Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the work was to analyze, on a comparative basis, the signaling pathways operating in the regulation of a panel of matrix metalloproteinases (MMP) expressed by human dermal fibroblasts submitted to mechanical stress relaxation by cytochalasin D (CD) and in a retracting collagen gel (RCG). The mRNA steady-state level of MMPs was measured by a quantitative RT-PCR procedure using a synthetic RNA as internal standard. In monolayer, most MMPs were barely detected, except MMP-2. Disruption of the actin stress fibers by CD induced a moderate increase of MMP-2 mRNA and a much larger stimulation of MMP-3, -9, -13 and -14 mRNAs. In RCG, a significant up-regulation of these MMPs was also observed although to a lower extent than in CD-treated monolayers. Among the investigated MMPs, the MMP-8 and -11 were not reproducibly detected. MMP-2 was processed to its active form both by CD and in RCG. The CD-induced up-regulation of gene expression was largely repressed by blocking protein synthesis by cycloheximide for all the MMPs, by inhibiting the tyrosine-kinases of the src family by herbimycin A for all MMPs, except MMP-2, and by inhibiting the TPA-inducible PKC isoforms by bisindoyl maleimide for all MMPs, except MMP-14. The up-regulation induced by stress relaxation in RCG was protein synthesis-dependent for MMP-2 and MMP-13, tyrosine kinases-dependent for MMP-3 and MMP-13, as previously described for MMP-1. Inhibiting TPA-inducible PKC did not affect any MMP in RCG except MMP-13, which was strongly induced. The processing of MMP-2 was tyrosine kinases-dependent but PKC-independent. Inhibitors of the ERK1,2 and p38 MAP kinases pathways diversely affected the MMPs expression. Inhibiting the Rho-kinase activity by Y-27632 was inactive. These results point to the potent regulation operated by the status of the cytoskeleton on the cell phenotype, and to distinct regulatory pathways involved in the control of different MMPs expression.
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PMID:Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. 1169 80

Hypericin, a perihydroxylated dianthraquinone is shown here to be a highly potent inhibitor of angiogenesis in several ocular models examined in rat eyes. Extensive angiogenesis induced in the cornea and iris by intra-ocular administration of FGF-2 was effectively inhibited by a minimum of four dose regimens of hypericin (2 mg/kg) administered via the intraperitoneal route at 48 h intervals. Maximal inhibition was achieved when animal treatment with hypericin was initiated 48 h prior to inoculation of FGF-2. The molecular basis for the hypericin-mediated inhibition of angiogenesis in the anterior eye compartment appears to involve several sites in the cascade leading to angiogenesis. We show that the activating phosphorylation of extracellular signal-regulated MAP kinases (ERK1/2) is inhibited by hypericin in human retinal pigment epithelial cells and in EA.hy926 cells, an endothelial hybridoma expressing endothelial cell properties. ERK1/2 activity is required for the transactivation of hypoxia-inducible factor 1 alpha (HIF-1alpha) and in VEGF-induced blood vessel sprouting. MT1-MMP activity in human microvascular endothelial cells was also inhibited. The findings identify hypericin as a potentially useful agent in the treatment of ophthalmic neovascularization pathogeneses.
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PMID:Anti-angiogenic activities of hypericin in vivo: potential for ophthalmologic applications. 1613 16

Matrix metalloproteinases (MMPs) play an important role in vascular remodeling and cardiovascular diseases by degrading extracellular matrix. Regulation of MMPs can be mediated by mitogen-activated protein kinases (MAPKs). Effects of pressure application on the proteolytic activity of MMP-2 and MAPK pathways were investigated in an organ culture of porcine muscular arteries. Inhibition of MAPKs (ERK1/2 and p38 MAPK) was carried out to prove their effects on MMP-2 activation. After tensile stress, activity and gene expression of MMP-2 were increased (p<0.05) as shown by gelatinase assays and real-time PCR. Whereas protein expression of MMP-2 and TIMP-2 showed no changes, its regulator MT1-MMP decreased in Western blot (p<0.001) and immunohistochemistry. In addition, p38 and ERK1/2 were activated (p38, p<0.05; ERK1/2, p<0.001) by pressure. After inhibition of p38 and ERK1/2 with SB203580 or PD98059, only the inhibition of the p38 pathway had an inhibitory effect on MMP-2 gelatinolytic activity. Tensile stress activates the MMP-2 system in muscular arterial walls. This mechanical signal is mediated by p38 MAPK and can be attenuated by blocking the p38 signal pathway. The regulation of the vascular gelatinolytic system by MAP kinases suggests a therapeutic option against cardiovascular diseases at the level of MAPK signal transduction.
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PMID:Induction of the matrix metalloproteinase-2 activation system in arteries by tensile stress. Involvement of the p38 MAP-kinase pathway. 1730 32