Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Retinoic acid modulates cell growth and differentiation of the vascular system. Vascular endothelial growth factor (VEGF) is known as a vascular permeability factor and a potent mitogen for vascular endothelial cells. In the present study, we investigated whether retinoic acid induces VEGF release in aortic smooth muscle A10 cells and if so, the mechanism of VEGF release. Retinoic acid stimulated VEGF release dose-dependently over the range 0.1 nM-0.1 microM. The retinoic acid-stimulated VEGF release was significantly reduced by actinomycin D. Retinoic acid induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase but not p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase among the MAP kinase superfamily. This effect of retinoic acid was dose-dependent (30 nM-5 microM) and the maximum effect was observed at 0.3 microM. The retinoic acid-stimulated release of VEGF was significantly reduced by PD98059 and U0126, specific MEK inhibitors, which attenuated the retinoic acid-induced phosphorylation of p44/p42 MAP kinase. These results strongly suggest that retinoic acid stimulates the release of VEGF in a p44/p42 MAP kinase-dependent manner in aortic smooth muscle cells.
Atherosclerosis 2004 Aug
PMID:Possible involvement of p44/p42 MAP kinase in retinoic acid-stimulated vascular endothelial growth factor release in aortic smooth muscle cells. 1526 80

Mitogen-activated protein (MAP) kinase cascades play a central role in mediating extracellular stimuli-induced intracellular signaling during cell activation. The fourth and least studied mammalian MAP kinase pathway, big MAP kinase 1 (BMK1), also known as extracellular signal regulated kinase 5 (ERK5), is activated in response to growth factors and stress. Activation of this signaling pathway has been implicated not only in physiological functions such as cell survival, proliferation and differentiation but also in pathological processes such as carcinogenesis, cardiac hypertrophy and atherosclerosis. In recent years a series of gene-targeted mice lacking components within the BMK1 cascade have been generated, which have enabled us to investigate the role of the BMK1 pathway within different tissues. Analyses of these knockout mice have led to major discoveries in the role of BMK1 signaling in angiogenesis and in cardiac development. Moreover, studies using conditional BMK1 knockout mice, which circumvent the early embryonic lethality of BMK1 knockouts, have unveiled the importance of BMK1 in endothelial survival and maintenance of vascular integrity during adulthood. Here we summarize current understanding of the function of BMK1, as well as include new data generated from a series of tissue-specific BMK1 knockout mice in an attempt to dissect the role of the BMK1 pathway in various cell types in animals.
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PMID:Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. 1551 28

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.
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PMID:Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway. 1571 Jul 85

The hypertrophy of vascular smooth muscle cells (VSMCs) is critical in vascular remodeling associated with hypertension, atherosclerosis, and restenosis. Recently, leptin has appeared to play a pivotal role in vascular remodeling. However, the mechanism by which leptin induces hypertrophy in vascular smooth muscle cells is still unknown. We studied the role of leptin as a potential hypertrophic factor in rat VSMCs. In the present study, leptin significantly increased [(3)H]leucine incorporation and the total protein/DNA ratio in VSMCs. The maximal hypertrophic effect was at 100ng/ml of leptin. Leptin induced phosphorylation and activation of p38 mitogen-activated protein (p38 MAP) kinase and of signal transducers and activators of transcription 3 in a concentration- and time-dependent manner. A p38 MAP kinase inhibitor SB203580 significantly inhibited leptin-induced hypertrophy, AG490 (a JAK2 inhibitor) partially inhibited it, and other MAP kinase inhibitors, PD98059 (an ERK inhibitor) and SP600125 (a JNK inhibitor), had no effect. These results indicate that leptin directly stimulates cellular hypertrophy via p38 MAP kinase in rat VSMCs.
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PMID:Leptin induces hypertrophy via p38 mitogen-activated protein kinase in rat vascular smooth muscle cells. 1572 Dec 67

In immortalized rat brain endothelial cells (GP8.39), we have previously shown that oxidized LDL (oxLDL), after 24-h treatment, stimulates arachidonic acid release and phosphatidylcholine hydrolysis by activation of cytosolic phospholipase A(2) (cPLA(2)). A putative role for MAPKs in this process has emerged. Here, we studied the contribution of Ca(2+)-independent phospholipase A(2) (iPLA(2)), and the role of the MAP kinase family as well as both cPLA(2) and iPLA(2) mRNA expression by RT-PCR in oxLDL toxicity to GP8.39 cells in vitro. The activation of extracellular signal-regulated kinases ERK1/2, p38 and c-Jun NH(2)-terminal kinase (JNK) was assessed with Western blotting and kinase activity assays. iPLA(2) activity, which was found as a membrane-associated enzyme, was more stimulated by oxLDL compared with native LDL. The phosphorylation of ERK1/2, p38 and JNKs was also significantly enhanced in a dose-dependent manner. PD98059, an ERK inhibitor, SB203580, a p38 inhibitor, and SP600125, an JNK inhibitor, abolished the stimulation of all three members of the MAPK family by oxLDL. Confocal microscopy analysis and subcellular fractionation confirmed either an increase in phosphorylated form of ERKs, p38 and JNKs, or their nuclear translocation upon activation. A strong inhibition of MAPK activation was also observed when endothelial cells were treated with GF109203X, a PKC inhibitor, indicating the important role of both PKC and all three MAPKs in mediating the maximal oxLDL response. Finally, compared with samples untreated or treated with native LDL, treatment with oxLDL (100 muM hydroperoxides) for 24 h significantly increased the levels of constitutively expressed iPLA(2) protein (by 5.1-fold) and mRNA (by 3.1-fold), as well as cPLA(2) protein (by 4.4-fold) and mRNA (by 1.5-fold). Together, these data link the stimulation of PKC-ERK-p38-JNK pathways and PLA(2) activity by oxLDL to the prooxidant mechanism of the lipoprotein complex, which may initially stimulate the endothelial cell reaction against noxious stimuli as well as metabolic repair, such as during inflammation and atherosclerosis.
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PMID:Activation of phospholipase A(2) and MAP kinases by oxidized low-density lipoproteins in immortalized GP8.39 endothelial cells. 1597 99

G2A is a G protein-coupled receptor that is predominantly expressed in lymphoid tissues and macrophages. G2A can be induced by diverse stimuli to cause cell cycle arrest in the G(2)/M phase in pro-B and T cells. G2A is also expressed in macrophages within atherosclerotic lesions, suggesting G2A involvement in atherosclerosis. Recently, G2A was discovered to possess proton-sensing ability. In this paper, we report another function of G2A, that is, as a receptor for 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized free fatty acids. G2A, expressed in CHO-K1 or HEK293 cells, showed 9-HODE-induced intracellular calcium mobilization, inositol phosphate accumulation, inhibition of cAMP accumulation, [(35)S]guanosine 5'-3-O-(thio)triphosphate binding, and MAP kinase activation. Furthermore, G2A was activated by various oxidized derivatives of linoleic and arachidonic acids, but it was weakly activated by cholesteryl-9-HODE. Oxidized phosphatidylcholine (1-palmitoyl-2-linoleoyl) when hydrolyzed with phospholipase A(2) also evoked intracellular calcium mobilization in G2A-expressing cells. These results indicate that G2A is activated by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate. Thus, G2A might have a biological role in diverse pathological conditions including atherosclerosis.
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PMID:Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. 1623 15

Matrix metalloproteinases (MMP-9 and MMP-2) production and smooth muscle cell (SMC) migration may play key roles in the phathogenesis of neointima formation and atherosclerosis. Especially inducible MMP-9 expression was directly involved in the cancer cell invasion and SMC migration through vascular wall. In this study, we reveal that cryptotanshinone (CT) purified from Salvia miltiorrhiza BUNGE had an inhibitory effect on MMP-9 production and migration of human aortic smooth muscle cells treated with TNF-alpha in a dose-dependent manner. The down regulation of transcription of MMP-9 mRNA was evidenced by RT-PCR and MMP-9 promoter assay using luciferase reporter gene. Eletrophoretic mobility shift assay showed NF-kappaB and AP-1 nuclear translocations were suppressed. In addition, Western blot analysis indicated that extracellular signal regulated kinase 1 and 2, p38 and JNK MAP kinase signaling pathways were inhibited. From the results, it is suggested that CT has anti-atherosclerosis and anti-neointimal formation activity.
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PMID:Cryptotanshinone from Salvia miltiorrhiza BUNGE has an inhibitory effect on TNF-alpha-induced matrix metalloproteinase-9 production and HASMC migration via down-regulated NF-kappaB and AP-1. 1699 37

Increasing evidence suggests that secreted phospholipases A2 (sPLA2s) play an important role in the pathophysiology of atherosclerosis. Among sPLA2s, the human group X (hGX) enzyme has the highest catalytic activity toward phosphatidylcholine, one of the major phospholipid species of cell membranes and low-density lipoprotein (LDL). Our study examined the presence of hGX sPLA2 in human atherosclerotic lesions and investigated the ability of hGX modified LDL to alter human endothelial cell (HUVEC) function. Our results show that hGX sPLA2 is present in human atherosclerotic lesions and that the hydrolysis of LDL by hGX sPLA2 results in a modified particle that induces lipid accumulation in human monocyte-derived macrophages. Acting on endothelial cells, hGX-modified LDL activates the MAP kinase pathway, which leads to increased arachidonic acid release, increased expression of adhesion molecules on the surface of HUVEC, and increased adhesion of monocytes to HUVEC monolayers. Together, our data suggest that LDL modified by hGX, rather than hGX itself may have strong proinflammatory and proatherogenic properties, which could play an important role in the propagation of atherosclerosis.
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PMID:Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function. 1707 89

The intracellular mechanism responsible for the mitogenic effects of lysophosphatidylcholine (LPC) is unclear. Import of proteins from the cytoplasm into the cell nucleus is integral to the regulation of gene expression and cell growth. We hypothesized that LPC exerts its intracellular effects through alterations in nuclear protein import. Rabbit aortic smooth muscle cells incubated with LPC induced a significant increase in cell proliferation in both quiescent cells (63.2+/-6.48% of control) and cells grown in 1% fetal bovine serum (FBS) (28.3+/-7.35% of control). Vascular smooth muscle cells were preincubated with LPC then microinjected with a marker protein for nuclear import. A significant stimulation of nuclear protein transport was observed. Using a conventional nuclear protein import assay in permeabilized cells, a significant stimulation of import (72.3+/-5.2% of control) was again observed when the cytosolic nuclear import cocktail was treated with LPC. This effect was not observed with other lysophosphatidyl species. LPC also activated the extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) pathway, and this was blocked by 2'-amino-3'-methoxyflavone (PD98059), which inhibits the activation of ERK 1/2. The stimulation of nuclear import was also blocked by PD98059. LPC-induced MAPK activation augmented GTP hydrolysis by RanGAP, a RanGTPase activating protein and a critical regulatory component of nuclear protein import, and this stimulation was again blocked by PD98059. We conclude that LPC alters gene expression and cell proliferation through striking effects on nuclear protein import via a MAP kinase-induced activation of RanGAP. This may play an important role in cancer and atherosclerosis and other disorders involving accelerated cell growth/proliferation.
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PMID:RanGAP-mediated nuclear protein import in vascular smooth muscle cells is augmented by lysophosphatidylcholine. 1710 74

Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC)in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier-protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrier-protective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rac activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection.
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PMID:Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. 1729 25


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