UMLS:C0004153 - FACTA Search

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

Interleukin-8 (IL-8) is one of cytokines detected at sites of inflammation and in macrophage-foam cells of atherosclerotic lesions. The expression of IL-8 gene can be induced in cholesterol loaded THP-1 macrophages by oxidized low density lipoprotein. We report for the first time that the expression of human IL-8 gene in THP-1 macrophages is upregulated in a time- and concentration-dependent manner by prostaglandin D2 metabolite 15-deoxy-delta12, 14 prostaglandin J2 (15d-PGJ2), which is a natural ligand for activation of peroxisome proliferator-activated receptor-gamma transcription factor. Studies to identify the signal transduction pathways involved showed that IL-8 upregulation-mediated by 15d-PGJ2 was markedly inhibited when the THP-1 macrophages were incubated with a highly selective and cell-permeable inhibitor of the mitogen-activated protein kinase (MAPK) signaling pathway, 2'-amino-3'-methoxyflavone (PD98059). This inhibition was concentration-dependent, suggesting that 15d-PGJ2 regulates the expression of IL-8 gene in THP-1 macrophages through a MAPK signaling pathway. In contrast, THP-1 macrophages when treated with pyrrolidine dithiocarbamate, an anti-oxidant and the selective inhibitor for nuclear factor kappaB, showed an enhanced 15d-PGJ2-mediated upregulation of IL-8 gene expression. The data presented in this report may contribute to unravel some of the mechanisms behind the inflammatory component of atherosclerosis.
Atherosclerosis 2002 Jan
PMID:Upregulation of interleukin-8 expression by prostaglandin D2 metabolite 15-deoxy-delta12, 14 prostaglandin J2 (15d-PGJ2) in human THP-1 macrophages. 1175 18

Sialic acid containing glycosphingolipids (gangliosides) are expressed on the surface of all mammalian cells and have been implicated in regulating various biological phenomena; however, the detailed signaling mechanisms involved in this process are not known. We report here a novel aspect of disialoganglioside, GD3-mediated regulation of cell proliferation and cell death via the recruitment of reactive oxygen species (ROS). A low concentration (2.5-10 microm) of GD3, incubated with human aortic smooth muscle cells for a short period of time (10-30 min), stimulates superoxide generation via the activation of both NADPH oxidase and NADH oxidase activity. This leads to downstream signaling leading to cell proliferation and apoptosis. However, [(3)H]GD3 incubated with the cells under such conditions was found in a trypsin-sensitive fraction that was separable from endogenous GD3. The exact mechanism causing ROS generation and downstream signaling remains to be elucidated. The uptake of GD3 was accompanied by a 2.5-fold stimulation in the activity of mitogen-activated protein (MAP) kinase and 5-fold stimulation in cell proliferation. Preincubation of cells with membrane-permeable antioxidants, pyrrolidine dithiocarbamate, and N-acetylcysteine abrogated the superoxide generation and cell proliferation. In contrast, at higher concentrations (50-200 microm) GD3 inhibited the generation of superoxides but markedly stimulated the generation of nitric oxide (NO) (10-fold compared with control). This in turn stimulated mitochondrial cytochrome c release and intrachromosomal DNA fragmentation, which lead to apoptosis. In sum, at a low concentration, GD3 recruits superoxides to activate p44 MAPK and stimulates cell proliferation. In contrast, at high concentrations GD3 recruits nitric oxide to scavenge superoxide radicals that triggered signaling events that led to apoptosis. These observations might have relevance in regard to the potential role of GD3 in aortic smooth muscle cell proliferation and apoptosis that may contribute to plaque rupture in atherosclerosis.
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PMID:GD3 recruits reactive oxygen species to induce cell proliferation and apoptosis in human aortic smooth muscle cells. 1186 54

Repeated cycles of oxidative injury by allylamine induce proliferative rat vascular smooth muscle cell (vSMC) phenotypes characterized by enhanced secretion of osteopontin (OPN). The present study was designed to evaluate the role of extracellular matrix (ECM) interactions in the induction of proliferative phenotypes in this model of oxidant injury. Because OPN is involved in ECM/integrin signaling, and may participate in proliferative control, the proliferation profiles of control and allylamine vSMCs seeded on different matrices were compared. Allylamine cells exhibited a proliferative advantage over controls when seeded on plastic, Pronectin, or fibronectin, but not type I collagen. Addition of GRGDS peptide selectively enhanced [3H]-thymidine incorporation in allylamine vSMCs, while anti-OPN antibodies nullified their proliferative advantage. Allylamine cells exhibited altered expression of alpha1, alpha5 and beta3 integrin subunits and enhanced downstream integrin-coupled increases in focal adhesion kinase, AP-1 and NF-kappaB binding activity. Inhibition of NF-kappaB by pyrrolidine dithiocarbamate selectively compromised proliferation of allylamine vSMCs, while seeding on a non-permissive collagen matrix ablated enhancement of NF-kappaB inducibility. These results implicate ECM interactions in the deregulation of vSMC proliferation following repeated cycles of oxidative chemical injury.
Atherosclerosis 2002 Jun
PMID:Collagen suppresses the proliferative phenotype of allylamine-injured vascular smooth muscle cells. 1199 48

Linoleic acid is a dietary fatty acid that appears to play an important role in activation of the vascular endothelium under a variety of pathological conditions, including development of atherosclerosis or cancer metastasis. Evidence indicates that inflammatory responses may be an underlying cause of endothelial cell pathology induced by linoleic acid. However, the profile of inflammatory mediators and the potential mechanisms involved in inflammatory reactions stimulated by the exposure to linoleic acid are not fully understood. The present study focused on the mechanisms of linoleic acid-induced expression of monocyte chemoattractant protein-1 (MCP-1) gene in human microvascular endothelial cells (HMEC-1). Treatment of HMEC-1 with increasing doses of linoleic acid markedly activated an oxidative stress-responsive transcription factor, nuclear factor-kappaB (NF-kappaB). In addition, exposure to linoleic acid induced a time- and concentration-dependent overexpression of the MCP-1 gene. Increased MCP-1 mRNA levels were observed in HMEC-1 treated with linoleic acid at doses as low as 10 &mgr;M. Linoleic acid-induced overexpression of the MCP-1 gene was associated with a significant elevation of MCP-1 protein levels. Most importantly, preexposure of HMEC-1 to antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), attenuated linoleic acid-induced MCP-1 mRNA expression. The obtained results indicate that linoleic acid triggers MCP-1 gene expression in human microvascular endothelial cells through oxidative stress/redox-related mechanisms.
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PMID:Linoleic acid induces MCP-1 gene expression in human microvascular endothelial cells through an oxidative mechanism. 1203 Dec 58

Inflammatory response and chemotaxis of vascular wall cells play an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes. Besides the induction of monocyte recruitment, it has been suggested that MCP-1 may directly activate smooth muscle cells. We investigated whether MCP-1 affects the proliferation and cytokine production of human vascular smooth muscle cells (VSMCs) and determined the underlying signal transduction pathways. Stimulation of VSMCs with MCP-1 induced proliferation and resulted in a concentration- and time-dependent release of the proinflammatory cytokine interleukin-6 (IL-6). Pretreatment with pertussis toxin, GF109203X, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 release, suggesting the involvement of G(i) proteins, protein kinase C, and nuclear factor-kappaB (NF-kappaB). MCP-1 also induced extracellular signal-regulated kinase, which, along with IL-6 release, was inhibited by pertussis toxin. PD98059 prevented MCP-1-induced extracellular signal-regulated kinase activation and cell proliferation. MCP-1 stimulated the binding activity of NF-kappaB and of activator protein-1 (AP-1). As demonstrated by cis element double-stranded (decoy) oligodeoxynucleotides, NF-kappaB was involved in IL-6 release by MCP-1, whereas proliferation was dependent on AP-1. The results clearly demonstrate that MCP-1 induces differential activation of NF-kappaB and AP-1 in VSMCs. Thus, our data propose a new mechanism for the proatherogenic effect of MCP-1.
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PMID:Monocyte chemoattractant protein-1 induces proliferation and interleukin-6 production in human smooth muscle cells by differential activation of nuclear factor-kappaB and activator protein-1. 1206 98

We examined the effects of high cholesterol diet and pyrrolidine dithiocarbamate (PDTC) on flow-dependent remodeling after angioplasty. After right common carotid balloon-injury, the right external carotid (low flow) or left common carotid artery were ligated (high flow) in rabbits fed normal diet, 1% cholesterol diet without or with the antioxidant PDTC for 7 days pre- and 7-28 days post-injury. Angiographic lumen diameter was significantly greater at 28 days in high flow than low flow normal diet animals, attributable on perfusion-fixed vessel morphometry to altered remodeling (area within the external elastic lamina: high flow 1.85+/-0.24 vs. low flow 1.31+/-0.04 mm(2), P<0.05) rather than differences in neointima formation or vessel tone. In animals on 1% cholesterol diet high flow remodeling was significantly enhanced (area within the external elastic lamina 3.13+/-0.17 mm(2), P<0.05 vs. high flow normal diet) but low flow inward remodeling was similar (area within the external elastic lamina 1.29+/-0.07 mm(2)). Mean Doppler flow velocities (initial/post-ligation/28 day follow-up, cm/s) had almost normalized in normal diet animals (high flow 30/49/35, low flow 32/9/26) but showed overcompensation in 1% cholesterol diet animals (high flow 32/49/22, low flow 30/11/25). PDTC therapy markedly attenuated remodeling (area within the external elastic lamina: high flow 2.20+/-0.18, and low flow 2.00+/-0.11 both P<0.05 vs. 1% cholesterol diet alone) and flow velocities only partially normalized (high flow 26/42/34, low flow 27/7/16). We conclude that hypercholesterolemia enhances and PDTC attenuates flow-dependent remodeling after angioplasty.
Atherosclerosis 2003 Jun
PMID:Flow-responsive remodeling after angioplasty is enhanced by high cholesterol diet. Prevention with pyrrolidine dithiocarbamate. 1280 17

Arterial regions exposed to oscillatory shear (OS) in branched arteries are lesion-prone sites of atherosclerosis, whereas those of laminar shear (LS) are relatively well protected. Here, we examined the hypothesis that OS and LS differentially regulate production of O2- from the endothelial NAD(P)H oxidase, which, in turn, is responsible for their opposite effects on a critical atherogenic event, monocyte adhesion. We used aortic endothelial cells obtained from C57BL/6 (MAE-C57) and p47phox-/- (MAE-p47-/-) mice, which lack a component of NAD(P)H oxidase. O2- production was determined by dihydroethidium staining and an electron spin resonance using an electron spin trap methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Chronic exposure (18 h) to an arterial level of OS (+/- 5 dynes/cm2) increased O2- (2-fold) and monocyte adhesion (3-fold) in MAE-C57 cells, whereas chronic LS (15 dynes/cm2, 18 h) significantly decreased both monocyte adhesion and O2- compared with static conditions. In contrast, neither LS nor OS were able to induce O2- production and monocyte adhesion to MAE-p47-/-. Treating MAE-C57 with a cell-permeable superoxide dismutase compound, polyethylene glycol-superoxide dismutase, also inhibited OS-induced monocyte adhesion. In addition, over-expressing p47phox in MAE-p47-/- restored OS-induced O2- production and monocyte adhesion. These results suggest that chronic exposure of endothelial cells to OS stimulates O2- and/or its derivatives produced from p47phox-dependent NAD(P)H oxidase, which, in turn, leads to monocyte adhesion, an early and critical atherogenic event.
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PMID:Oscillatory shear stress stimulates endothelial production of O2- from p47phox-dependent NAD(P)H oxidases, leading to monocyte adhesion. 1295 9

Pyrrolidine dithiocarbamate (PDTC), a metal chelating compound, is known to induce cell death in vascular smooth muscle cells (VSMC). However, the molecular mechanism for PDTC-induced VSMC death is not well understood. Addition of PDTC reduced cell growth and DNA synthesis on VSMC in low density conditions. However, in serum depleted medium, PDTC did not affect the cell viability, suggesting that certain factors in serum may mediate the cytotoxic effect of PDTC. Several metal chelators prevented the cell death induced by PDTC. In a serum-deprived condition, addition of exogenous metals, copper, iron, and zinc, restored the cytotoxic effect of PDTC. These data indicate that metals such as copper, iron, and zinc in serum may mediate the cytotoxic effect of PDTC. At low VSMC density in 10% FBS, treatment of PDTC, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by PDTC was not observed. Finally, we determined PDTC-mediated signaling pathway involved in VSMC death. Among relevant pathways, PDTC induced marked activation of p38MAPK and JNK. Expression of dominant negative p38MAPK and SB203580, a p38MAPK specific inhibitor, blocked PDTC-dependent p38MAPK, growth inhibition, and p21 expression. These data demonstrate that the p38MAPK pathway participates in p21 induction, which consequently leads to decrease of cyclin D1/cdk4 and cyclin E/cdk2 complexes and PDTC-dependent VSMC growth inhibition. In conclusion, an understanding of the molecular mechanisms of PDTC in VSMC provides a theoretical basis for clinical approaches using antioxidant therapies in atherosclerosis.
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PMID:PDTC, metal chelating compound, induces G1 phase cell cycle arrest in vascular smooth muscle cells through inducing p21Cip1 expression: involvement of p38 mitogen activated protein kinase. 1460 33

Oxidative stress contributes to the pathogenesis of atherosclerosis. p22phox-based NAD(P)H oxidases exist in the vessel wall, acting as important superoxide-generating systems in the vasculature. Some studies have identified reduced atherosclerosis in the presence of the C242T CYBA polymorphism, whereas others have not. Because vascular p22phox is identical to neutrophil p22phox, we studied the association between the C242T, A640G, and -930A/G CYBA polymorphisms and the quantity of superoxide produced from neutrophils isolated from healthy adults to determine if these polymorphisms had any functional impact on NADPH oxidase function. Neutrophils were isolated from 90 subjects by Percoll density gradient centrifugation. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping, as well as real-time PCR. The oxidative burst was stimulated with phorbol 12-myristate 13-acetate. Superoxide was quantified using the superoxide dismutase inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine, detected by electron paramagnetic resonance. Superoxide production was significantly affected by the C242T polymorphism, being 8.7+/-0.7, 7.9+/-0.6, and 5.9+/-1.2 micromol/L per minute per 10(6) neutrophils for the C242T CC, CT, and TT genotypes, respectively (P<0.05). In contrast, the A640G and the -930A/G polymorphisms did not alter the neutrophil respiratory burst. Phagocytic respiratory burst activity in homozygous individuals with the T allele of the C242T CYBA polymorphism is significantly lower than of wild-type carriers and heterozygous individuals. Because p22phox exists in both the neutrophil and vessel wall, vascular oxidative stress is likely diminished in individuals with this polymorphism.
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PMID:C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils. 1507 63

Low flow (LF) promotes late lumen loss after angioplasty by exacerbating inward remodelling through redox-sensitive mechanisms. Stents eliminate inward remodelling and the effect of LF on in-stent restenosis is uncertain. We performed over-sized (1.3-1.5:1) stenting (S) and balloon injury (in the same vessel, B) to the carotid arteries of cholesterol-fed rabbits and compared 28-day late lumen loss with that in an uninjured segment in the same vessel (U). Vessels (n = 5 animals per group) were subjected to high (H), normal (N) and low (L) flow in animals fed either vehicle (V) or the antioxidant pyrrolidine dithiocarbamate, PDTC (P). LF significantly increased in-stent neointima formation relative to normal and high flow (SLV 0.72 +/- 0.07 mm(2) versus SNV 0.43 +/- 0.08 mm(2) versus SHV 0.28 +/- 0.04 mm(2), P < 0.05). However, LF resulted in greater lumen loss in segments from the same vessel subject to balloon injury (lumen SLV 5.18 +/- 0.40 mm(2) and SNV 5.32 +/- 0.40 mm(2) versus BLV 1.28 +/- 0.33 mm(2) and BNV 2.19 +/- 0.28 mm(2)), by greater enhancement of inward remodelling. In addition, inward remodelling and lumen loss due to LF were greater in balloon-injured segments than in adjacent uninjured segments where shear homeostatic remodelling occurs (lumen BLV 1.28 +/- 0.33 mm(2) versus ULV 1.52 +/- 0.22 mm(2)). Lastly, while PDTC effectively reduced intima formation and inward remodelling due to LF in balloon-injured vessels there was no effect on flow-dependent neointima formation in stented vessels. We conclude that LF accentuates in-stent neointima formation, but that flow-dependent lumen loss after stenting is less than that after balloon injury. When LF is present lumen loss can be minimised by antioxidants or stenting.
Atherosclerosis 2004 Dec
PMID:Low flow promotes instent intimal hyperplasia. Comparison with lumen loss in balloon-injured and uninjured vessels and the effects of the antioxidant pyrrolidine dithiocarbamate. 1553 Aug 99

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