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: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic exposure to arsenic has been linked to tumorigenesis, cardiovascular disease, hypertension, atherosclerosis, and peripheral vascular disease; however, the molecular mechanisms underlying its pathological effects remain elusive. In this study, we investigated arsenic-induced alteration of focal adhesion protein complexes in normal, primary vascular smooth muscle cells. We demonstrate that exposure to environmentally relevant concentrations of arsenic (50 ppb As(3+)) can alter focal adhesion protein co-association leading to activation of downstream pathways. Co-associated proteins were identified and quantitated via co-immunoprecipitation, SDS-PAGE, and Western blot analysis followed by scanning densitometry. Activation of MAPK pathways in total cell lysates was evaluated using phosphor-specific antibodies. In our model, arsenic treatment caused a sustained increase in FAK-src association and activation, and induced the formation of unique signaling complexes (beginning after 3-hour As(3+) exposure and continuing throughout the 12-hour time course studied). The effects of these alterations were manifested as chronic stimulation of downstream PAK, ERK and JNK pathways. Past studies have demonstrated that these pathways are involved in cellular survival, growth, proliferation, and migration in VSMCs.
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PMID:Arsenic alters vascular smooth muscle cell focal adhesion complexes leading to activation of FAK-src mediated pathways. 1848 77

Endothelial apoptosis is a driving force in atherosclerosis development. Oxidized LDL promotes inflammatory and thrombotic processes and is highly atherogenic, as it stimulates macrophage cholesterol accumulation and foam cell formation. This study investigated multiple mitogen-activated protein kinase (MAPK)-responsive death/survival signaling pathways, through which flavonoids of (-)epigallocatechin gallate (EGCG) and hesperetin exerted antiapoptosis in endothelial cells exposed to oxidized LDL. EGCG and hesperetin substantially diminished the oxidized LDL-induced 2',7'-dichlorofluorecein staining, suggesting that these flavonoids inhibited intracellular accumulation of oxidized LDL-triggered reactive oxygen species and consequent apoptosis. The Western-blot data revealed that oxidized LDL upregulated c-Jun N-terminal kinase (JNK) phosphorylation, which was rapidly reversed by EGCG and hesperetin. They mitigated the consequent activation of the JNK downstream on p53 and c-Jun. Moreover, oxidized LDL increased luciferase activity of p53 in endothelial cells transfected with a p53 promoter construct, the increase of which was strikingly downregulated by EGCG and hesperetin. Surprisingly, hesperetin but not EGCG attenuated phosphorylation of p38MAPK and its downstream c-myc and signal transducers and activators of transcription (STAT)1 evoked by oxidized LDL. This study also attempted to explore a linkage of Janus kinase (JAK)2/STAT3 activation to MAPK signaling in oxidized LDL-induced endothelial apoptosis. Notably, we found that the JAK2 inhibitor substantially blocked the JNK activation. Our findings suggest that EGCG and hesperetin may act as antiatherogenic agents blocking oxidized LDL-induced endothelial apoptosis via differential cellular apoptotic machinery. These data provide evidence that the interplay between p38MAPK and JAK-STAT pathways is involved in dietary flavonoid protection against oxidized LDL through hampering MAPK-dependent pathways involving the activation of JAK2.
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PMID:Dietary flavonoids differentially reduce oxidized LDL-induced apoptosis in human endothelial cells: role of MAPK- and JAK/STAT-signaling. 1849 23

Medial-to-intimal migration of SMCs is critical to atherosclerotic plaque formation and remodeling of injured arteries. Considerable amounts of the shed soluble form of the LDL receptor relative LR11 (sLR11) produced by intimal SMCs enhance SMC migration in vitro via upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. Here, we show that circulating sLR11 is a novel marker of carotid intima-media thickness (IMT) and that targeted disruption of the LR11 gene greatly reduces intimal thickening of arteries through attenuation of Ang II-induced migration of SMCs. Serum concentrations of sLR11 were positively correlated with IMT in dyslipidemic subjects, and multivariable regression analysis suggested sLR11 levels as an index of IMT, independent of classical atherosclerosis risk factors. In Lr11-/- mice, femoral artery intimal thickness after cuff placement was decreased, and Ang II-stimulated migration and attachment of SMCs from these mice were largely abolished. In isolated murine SMCs, sLR11 caused membrane ruffle formation via activation of focal adhesion kinase/ERK/Rac1 accompanied by complex formation between uPAR and integrin alphavbeta3, a process accelerated by Ang II. Overproduction of sLR11 decreased the sensitivity of Ang II-induced activation pathways to inhibition by an Ang II type 1 receptor blocker in mice. Thus, we demonstrate a requirement for sLR11 in Ang II-induced SMC migration and propose what we believe is a novel role for sLR11 as a biomarker of carotid IMT.
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PMID:Ang II-stimulated migration of vascular smooth muscle cells is dependent on LR11 in mice. 1861 22

RGD-peptides can inhibit the binding of ligands to certain beta3 integrins, alphaIIbbeta3 and alphavbeta3, both of which are involved in neointimal hyperplasia that contributes to atherosclerosis and restenosis of arterial walls. Saxatilin, a disintegrin from a Korean snake (Gloydius saxatilis), interacts with integrins alphaIIbbeta3 and alphavbeta3. It suppressed the adhesion of human coronary artery smooth muscle cells (HCASMCs) to vitronectin with an IC(50) of 2.5 microM, and growth factor (PDGF-BB or bFGF)-induced proliferation was inhibited at an IC(50) of 25 microM. Saxatilin disassembled the actin cytoskeleton of focal adhesion and induced cell detachment. This disassembly of focal adhesion in saxatilin-treated HCASMCs involved caspase-induced paxillin degradation. Saxatilin temporally phosphorylated FAK and ERKs and affected the cell cycle of HCASMCs by increasing CDK inhibitors (p21 and p27) and reducing cyclins (D1/2 and E). These results may have significant implications for integrin antagonistic therapy used for the treatment of atherosclerosis and restenosis.
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PMID:Suppressive effect and mechanism of saxatilin, a disintegrin from Korean snake (Gloydius saxatilis), in vascular smooth muscle cells. 1862 63

Smooth muscle cells (SMCs) play an important role in the development of atherosclerosis and restenosis after angioplasty and coronary bypass grafting. The pathogenesis of these vascular diseases includes the abnormal production of extracellular matrix (ECM) proteins by SMCs and their interactions with this newly synthesized and preexisting ECM. Litebamine, a natural phenanthrene alkaloid from the wood of Litsea cubeba, has been shown to inhibit platelet aggregation and thromboxane B(2) formation, suggesting its antithrombotic activity. In the present study we examined litebamine effects on vascular SMC adhesion and migration. Our results indicated that litebamine inhibited rat aortic SMCs (RASMCs) and A10 thoracic SMCs adhesion to collagen but not to other matrix proteins, suggesting its specificity on collagen. This inhibition was possibly resulted from that litebamine attenuated immobilized collagen-induced focal adhesion kinase (FAK) phosphorylation and actin cytoskeleton reorganization in RASMCs, as determined by Western blotting and immunofluorescence microscopy. In a functional study, litebamine also inhibited platelet-derived growth factor (PDGF)-induced RASMC migration but did not affect PDGF-induced matrix metalloproteinases (MMPs) secretion. Strikingly, among the tested kinases involved in PDGF-induced migration, only PDGF-induced phosphatidylinositol-3 kinase (PI-3K) activation was inhibited by litebamine. Taken together, we demonstrated here that litebamine can functionally inhibit vascular SMC adhesion and migration and elucidated its possible mechanisms of action. As SMC adhesion and migration are critical events in disease-related vascular remodeling, this compound may have beneficial effects in preventing cardiovascular diseases.
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PMID:Litebamine, a phenanthrene alkaloid from the wood of Litsea cubeba, inhibits rat smooth muscle cell adhesion and migration on collagen. 1877 89

Bisphosphonates, which are extensively used in bone-related disorders, have been reported to inhibit atherosclerosis and neointimal hyperplasia. In the present study, we investigated the effects of a bisphosphonate, zoledronate, on the proliferation, adhesion, migration and microstructure of vascular smooth muscle cells (VSMCs) from Sprague-Dawley rats. It was shown that zoledronate suppressed VSMCs proliferation after 48 h cultivation in a dose depend manner, most obviously at concentrations above 10 microM. Cell cycle analysis indicated that zoledronate inhibited the proliferation of VSMCs via cell cycle arrest at S/G2/M phase. This inhibition was not associated with cell death. In a modified Boyden chamber model, it was shown that zoledronate dose-dependently inhibited VSMCs adhesion to collagen and migration stimulated by platelet-derived growth factor-BB. Western blot analysis suggested that zoledronate significantly inhibited the phosphorylation of focal adhesion kinase. Furthermore, we observed that more and more VSMCs changed from a bipolar appearance to a globular shape under inverted light microscope as zoledronate concentration increased from 0.1 to 100 microM. Images under transmission electron microscope confirmed this morphological change, and many electron density bodies were observed in zoledronate-treated VSMCs. These findings indicated that bisphosphonates' effects of suppressing atherosclerosis and neointimal hyperplasia might be due to inhibition of VSMCs, at least for zoledronate.
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PMID:Zoledronate inhibits the proliferation, adhesion and migration of vascular smooth muscle cells. 1900 Jun 70

The trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherogenesis. However, the mechanism by which this occurs is not clearly defined. Here, we tested in mice the hypothesis that CD36, a class B scavenger receptor expressed on macrophages, has a role in this process. Using both in vivo and in vitro migration assays, we found that oxidized LDL (oxLDL), but not native LDL, inhibited migration of WT mouse macrophages but not CD36-deficient cells. We further observed a crucial role for CD36 in modulating the in vitro migratory response of human peripheral blood monocyte-derived macrophages to oxLDL. oxLDL also induced rapid spreading and actin polymerization in CD36-sufficient but not CD36-deficient mouse macrophages in vitro. The underlying mechanism was dependent on oxLDL-mediated CD36 signaling, which resulted in sustained activation of focal adhesion kinase (FAK) and inactivation of Src homology 2-containing phosphotyrosine phosphatase (SHP-2). The latter was due to NADPH oxidase-mediated ROS generation, resulting in oxidative inactivation of critical cysteine residues in the SHP-2-active site. Macrophage migration in the presence of oxLDL was restored by both antioxidants and NADPH oxidase inhibitors, which restored the dynamic activation of FAK. We conclude therefore that CD36 signaling in response to oxLDL alters cytoskeletal dynamics to enhance macrophage spreading, inhibiting migration. This may induce trapping of macrophages in the arterial intima and promote atherosclerosis.
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PMID:CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. 1950 73

Lipoma preferred partner (LPP) localizes to focal adhesions/dense bodies, is selectively expressed in smooth muscle cells (SMC) and enhances cell migration. SMCs cultured on denatured collagen or on a rigid substrate, up regulated expression of LPP, its partner palladin, tenascin C (TN-C), phosphorylated focal adhesion kinase (pFAK) and exhibited robust stress fibers. In an endothelial (EC)/SMC hemodynamic flow system, shear stress waveforms mimicking atheroprone flow, applied to the EC layer, significantly decreased expression of SMC LPP and palladin. They were also down regulated with TN-C, in an ApoE murine model of atherosclerosis and with oxidative stress but up regulated in an arterial injury model in response to upstream sequential changes in pFAK, Prx1 and TN-C. In conclusion, expression of LPP and palladin are modulated by a mix of mechanical cues, oxidative stress and substrate composition which translate into their up or down regulation in vessel wall injury and early atherogenesis.
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PMID:Mechanical properties of the extracellular matrix alter expression of smooth muscle protein LPP and its partner palladin; relationship to early atherosclerosis and vascular injury. 1920 7

Integrins are heterodimeric cell-surface molecules, which act as the principle mediators of molecular dialog between a cell and its extracellular matrix environment. In addition to their structural functions, integrins mediate signaling from the extracellular space into the cell through integrin-associated signaling and adaptor molecules such as FAK (focal adhesion kinase), ILK (integrin-linked kinase), PINCH (particularly interesting new cysteine-histidine rich protein) and Nck2 (non-catalytic (region of) tyrosine kinase adaptor protein-2). Via these molecules, integrin signaling tightly and cooperatively interacts with receptor tyrosine kinases (RTKs) signaling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In the heart and blood vessels, the function and regulation of these molecules can be partially disturbed and thus contribute to cardiovascular diseases such as cardiac hypertrophy and atherosclerosis. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these systems (1).
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PMID:Integrins and proximal signaling mechanisms in cardiovascular disease. 1927 3

IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, and atherosclerosis. We investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would up-regulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT, HEK293 cells, chondrocytes, monocytes, and glioblastoma cells. Inhibition of hypoxia-inducible factor 1alpha inhibited CoCl(2)-induced IL-20 expression. We identified two putative hypoxia response elements in the human il20 gene promoter. Promoter activity assays showed that CoCl(2) mimicked hypoxia-activated luciferase reporter gene expression. In vivo, experimental ischemic stroke up-regulated IL-20 in the sera and brain tissue of rats. IL-20 stained positively in glia-like cells in peri-infarcted lesions, but not in contralateral tissue. Administration of IL-20 mAb ameliorated ischemia-induced brain infarction of rats after experimental ischemic stroke. In vitro, RT-PCR analysis showed that glioblastoma cells, GBM8901, expressed IL-20 and its receptor subunits IL-20R1, IL-20R2, and IL-22R1. IL-20 induced cell proliferation in GBM8901 cells by activating the JAK2/STAT3 and ERK1/2 pathways. IL-20 also induced production of IL-1beta, IL-8, and MCP-1 in GBM8901 cells. We conclude that IL-20 was responsive to hypoxia in vitro and in the ischemic stroke model and that up-regulation of IL-20 in the ischemic brain may contribute to brain injury.
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PMID:IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. 1934 80


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