transforming growth factor (TGF)-beta antibody restored the levels of C-FN in SMCs cultured in 20 microg/ml of AGE-BSA, suggesting that TGF-beta might act as an intermediate factor in AGE-induced fibronectin production by SMCs. Our results suggest that interaction of AGE-modified proteins with SMCs may play a role in the development of atherosclerosis in diabetic and non-diabetic patients.
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PMID:Effects of advanced glycation end products on the proliferation and fibronectin production of smooth muscle cells. 1148 Apr 59

Serum apolipoprotein AI (apoAI) levels correlate with the risk of developing atherosclerosis. Previous studies have suggested that dehydroepiandrosterone (DHEA) lowers high-density lipoprotein (HDL)-cholesterol levels. We investigated whether or not DHEA may lower HDL-cholesterol levels by suppressing apoAI gene transcription in hepatocytes. ApoAI mRNA levels, assessed by Northern blotting, were suppressed in HepG2 cells treated with DHEA (34%) (10 microg/mL) or testosterone (36%) (T, 1 microg/mL). Estradiol alone (E2, 1 microg/mL) had relatively little effect on apoAI mRNA levels, while E2 in combination with DHEA prevented a decrease in apoAI mRNA levels compared to DHEA alone. To determine whether these effects were due to changes in apoAI gene transcription, HepG2 cells were transfected with a plasmid carrying the full-length promoter of the rat apoAI gene ligated into a chloramphenicol acetyltransferase (CAT) reporter construct. The plasmid pCMV.SPORT-beta-gal was included in each transfection to normalize the data to transfection efficiency. Cells were then cultured in the presence or absence of DHEA (10 microg/mL), T (1 microg/mL), 17alpha-methyltestosterone (MTT, 1 microg/mL), 5alpha-dihydrotestosterone (DHT, 1 microg/mL), E2 (1 microg/mL), or a combination of DHEA plus E2, T plus E2, MTT plus E2, and DHT plus E2, for 24 hours. CAT activity, relative to beta-galactosidase activity, was reduced by 19.6%, 57.6%, 38.6%, and 54.6% with DHEA, T, DHT, and MTT addition, respectively. E2 increased CAT activity by 43.8%. When the androgens (ie, DHEA, T, DHT, or MTT) were combined with E2, apoAI promoter activity was suppressed. We conclude, therefore, that androgens downregulate apoAI promoter activity in the presence or absence of E2. However, the changes in mRNA levels do not always reflect changes in promoter activity, suggesting that these steroids may have additional post-transcriptional effects on steady-state apoAI mRNA levels. It remains to be established if the transcriptional effects we observed are mediated through an androgen response element.
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PMID:Effects of dehydroepiandrosterone on rat apolipoprotein AI gene expression in the human hepatoma cell line, HepG2. 1188 77

Lysophosphatidylcholine (lysoPC) is a component of oxidized low density lipoprotein (LDL) and is involved in the pathogenesis of atherosclerosis and inflammation. Previous studies demonstrated that lysoPC can induce various protein kinases including tyrosine kinases, protein kinase C (PKC), and mitogen-activated protein kinases (MAPK) in vascular endothelial cells. However, the role of lysoPC-activated kinases remains undefined. In this study, we examined the effect of lysoPC on apoptosis and investigated the role of lysoPC-activated protein kinases in human umbilical vein endothelial cells (HUVEC). The presence of apoptosis was evaluated by morphological criteria, MTT assay, and electrophoresis of DNA fragments showing the characteristic apoptotic ladder, TUNEL analysis, and quantified as the proportion of hypodiploid cells by flow cytometry. The lysoPC induced apoptosis in a time- and dose-dependent manner. It stimulated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and p38-MAPK in HUVEC. The use of specific pharmacologic inhibitors indicated that the p38-MAPK-signaling pathway (SB203580) is required for lysoPC-induced apoptotic signals. Furthermore, lysoPC-induced apoptosis was inhibited by DEVD-FMK (a caspas-3/CPP32 inhibitor), suggesting involvement of an important segment in the apoptosis. These results demonstrate that lysoPC induces apoptosis in human endothelial cells through a p38-MAPK-dependent pathway.
Atherosclerosis 2002 Apr
PMID:Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism. 1188 22


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