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)

Atherosclerosis preferentially occurs in areas of turbulent blood flow and low fluid shear stress, whereas laminar blood flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent findings suggest a steady laminar blood flow decreases EC apoptosis and inhibits TNF-mediated EC activation. EC apoptosis or activation is suggested to be involved in plaque erosion, which may lead to platelet aggregation. TNF-alpha regulates gene expression in ECs, in part, by stimulating mitogen-activated protein (MAP) kinases, which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAP kinases in ECs. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm(2)) on TNF-alpha-stimulated activity of three MAP kinases in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. TNF-alpha activated ERK1/2, JNK, and p38 maximally at 15 min in HUVEC. Pre-exposing HUVEC for 10 min to flow inhibited TNF-alpha activation of JNK, but showed no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, a specific ERK1/2 inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Transfection studies with dominant-negative constructs of the protein kinase MEK5 suggested an important role for big mitogen-activated protein kinase 1 (BMK1) in flow-mediated regulation of EC activation by TNF-alpha. Understanding the mechanisms by which steady laminar flow regulates JNK activation by cytokines may provide insight into the atheroprotective mechanisms induced by laminar blood flow.
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PMID:Stress and vascular responses: atheroprotective effect of laminar fluid shear stress in endothelial cells: possible role of mitogen-activated protein kinases. 1268 37

Proliferation and migration of vascular smooth muscle cells (SMCs) are important processes involved in the pathogenesis of vascular disorders such as atherosclerosis and post-angioplasty restenosis. Here we demonstrate that proliferation and migration of specific SMC subtypes is mitogen-activated protein (MAP) kinase-dependent. WKY12-22 SMCs derived from the aortae of 12 day-old pup rats proliferate and migrate faster than WKY3M-22 SMCs derived from the aortae of adult rats. WKY12-22 and WKY3M-22 cells equally expressed the active forms of phospho (Thr(183)/Tyr(185))-c-Jun N-terminal kinase (JNK) and phospho (Tyr(182))-p38, whereas the activity of extracellular signal-regulated kinase (ERK) was greater in WKY12-22 cells compared with WKY3M-22 cells. Proliferation of both SMC subtypes was attenuated by PD98059, SP600125 and SB202190, inhibitors of ERK, JNK, and p38, respectively. However, inhibition of PD98059 had a more profound effect on WKY12-22 SMCs. Furthermore, migration of WKY12-22 and WKY3M-22 cells was inhibited by SP600125 and SB202190, however, PD98059 failed to influence migration of either SMC subtype. Hence, migration of both SMC subtypes is JNK- and p38-dependent, but not ERK-dependent. These findings demonstrate that SMC heterogeneity is mediated, at least in part, by the activity of specific MAP kinase subtypes.
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PMID:ERK, JNK, and p38 MAP kinases differentially regulate proliferation and migration of phenotypically distinct smooth muscle cell subtypes. 1270 92

P2Y2 receptor up-regulation and activation induces intimal hyperplasia and monocyte/macrophage infiltration in the collared rabbit carotid artery model of vascular injury, suggesting a potential role for P2Y2 receptors in monocyte recruitment by vascular endothelium. In this study, we addressed the hypothesis that activation of P2Y2 receptors by extracellular nucleotides modulates the expression of adhesion molecules on vascular endothelial cells that are important for monocyte recruitment. Results indicated that the equipotent P2Y2 receptor agonists UTP or ATP (1-100 microm) stimulated the expression of vascular cell adhesion molecule-1 (VCAM-1) in human coronary artery endothelial cells (HCAEC) in a time- and dose-dependent manner. P2Y2 antisense oligonucleotides inhibited VCAM-1 expression induced by UTP but not by tumor necrosis factor-alpha. Furthermore, UTP induced VCAM-1 expression in human 1321N1 astrocytoma cell transfectants expressing the recombinant P2Y2 receptor, whereas vector-transfected control cells did not respond to UTP. The effect of UTP on VCAM-1 expression in HCAEC was prevented by depletion of intracellular calcium stores with thapsigargin or by inhibition of p38 mitogen-activated protein kinase or Rho kinase, but was not affected by inhibitors of the mitogen-activated protein/extracellular signal-regulated kinase pathway (i.e. MEK1/2). Consistent with a role for VCAM-1 in the recruitment of monocytes, UTP or ATP increased the adherence of monocytic U937 cells to HCAEC, an effect that was inhibited by anti-VCAM-1 antibodies. These findings suggest a novel role for the P2Y2 receptor in the p38- and Rho kinase-dependent expression of VCAM-1 that mediates the recruitment of monocytes by vascular endothelium associated with the development of atherosclerosis.
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PMID:The P2Y2 nucleotide receptor mediates UTP-induced vascular cell adhesion molecule-1 expression in coronary artery endothelial cells. 1271 97

Increased levels of isoprostanes have been detected in human atherosclerotic lesions. To examine a possible role for 8-iso-prostaglandin E(2) (8-iso-PGE(2)) in atherogenesis, we tested the effect of 8-iso-PGE(2) on adhesion of leukocytes to human umbilical vein endothelial cells (EC). We demonstrate that 8-iso-PGE(2) stimulates EC to bind monocytes, but not neutrophils. This effect was inhibited by the thromboxane A(2) receptor antagonist SQ29548. Moreover, 8-iso-PGE(2) increased levels of cyclic AMP in EC, and monocyte adhesion induced by 8-iso-PGE(2) was blocked by a protein kinase A inhibitor, H89. In addition, 8-iso-PGE(2 )induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase and stimulated expression of EGR-1. A specific inhibitor of p38 MAP kinase (SB203580) abrogated monocyte binding, whereas an inhibitor of the ERK pathway (PD98059) did not block monocyte adhesion induced by 8-iso-PGE(2). Activation of nuclear factor-kappaB (NF-kappaB) and expression of NFkappaB-dependent genes intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were not induced by 8-iso-PGE(2). Taken together, these results demonstrate that 8-iso-PGE(2) stimulates EC to specifically bind monocytes, but not neutrophils. This effect is mediated by cyclic AMP/protein kinase A- and p38 MAP kinase-dependent pathways and is independent of the classical inflammatory NFkappaB pathway. Thus, formation of 8-iso-PGE(2) may play an important role in chronic inflammatory diseases such as atherosclerosis by increasing adhesion and extravasation of monocytes.
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PMID:The isoprostane 8-iso-PGE2 stimulates endothelial cells to bind monocytes via cyclic AMP- and p38 MAP kinase-dependent signaling pathways. 1271 76

Oxidized phospholipids, including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), typically present in minimally modified low density lipoprotein, have been found in atherosclerotic lesions. These compounds are gaining increasing importance as inducers of different cellular responses (inflammation, proliferation, or cell death). It was the aim of this study to understand their impact on intracellular signal transduction pathways that are responsible for these biological effects. We found that in arterial smooth muscle cells, PGPC and POVPC activated sphingomyelinases, in particular the acid isoform, which is known to participate in the very early phase of apoptotic stress responses. In addition, mitogen-activated protein kinases, which are involved in induction of stress response and apoptosis were phosphorylated (activated). Finally, activation of caspase 3 was observed, showing that stimulation of smooth muscle cells with POVPC and PGPC is associated with apoptosis. Stimulation of all these enzymes by the oxidized phospholipids almost perfectly matched their activation by minimally modified LDL. Consequently, these phospholipids seem to be responsible for the effect of this particle on cell signaling. Survival and proliferation pathways including NF-kappa B or AKT kinase were not induced by POVPC and PGPC. Experiments with a specific inhibitor of acid sphingomyelinase named NB6 showed that this enzyme plays a central role in mediating the apoptotic effects of the oxidized lipids. Thus, we conclude that modified phospholipids induce signaling cascades via activation of acid sphingomyelinase finally leading to apoptosis of smooth muscle cells, which is a detrimental process in the development of atherosclerosis.
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PMID:Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. 1281 58

Platelet-derived growth factor (PDGF) plays an important role in the pathogenic course of atherosclerosis, pulmonary fibrosis, and glomerulonephritis, and increased activity of the PDGF signaling pathway has been implicated as a contributing factor in the progression of the diseases. Taurine may be a prophylactic amino acid for atherosclerosis not only by decreasing plasma cholesterol level, but also by inhibiting the cell proliferation-signaling pathway. To elucidate how taurine affects the signaling pathway, we investigated the effect of taurine on the expression of immediate-early genes and activation of mitogen-activated protein kinases (MAPKs) in NIH/3T3 cells as standard mesenchymal cells. Taurine inhibited PDGF-BB-induced c-fos and c-jun mRNA expressions dose-dependently, although structural analogues of taurine did not. Taurine decreased the PDGF-induced p44/p42 ERK (extracellular signal-regulated kinase) phosphorylation state dose-dependently, although no phosphorylation was observed on JNK/SAPK (c-Jun N-terminal kinase/stress-activated protein kinase) and p38 MAPK. Further, PDGF-BB-induced tyrosine phosphorylation of the PDGF-beta receptor was not influenced by treatment with taurine, indicating that taurine never affects ligand-receptor interaction, and may act downstream of the PDGF receptor. Thus, the inhibitory mechanism of taurine on PDGF-induced c-fos and c-jun mRNA expressions may depend on the p44/p42 ERK pathway, but not on PDGF-beta receptor tyrosine phosphorylation, JNK/SAPK or p38 MAPK pathway. These results suggest that taurine may suppress the cell proliferation-signaling pathway through the inhibition of ERK activity and immediate-early gene expression.
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PMID:Suppressive effect of taurine on platelet-derived growth factor (PDGF) BB-induced c-fos and c-jun mRNA expressions through extracellular signal-regulated kinase (ERK) in mesenchymal cell lines. 1295 97

Proliferation of vascular smooth muscle cells (VSMC) plays a major role as an initiating event of atherosclerosis. Although estrogen directly inhibits the proliferation of VSMC, the mechanism has not been firmly established. In addition, the effect of raloxifene on VSMC remains unknown. 17Beta-estradiol (E(2)) and raloxifene significantly inhibited the growth of VSMC under growth-stimulated conditions. Since mitogen-activated protein (MAP) kinases have been implicated in VSMC proliferation, the role of MAP kinases in both the E(2)- and raloxifene-induced growth inhibition of VSMC was studied. Both E(2) and raloxifene caused rapid, transient phosphorylation and activation of p38 that was not affected by actinomycin D and was blocked by ICI 182,780. In contrast with p38 phosphorylation, extracellular signal-regulated protein kinase (ERK) phosphorylation was significantly inhibited and c-Jun N-terminal kinase (JNK) phosphorylation was not changed by E(2). Because VSMC expressed both estrogen receptor (ER) alpha and ERbeta, it is not known which of them mediates the E(2)-induced phosphorylation of p38. Although E(2) did not affect the p38 phosphorylation in A10 smooth muscle cells, which express ERbeta but not ERalpha, transfection of ERalpha expression vector into A10 cells rendered them susceptible to induction of p38 phosphorylation by E(2). We then examined whether E(2) and raloxifene induce apoptosis through a p38 cascade. Both E(2) and raloxifene induced apoptosis under growth-stimulated conditions. The p38 inhibitor SB 203580 completely blocked the E(2)-induced apoptosis. Our findings suggest that both E(2)- and raloxifene-induced inhibition of VSMC growth is due to induction of apoptosis through a p38 cascade whose activation is mediated by ERalpha via a nongenomic mechanism.
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PMID:Estrogen and raloxifene induce apoptosis by activating p38 mitogen-activated protein kinase cascade in synthetic vascular smooth muscle cells. 1296 34

Activation of vascular NAD(P)H oxidases and the production of reactive oxygen species (ROS) by these enzyme systems are common in cardiovascular disease. In the past several years, a new family of NAD(P)H oxidase subunits, known as the non-phagocytic NAD(P)H oxidase (NOX) proteins, have been discovered and shown to play a role in vascular tissues. Recent studies make clearer the mechanisms of activation of the endothelial and vascular smooth muscle NAD(P)H oxidases. ROS produced following angiotensin II-mediated stimulation of NAD(P)H oxidases signal through pathways such as mitogen-activated protein kinases, tyrosine kinases and transcription factors, and lead to events such as inflammation, hypertrophy, remodeling and angiogenesis. Studies in mice that are deficient in p47(phox) and gp91(phox) (also known as NOX2) NAD(P)H oxidase subunits show that ROS produced by these oxidases contribute to cardiovascular diseases including atherosclerosis and hypertension. Recently, efforts have been devoted to developing inhibitors of NAD(P)H oxidases that will provide useful experimental tools and might have therapeutic potential in the treatment of human diseases.
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PMID:The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. 1296 72

The terminal complement complex C5b-9 is known to participate in inflammatory processes including atherosclerosis. Inflammation appears to be a direct consequence of C5b-9-mediated cell stimulation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may exert anti-inflammatory effects on vascular cells independent of lowering plasma cholesterol. Thus, we studied activation of vascular smooth muscle cells (VSMCs) by C5b-9 focusing on whether inhibition of the HMG-CoA reductase can reduce the proinflammatory effects of C5b-9.C5b-9 in sublytic concentrations increased the proliferation of human VSMCs and induced a time-dependent activation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Proliferation and ERK1/2 activation could be inhibited by the specific ERK inhibitor PD98059. HMG-CoA inhibition with cerivastatin-reduced VSMC proliferation and C5b-9-induced ERK1/2 activation. Cerivastatin also reduced the C5b-9-induced synthesis of the proinflammatory interleukin-6 (IL-6). Furthermore, C5b-9 induced activation of the transcription factors activator protein- 1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which could be inhibited by pretreatment of VSMCs with cerivastatin. L-mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effects of cerivastatin. The present study in VSMCs shows that cerivastatin inhibits IL-6 synthesis and cell proliferation induced by the terminal complement complex C5b-9. This may be an important mechanism contributing to the beneficial effects of HMG-CoA reductase inhibitors beyond lowering of plasma cholesterol.
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PMID:HMG-CoA reductase inhibition reduces the proinflammatory activation of human vascular smooth muscle cells by the terminal complement factor C5b-9. 1455 80

Peroxisome proliferator-activated receptor (PPAR)-gamma and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the --58/--34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-gamma function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-gamma and modulates its activity. Since both the MAP kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-gamma-mediated AT1R gene transcription suppression. We observed that 1) PPAR-gamma-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect; 2) the PPAR-gamma-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-gamma-mediated AT1R gene transcription suppression; and 4) the CBP effect was eliminated when the --58/--34 GC-box related element was disrupted. It is therefore speculated that: 1) PPAR-gamma phosphorylation by the MAP kinase pathway may attenuate PPAR-gamma-mediated AT1R gene transcription suppression through the inhibition of PPAR-gamma activity; and 2) CBP may enhance the activity of the remaining Sp1 on the --58/--34 GC-box related element, resulting in a reduction in PPAR-gamma-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-gamma in AT1R gene transcription, probably leading to the progression of atherosclerosis.
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PMID:Effects of mitogen-activated protein kinase pathway and co-activator CREP-binding protein on peroxisome proliferator-activated receptor-gamma-mediated transcription suppression of angiotensin II type 1 receptor gene. 1456 1


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