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)

Oxidized LDL (oxLDL) may contribute to the accumulation of apoptotic cells in atherosclerotic plaques. Although it is well established in monophasic chemical systems that the highly unsaturated EPA and DHA will oxidize more readily than FA that contain fewer double bonds, our previous studies showed that enrichment of LDL, which has discrete polar and nonpolar phases, with these FA did not increase oxidation. The objective of this study was to compare the extent of apoptosis induced by EPA/DHA-rich oxLDL to that induced by EPA/DHA-non-rich oxLDL in U937 cells. LDL was obtained from one healthy subject three times before and after supplementation for 5 wk with 15 g/d of fish oil (FO), an amount easily obtainable from a diet that contains fatty fish. After supplementation, an EPA/DHA-rich LDL was obtained. Oxidative susceptibility of LDL, as determined by measuring the formation of conjugated dienes and the accumulation of cholesteryl ester hydroperoxides, was not higher in EPA/DHA-rich LDL. The oxLDL-induced cell apoptosis was detected by the activation of caspase-3, the translocation of PS to the outer surface of the plasma membrane using the Annexin V-fluorescein isothiocyanate binding assay, and the presence of chromatin condensation and nuclear fragmentation using the 4,6-diamidino-2-phenylindole staining assay. All three measures showed that after FO supplementation, EPA/DHA-rich oxLDL-induced cell apoptosis decreased. The decrease was not related to the concentration of lipid hydroperoxides. This study suggests that a possible protective effect of EPA/DHA-rich diets on atherosclerosis may be through lessening cell apoptosis in the arterial wall.
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PMID:Enrichment of LDL with EPA and DHA decreased oxidized LDL-induced apoptosis in U937 cells. 1237 50

Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion. Here, the hypothesis was tested that these anti-adhesive components promote apoptosis in vascular cells. PAI-1 or HKa induced a 2- to 3-fold increase in apoptosis of human umbilical-vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) adherent to vitronectin, as determined by annexin V-FACS assay, similar to alphav-integrin inhibitor cyclo-(Arg-Gly-Asp-D-Phe-Val)-peptide (cRGDfV). Apoptosis occurred after 12 h incubation and was attributable to caspase 3 activation that in turn induced DNA fragmentation. Induction of apoptosis strongly correlated with the anti-adhesive effect of PAI-1 and HKa on these cells. In contrast, PAI-1 and HKa did not affect fibronectin-dependent adhesion or cell survival. uPA did not influence apoptosis in vitronectin- or fibronectin-adherent cells. In atherosclerotic vessel sections, congruent distribution of vitronectin, PAI-1, HK, and of components of the urokinase plasminogen activator/receptor system with apoptotic cells lining foam cell lesions was demonstrated by immunostaining. These results indicate that inhibition of vitronectin-dependent cell adhesion through PAI-1 and HKa correlates with apoptosis induction in vascular cells mediated through the caspase 3 pathway. Co-distribution of apoptosis with plasminogen activation system components in atherosclerosis exemplifies the significance of anti-adhesive mechanisms and apoptosis for tissue remodeling, such as in neointima development.
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PMID:Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. 1271 93

The endothelium is a single layer of cells lining the inside face of all blood vessels. It constitutes a major metabolic organ which is critically involved in the generation and the regulation of multiple physiological and pathological processes such as coagulation, hemostasis, inflammation, atherosclerosis, angiogenesis and cancerous metastasis dissemination. In order to increase our knowledge about the protein content and the main biological pathways of human vascular endothelial cells, we have undertaken the proteomic analysis of the most explored present endothelial cell model, i.e. primocultures of human umbilical vein endothelial cells (HUVECs). Using low levels of protein loads (~ 30 nug), the association of two-dimensional electrophoresis with matrix-assisted laser desorption/ionization-time of flight mass spectrometry, liquid chromatography-tandem mass spectrometry and database interrogations allowed us to identify 53 proteins of suspected endothelial origin in quiescent HUVECs. Beside cytoskeletal proteins such as actin, tubulin, tropomyosin and vimentin, we identified various proteins more especially implicated in cellular motility and plasticity (e.g. cofilin, F-actin capping protein and prefoldin), in regulation of apoptosis and senescence (protease inhibitor 9, glucose related proteins, heat shock proteins, thioredoxin peroxidase, nucleophosmin) as well as other proteins implicated in coagulation (annexin V, high mobility group protein), antigen presentation (valosin containing protein and ubiquitin carboxyl terminal hydrolase isozyme L1) and enzymatic capabilities (glutathione-S-transferase, protein disulfide isomerases, lactate deshydrogenase). The presented annotated 2-D maps of HUVECs will be soon available on the web at http://www. huvec.com.
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PMID:Proteomic study of human umbilical vein endothelial cells in culture. 1274 50

In the context of atherogenesis and restenosis, vascular smooth muscle cell (SMC) proliferation and apoptosis play a crucial role. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) have been shown to inhibit the migration and proliferation of SMC, and to induce apoptosis in different cell types including SMC. However, it is not known whether these agents induce apoptosis in neointimal SMC. We investigated the effects of statin treatment on neointimal SMC as compared to medial cells by using trypan blue counting, MTT test, Annexin V staining, cell cycle analysis and a co-culture model. The incubation of neointimal or medial SMC with lovastatin reduced the MTT activity as well as the total cell number, and increased the amount of trypan blue positive cells, indicative of cell death. We tested by staining with Annexin V/propidium iodide, specific antibodies to active caspase-3, TUNEL reaction, and by the appearance of a sub-G1 peak, whether the observed increase in cell death was due to apoptosis. After treatment with lovastatin, programmed cell death was slightly increased in medial SMC, while neointimal cells showed a pronounced rate of apoptosis. In an attempt to mimic early phases of restenosis in vitro by seeding low density neointimal cells onto high density medial cells, we found that statin treatment induced cell death preferentially in the neointimal SMC. Our results suggest that statins enhance the rate of apoptosis in neointimal SMC, which may be an interesting feature to reduce restenosis after successful angioplasty.
Atherosclerosis 2003 Aug
PMID:HMG-CoA reductase inhibitors induce apoptosis in neointima-derived vascular smooth muscle cells. 1292 76

Atherosclerosis is the leading cause of death in patients with diabetes mellitus, increasing mortality in all forms of the disease. Classical risk factors, including hyperlipidemia, hypertension and obesity, do not completely account for the increased incidence of atherosclerosis in diabetes. Some platelet activation markers such as CD62P, CD63, PAC-1, Annexin V and platelet-derived microparticles (PDMP) are elevated in patients with diabetes, since diabetic platelets often have increased sensitivity to secondary aggregation in response to agonist. PDMPs are thought to play a role in clinical disease because they express phospholipids that function as procoagulants. High shear stress can initiate both platelet aggregation and shedding of procoagulant-containing PDMP, suggesting that PDMP generation by high shear stress occurs in small diseased arteries and arterioles under various clinical conditions. Platelet activation markers were significantly higher in the hypertensive or hyperlipidemic patients than in the controls. Selectins and cell adhesion molecules were also higher in the hypertensive or hyperlipidemic patients, and they were significantly higher in these patients with diabetes. Activated microparticles and PDMP may contribute to the development of atherosclerosis in diabetes, and platelet activation markers seem to be useful for the assessment of vascular damage in these patients.
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PMID:[Platelet activation marker]. 1467 88

The revolution in molecular imaging techniques is profoundly changing the understanding of the pathophysiology and treatment of atherosclerosis. With these rapid changes there is an increasing demand for development of sensitive and well tolerated novel imaging agents that can be rapidly translated from small animal models into patients with atherosclerosis. Nuclear medicine and positron emission tomography techniques have the ability to detect and serially monitor a variety of biologic and pathophysiologic processes usually with tracer quantities of radiolabeled peptides, drugs, and other molecules at dosages free of pharmacologic adverse effects unlike the current generation of intravenous agents required for magnetic resonance imaging (MRI) and computed axial tomography (CT) scanning. A representative sampling of the wide array of radiopharmaceuticals developed specifically for radionuclide imaging of atherosclerosis, that have been approved for clinical use and those in pre-clinical trials, have been reviewed in this article. The presence of an inflammatory stimulus increases expression of CC (cysteine-cysteine motif) chemokine receptor (CCR)-2 on monocytes and macrophages, and somatostatin receptors on T lymphocytes. Radiolabeled monocyte chemoattractant protein (MCP)-1 binds with high affinity to CCR-2 and can be used to detect subacute and chronic inflammatory lesions. Similarly, radiolabeled octreotide or depreotide can be used to detect activated T lymphocytes which may identify the vulnerable plaque. Animal models indicate that (99m)Tc-annexin V, (125)I-MCP-1 and [(18)F]-fluoro-2-deoxyglucose are effective in identifying apoptotic cell death, macrophage infiltration and metabolic activity in atheromatous lesions, respectively. Expression of alpha(v)beta(3) integrin is increased in activated endothelial cells and vascular smooth muscle cells after vascular injury, and alpha(v)beta(3) integrin is minimally expressed on smooth muscle cells and is not expressed on quiescent epithelial cells. Radiolabeled high-affinity peptides can be used to target the alpha(v)beta(3) integrin and visualize areas of vascular damage. Advances in technology such as the micro-single photon emission computed tomography (microSPECT) have the potential to overcome the drawbacks of older CT and MRI methodologies, such as lack of biologically relevant ligands and compatible blood pool contrast agents for imaging. Despite these advances in imaging technology, the small size of atheromatous lesions makes it difficult to detect using external imaging techniques. Therefore, recently there has been renewed interest in the use of intravascular catheter-based radiation detectors.
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PMID:Development of radiocontrast agents for vascular imaging: progress to date. 1472 51

We investigated the effects of probucol and ticlopidine on circulating levels of platelet activation markers, microparticles, soluble selectins, and malondialdehyde-low density lipoprotein (MDA-LDL) in hyperlipidemic patients with or without type 2 diabetes. There were significant differences in the levels of CD62P, PAC-1, annexin V, PDMP, MDMP, sP-selectin, sE-selectin and MDA-LDL between the hyperlipidemic patients and the controls. In particular, these markers were significantly increased in hyperlipidemic patients who had type 2 diabetes. In the hyperlipidemic patients with diabetes, MDA-LDL was decreased by both monotherapy with probucol and combination therapy (probucol and ticlopidine). In these patients, CD62P, PAC-1, annexin V, MDMP, PDMP, sP-selectin, and sE-selectin were also significantly decreased after treatment. The decreases of CD62P, PAC-1, annexin V, PDMP and sP-selectin were greater combination therapy than with monotherapy. These findings suggest that administration of probucol and ticlopidine to hyperlipidemic patients with type 2 diabetes may help to prevent the development of cardiovascular complications caused by modified LDL, selectins, or activated platelets and monocytes.
Atherosclerosis 2004 Jun
PMID:Probucol and ticlopidine: effect on platelet and monocyte activation markers in hyperlipidemic patients with and without type 2 diabetes. 1513 63

The aim of this study was to elucidate death pathways in macrophages resulting from exposure to triacylglycerols (TG), mechanisms which may be relevant to the development of atherosclerosis. A commercial TG emulsion (lipid emulsion, LE; 0.1-1.5 mg lipids/ml) was added to J774.2 cells in culture. Within the first 24 h after TG treatment, cellular reactive oxygen species (ROS) levels were strongly elevated and basal caspase-3 activity was attenuated. In contrast, after 48 h, ROS production was arrested. TG-mediated ROS production was demonstrated to be via mitochondrial complex 1 of the electron-transfer chain since the inhibitor of complex 1 rotenone significantly attenuated the cellular ROS levels in TG-treated cells. The TG effect culminated in cell death, with no caspase-3 activation. We therefore evaluated the effect of TG on apoptotic cells showing high caspase activity. TG induced elevated ROS levels and suppressed caspase-3 in apoptotic cells pretreated for 24 h with cycloheximide. Dual staining with propidium iodide and Annexin V followed by flow cytometric analysis showed that TG facilitated cell death with clear necrotic characteristics. To elucidate whether the necrotic cell death process is indeed oxidant dependent, antioxidant protection was studied. Treatment with N-acetylcysteine (NAC) (0.5 mM), ascorbic acid (0.5 mM), and resveratrol (0.2 mM) protected against the TG lipotoxic effect, while, surprisingly, lipophilic antioxidants did not. The combination of NAC, ascorbic acid, and resveratrol, each at much lower concentrations, had a synergistic protective effect. In conclusion, we show here for the first time that exposure to TG can directly regulate lipotoxicity in macrophages by inducing mitochondria-mediated prolonged oxidative stress; this, in turn, can inactivate the apoptotic caspase system, resulting in necrotic cell death which can be prevented by specific antioxidants.
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PMID:Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis. 1580 20

Endothelial dysfunction/activation underlies the development of long-term cardiovascular complications and atherosclerosis. The aim of this study was to examine a direct role for exogenous sublethal flux of superoxide on endothelial cell dysfunction. Human umbilical vein endothelial cells (HUVEC) were exposed to superoxide generated by 0.1 mM xanthine and 4 mU/ml xanthine oxidase for 15 min and essential endothelial functions were examined. Superoxide dismutase and/or catalase was used as scavenger for O(2)(-)/H(2)O(2) to determine the key culprit. HUVEC detachment was determined by neutral red uptake and apoptosis by annexin V binding. Inflammation was estimated by IL-8 mRNA expression and cellular adhesion molecules (CAM). eNOS and iNOS message and eNOS protein served as an indirect measure for NO. Procoagulable state was evaluated by estimating the intracellular tissue factor. Activation of endothelial NADPH oxidase was determined by lucigenin chemiluminescence. Sublethal superoxide dose evoked: (1) proinflammatory state manifested by increased IL-8 mRNA expression and CAM on the endothelial surface, (2) HUVEC apoptosis and activated endothelial NADPH oxidase, (3) increase in intracellular tissue factor, and (4) decrease in eNOS mRNA and protein and up-regulation of iNOS mRNA. We conclude that extracellular low flux of superoxide exhibits pleiotropic characteristics, triggering activation/dysfunction of endothelial cells.
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PMID:Exogenous superoxide mediates pro-oxidative, proinflammatory, and procoagulatory changes in primary endothelial cell cultures. 1621 39

Atherosclerosis, a major cause of disease and death from cardiovascular disease (CVD), is an inflammatory disease characterized by T cell and monocyte/macrophage infiltration in the intima of large arteries. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in systemic lupus erythematosus (SLE), often considered a prototypic autoimmune disease. A combination of traditional and non-traditional risk factors, including dyslipidemia, inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. aPL are highly thrombogenic, and possible mechanisms include direct effects of aPL on endothelial and other cells, and interference with coagulation reactions. More than a thousand proteins of the annexin-superfamily are expressed in eukaryotes. Annexins are ubiquitous, highly conserved, predominantly intracellular proteins, widely distributed in tissues. Annexin A5 (ANXA5) is an important member of the annexin family due to its antithrombotic properties. These are believed to be caused by it forming a two-dimensional protective shield, covering exposed potentially thrombogenic cell surfaces. Recently, ANXA5 has been implicated in SLE since aPL interfere with ANXA5 binding to placental trophoblasts, causing microthrombosis and miscarriage, a rather common complication in SLE. We recently demonstrated that ANXA5 may play a role in CVD and is abundant in late-stage atherosclerotic lesions. Sera from SLE-patients with a history of CVD inhibited ANXA5 binding to endothelium, caused by IgG antibodies, to a significant degree aPL. This review will focus on potential involvement of ANXA5 in pathogenesis of CVD, particularly caused by underlying atherosclerosis and atherothrombosis.
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PMID:Annexin A5 in cardiovascular disease and systemic lupus erythematosus. 1632 95


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