Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of the precursor of tissue collagenase/matrix metalloproteinase 1 (proMMP-1) by cultured human aortic medial smooth muscle cells (SMCs) was significantly enhanced by the treatment of the cells with platelet-derived growth factor (PDGF), interleukin 1 or 12-O-tetradecanoylphorbol-13-acetate (TPA). The response to PDGF of SMCs exhibited a tendency to be age-dependent: only SMCs obtained from older individuals (age: 54, 56, 72 and 74 years) responded to PDGF and synthesized proMMP-1, but not SMCs from young individuals (age: 10, 16 and 41 years), and weak responsiveness with a 19-year-old individual. On the other hand, induction of proMMP-1 synthesis in SMCs by TPA was not discriminated by age. The synthesis of two other related matrix metalloproteinases was also examined. Matrix metalloproteinase 2 was found to be constitutively expressed in zymogen form in SMCs and its synthesis was not affected by the treatments with PDGF, interleukin 1 or TPA. The synthesis of matrix metalloproteinase 3 (stromelysin) was not detected in SMCs from both young and old individuals even after the treatment with PDGF, interleukin-1, prostaglandin E2 or TPA. The ability of SMCs to synthesize and secrete proMMP-1 in response to PDGF suggests that this enzyme plays an important role in the migration of PDGF-stimulated SMCs from the media into the intima of aorta and the eventual formation of atherosclerotic plaques.
Atherosclerosis 1991 Dec
PMID:Production of tissue collagenase (matrix metalloproteinase 1) by human aortic smooth muscle cells in response to platelet-derived growth factor. 166 62

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.
 ...
PMID:Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. 783 Dec 99

Degradation of elastic fibers in the arterial walls is an important step in the development of atherosclerosis. To identify the enzyme(s) responsible for the elastinolysis, we have designed an ex vivo model of aortic explants cultured with or without THP-1 cells (human monocyte/macrophage-like cells). After culturing with THP-1 cells for 5 days elastic fibers of the aortic explants were fragmented and lost. With insoluble [3H] elastin as a substrate, elastin-degrading activity could be detected in the culture medium. Zymography in sodium dodecyl sulfate-polyacrylamide gel electrophoresis containing alpha-elastin showed the presence of elastinolytic activity with 92 kd in the medium from the aortic tissue with THP-1 cell cultures, whereas the medium from the aortic tissue without THP-1 cells contained negligible elastinolytic activity. The activity was inhibited by ethylenediamine tetraacetic acid but not by phenylmethane sulfonyl fluoride, N-ethylmaleimide, or pepstatin A, indicating that the enzyme belongs to a class of metalloproteinases. In addition, destruction of the elastic fibers of the aortic explants cultured with THP-1 cells was completely inhibited only by metalloproteinase inhibitors. Immunoblot analyses demonstrated that the proteinase responsible for the elastinolytic activity is matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase = gelatinase B). Using immunocytochemistry, the metalloproteinase was localized in the THP-1 cells but not in the medial smooth muscle cells. These results suggest that matrix metalloproteinase-9 produced by THP-1 cells is of importance to degradation of elastic fibers in the aortic explants. The role of macrophages in the atherosclerosis is discussed with reference to elastinolysis of the arterial walls.
 ...
PMID:Matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase equals gelatinase B) can degrade arterial elastin. 797 51

The extracellular matrix (ECM) is an intricate network composed of an array of macromolecules capable of regulating the functional responsiveness of cells. Its composition greatly varies among different types of tissue, and dysregulation of its metabolism may contribute to vascular remodeling during the pathogenesis of various diseases, including atherosclerosis. In view of their antiatherosclerotic effects, the role of Ca2+ channel blockers in the metabolism of ECM was examined. Nanomolar concentrations of the five Ca2+ channel blockers amlodipine, felodipine, manidipine, verapamil, or diltiazem significantly decreased both the constitutive and platelet-derived growth factor BB-dependent collagen deposition in the ECM formed by human vascular smooth muscle cells and fibroblasts. The drugs inhibited the expression of fibrillar collagens type I and III and of basement membrane type IV collagen. Furthermore, Ca2+ channel blockers specifically increased the proteolytic activity of the 72-kDa type IV collagenase as shown by gelatin zymography and inhibited the transcription of tissue inhibitor of metalloproteinases-2.
 ...
PMID:Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix. 864

The migration and proliferation of vascular smooth muscle cells (SMCs) during neointima formation in atherosclerosis and angioplasty restenosis is mediated by certain growth factors and cytokines, one action of which may be to promote basement-membrane degradation. To test this hypothesis further, the effects of such growth factors and cytokines on the synthesis of two basement-membrane-degrading metalloproteinases, namely the 72 kDa gelatinase (MMP-2, gelatinase A) and the 95 kDa gelatinase (MMP-9, gelatinase B) and three tissue inhibitors of metalloproteinases (TIMPs) was studied in primary cultured rabbit aortic SMCs. Expression of the 95 kDa gelatinase was increased by phorbol myristate acetate, foetal calf serum, thrombin and interleukin-1alpha (IL-1alpha); platelet-derived growth factor (PDGF) BB alone had no effect but acted synergistically with IL-1alpha. A selective protein kinase C inhibitor, Ro 31-8220, abolished induction of the 95 kDa gelatinase. In contrast, none of the agents tested modulated the synthesis of the 72 kDa gelatinase. We conclude that maximal up-regulation of 95 kDa gelatinase expression requires the concerted action of growth factors and inflammatory cytokines mediated, in part, by a protein kinase C-dependent pathway. TIMP-1 and TIMP-2 were highly expressed, and their synthesis was not affected by growth factors or cytokines. Expression of TIMP-3 mRNAs was, however, increased by PDGF and transforming growth factor beta, especially in combination. Divergent regulation of gelatinase and TIMP expression implies that either net synthesis or net degradation of basement membrane can be mediated by appropriate combinations of growth factors and cytokines.
 ...
PMID:Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. 867 Jan 28

Matrix metalloproteinases (MMPs) can degrade a number of proteins that constitute the extracellular matrix. Previous studies have shown that atherosclerotic plaques contain substantial amounts of fibrin(ogen)-related antigen, and more recently, MMPs have been identified in such lesions. The hypothesis that MMPs play a role in the degradation of fibrinogen (Fg) and cross-linked fibrin (XL-Fb) was investigated. Fibrinogen became thrombin-unclottable when treated with matrix metalloproteinase 3 (MMP-3, stromelysin 1) but not with matrix metalloproteinase 2 (MMP-2, gelatinase A). Incubation of XL-Fb clots (made with 125I-Fg) with MMP-3 resulted in complete lysis after 24 h. A D monomer-like fragment was generated by MMP-3 degradation of fibrinogen, XL-Fb, and fragment DD. Immunoreactivity with monoclonal antibody (MoAb)/4-2 (anti-gamma 392-406) but not with MoAb/4A5 (anti-gamma 397-411) suggested that a major cleavage site was within the sequence participating in the cross-linking of two gamma-chains. NH2-terminal sequence analysis of they gamma-chain of the D monomer-like fragment and of a dipeptide isolated from the MMP-3 digest of XL-fibrin identified the hydrolysis of the gamma Gly 404-Ala 405 peptide bond. These data indicate that the degradation of Fg and XL-Fb by MMP-3 is specific and different from plasmin. This mechanism of fibrinolysis might be of relevance in wound healing, inflammation, atherosclerosis, and other pathophysiological processes.
 ...
PMID:Degradation of cross-linked fibrin by matrix metalloproteinase 3 (stromelysin 1): hydrolysis of the gamma Gly 404-Ala 405 peptide bond. 885 41

Blood platelets limit blood loss at sites of vascular injury by forming a mechanical plug. They are also involved in thrombosis, atherosclerosis, inflammation and metastasis. Platelet activation is essential for these physiological and pathological reactions and depends upon their adhesion to the vessel wall and attachment to each other in the aggregation process. The two known pathways of aggregation are mediated by the release of endoperoxides/thromboxane A2 and ADP which amplify platelet aggregation. Here we report the identification of a new pathway of aggregation which is mediated by the release of a metalloproteinase enzyme, gelatinase A.
 ...
PMID:Release of gelatinase A during platelet activation mediates aggregation. 912 86

Basement membrane degrading metalloproteinases (gelatinases) have been implicated in the regulation of vascular smooth muscle cell migration and proliferation in culture and during neointima formation in vivo. We compared the expression and activation of gelatinases A and B in explants derived from the arch, mid and distal portions of thoracic aortas of normal rabbits and those given a 1% cholesterol-containing diet for 8 weeks. Neointimal/medial ratio was less than 0.01 in normal rabbits but was significantly increased by cholesterol feeding in the arch (1.08 +/- 0.26), mid (0.75 +/- 0.28) and distal (0.32 +/- 0.12) portions of the aorta (mean +/- S.E.M., n = 6), and to a significantly (P < 0.05) greater extent in the arch and mid than distal portions. Secretion of gelatinase B measured by densitometric scanning of zymograms was undetectable from normal aortas, but was significantly increased by cholesterol feeding in the arch (0.16 +/- 0.06), mid (0.26 +/- 0.08) and distal (0.11 +/- 0.05) portions (optical density units, n = 6, each P < 0.05 versus normal diet). The increase in gelatinase B expression was localised by in situ hybridisation to neointimal vascular smooth muscle cells, macrophages and endothelial cells. Secretion of pro-gelatinase A was detected from normal aortas; it was increased by cholesterol feeding from the arch (4.0 versus 2.8, P < 0.05) and mid (3.6 versus 2.8, P < 0.05) but not distal portions of the aorta (1.8 versus 1.2, n.s.). Similar results were obtained for active gelatinase A secretion from the arch (0.50 versus 0.28, P < 0.05) and mid (0.47 versus 0.23, P < 0.05) but not distal portions (0.19 versus 0.20, n.s.). Increases in pro- and active gelatinase A secretion therefore paralleled the severity of atheroma formation. The results imply that increased basement membrane turnover mediated by gelatinases occurs during cholesterol induced atherosclerosis formation.
Atherosclerosis 1997 Apr
PMID:Increased secretion of gelatinases A and B from the aortas of cholesterol fed rabbits: relationship to lesion severity. 912 49

Matrix metalloproteinases (MMPs), also called matrixins, function in the turnover of extracellular matrix components. These enzymes are considered to play important roles in embryo development, morphogenesis and tissue remodeling, and in diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and in cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes and most of them are secreted from the cells as proenzymes. Thus, the activation of these proenzymes is one of the critical steps that leads to extracellular matrix breakdown. This review describes recent progress made to elucidate the activation mechanisms of pro-matrixins which include extracellular stepwise activation common to most proMMPs, cell surface activation of progelatinase A and procollagenase 3, and intracellular activation of prostromelysin 3 and pro-membrane-type-1 MMP.
 ...
PMID:Activation mechanisms of matrix metalloproteinases. 916 65

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.
 ...
PMID:In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. 940 19


1 2 3 4 5 Next >>