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)

Myocardium consists of diverse cell types suggesting a role for cell-cell interaction in maintaining the structural and functional integrity of the heart. Cardiac fibroblasts are the source of extracellular matrix, growth factors and cytokines in the heart and their interactions with cardiac myocytes are recognized. Their effects on biological responses of endothelial cells, however, are vastly unexplored. Proliferation of endothelial cells is an essential stage of angiogenesis and contributes to development of coronary collaterals. This study was designed to evaluate the effect of soluble factors produced by cardiac fibroblasts on endothelial cell proliferation. Human cardiac fibroblast-conditioned medium (CF-CM) caused a significant increase (47%, P < 0.0001) in DNA synthesis in human umbilical vein endothelial cells (HUVEC), as determined by [(3)H]thymidine incorporation. This effect was dependent on de novo protein synthesis and activation of MAP kinases. Consistently, CF-CM induced the expression and activation of ERK2 in HUVEC. The CF-CM from which heparin-binding proteins were removed, had a significantly enhanced stimulatory effect on DNA synthesis in HUVEC compared to that of 'whole CF-CM'. Western analysis showed the presence of VEGF, bFGF, PDGF, TGF-beta(1), fibronectin and thrombospondin-1 in whole CF-CM. The individual immunodepletion of each factor from whole CF-CM showed that all were necessary for full activity of CF-CM. CF-CM caused a significant reversal of hypoxia-induced inhibition of DNA synthesis and enhanced expression of survival-associated protein, Bcl(2), in HUVEC. Together, these data show that cardiac fibroblasts release inhibitory and stimulatory factors, the net effect of which is an enhancement of DNA synthesis in endothelial cells. These results point to the role that cardiac fibroblasts may play in angiogenesis in the heart.
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PMID:Release of pro- and anti-angiogenic factors by human cardiac fibroblasts: effects on DNA synthesis and protection under hypoxia in human endothelial cells. 1133 98

Interleukin (IL)-17 promotes cartilage breakdown by inducing matrix metalloproteinases (MMPs) and aggrecanases (a disintegrin and metalloproteinase with thrombospondin motif, ADAMTS) in arthritic joints. We investigated IL-17 signaling pathways inducing MMP-3, MMP-13 and ADAM-TS4 genes in bovine articular chondrocytes. IL-17 stimulated phosphorylation of extracellular signal-regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK). ERK pathway inhibitors, PD98059 and U0126, down-regulated IL-17-induced MMP and ADAM-TS4 gene expression. Protein 38 and JNK pathway inhibitors, SB203580 and SP600125, also reduced induction of these genes. Antioxidants and activating protein-1 transcription factor inhibitors, nordihydroguaiaretic acid and N-acetyl-L-cysteine (NAC) suppressed MMP and ADAM-TS4 genes. Similarly, nuclear factor kappa B (NF-kappaB) pathways inhibitors curcumin and Bay-11-7085 also blocked their induction. Thus MMP-3, MMP-13 and ADAM-TS4 genes are coordinately up-regulated by IL-17 via MAP kinases, activating protein-1 (AP-1) and NF-kappaB mediators, which could be targeted for reducing IL-17-triggered cartilage damage.
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PMID:Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes. 1470 35

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.
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PMID:Antiangiogenesis drug design: multiple pathways targeting tumor vasculature. 1661 Oct 71

Under usual conditions, the role of IGF-I in vascular cell types is to maintain cellular protein synthesis and cell size, and even excess IGF-I does not stimulate proliferation. In pathophysiologic states, such as hyperglycemia, smooth muscle cells (SMC) dedifferentiate and change their responsiveness to IGF-I. During hyperglycemia IGF-I stimulates both SMC migration and proliferation. Our laboratory has investigated the molecular mechanism by which this change is mediated. During hyperglycemia SMC secrete increased concentrations of thrombospondin, vitronectin and osteopontin, ligands for the integrin alphaVbeta3. Activation of alphaVbeta3 stimulates recruitment of a tyrosine phosphatase, SHP-2. Exposure of SMC to IGF-I results in phosphorylation of the transmembrane protein, SHPS-1, which provides a docking site for alphaVbeta3-associated SHP-2. After IGF-I stimulation SHP-2 associates with Src kinase, which associates with the signaling protein Shc. Src phosphorylates Shc, resulting in activation of MAP kinases, which are necessary both for stimulation of cell proliferation and migration. Blocking activation of alphaVbeta3 results in an inability of IGF-I to stimulate Shc phosphorylation. Under conditions of normoglycemia, there are insufficient alphaVbeta3 ligands to recruit SHP-2, and no increase in Shc phosphorylation can be demonstrated in SMC. In contrast, if alphaVbeta3 ligands are added to cells in normal glucose, the signaling events that are necessary for Shc phosphorylation can be reconstituted. Therefore when SMC are exposed to normal glucose they are protected from excessive stimulation of mitogenesis by IGF-I. With hyperglycemia there is a marked increased in alphaVbeta3 ligands and Shc phosphorylation in response to IGF-I is sustained. These findings indicate that in SMC hyperglycemic stress leads to altered IGF-I signaling, which allows the cells to undergo a mitogenic response, and which may contribute to the development of atherosclerosis.
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PMID:Role of the integrin alphaVbeta3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress. 1741 27

Aggregating proteoglycans (PG) bearing chondroitin sulfate (CS) side chains associate with hyaluronan and various secreted proteins to form a complex of extracellular matrix (ECM) that inhibits neural plasticity in the central nervous system (CNS). Chondroitinase treatment depletes PGs of their CS side chains and enhances neurite extension. Increasing evidence from in vivo models indicates that proteolytic cleavage of the PG core protein by members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of glutamyl-endopeptidases also promotes neural plasticity. The purpose of this study was to determine whether proteolytic action of the ADAMTSs influences neurite outgrowth in cultured neurons. Transfection of primary rat neurons with ADAMTS4 cDNA induced longer neurites, whether the neurons were grown on a monolayer of astrocytes that secrete inhibitory PGs or on laminin/poly-L-lysine substrate alone. Similar results were found when neurons were transfected with a construct encoding a proteolytically inactive, point mutant of ADAMTS4. Addition of recombinant ADAMTS4 or ADAMTS5 protein to immature neuronal cultures also enhanced neurite extension in a dose-dependent manner, an effect demonstrated to be dependent on the activation of MAP ERK1/2 kinase. These results suggest that ADAMTS4 enhances neurite outgrowth via a mechanism that does not require proteolysis but is dependent on activation of the MAP kinase cascade. Thus a model to illustrate multimodal ADAMTS activity would entail proteolysis of CS-bearing PGs to create a loosened matrix environment more favorable for neurite outgrowth, and enhanced neurite outgrowth directly stimulated by ADAMTS signaling at the cell surface.
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PMID:Multimodal signaling by the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) promotes neurite extension. 1817 86

Osteoarthritis (OA) is the most common form of arthritis worldwide. In this condition, damage to the extracellular matrix (ECM) of cartilage occurs, resulting in joint destruction. Factors mediating cartilage damage include mechanical injury, cytokine and superoxide release on a background of genetic susceptibility and obesity. Studies of arthritic cartilage show increased production of ECM molecules including type II collagen, cartilage oligomeric matrix protein, fibronectin (FN) and fibromodulin. Recent reports suggest that ECM proteins may become endogenous catabolic factors during joint damage. Activation of pro-inflammatory pathways by ECM proteins has led to their description as damage-associated molecular patterns (DAMPs). The ECM proteins involved include fibromodulin, which activates the complement pathway and may promote the persistence of joint inflammation. Fragmentation of type II collagen, FN and hyaluronan reveals cryptic epitopes that stimulate proteolytic enzymes including matrix metalloproteinases and aggrecanases (ADAMTSs - a disintegrin and metalloproteinase with thrombospondin type 1 motifs). Proteolytic fragments also stimulate the release of nitric oxide, chemokines and cytokines and activation of the MAP kinases. Reports are emerging that the receptors for the fragments described involve interaction with integrins and toll-like receptors. In this review the contribution of endogenous ECM molecules to joint destruction will be discussed. A deeper understanding of the pathways stimulated by endogenous ligands could offer potential avenues for novel therapies in the future.
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PMID:Analysing the role of endogenous matrix molecules in the development of osteoarthritis. 1976 1