Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the expression and activity of the matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in tissue remodeling in a number of disease states. One of the better characterized TIMPs, TIMP-1, has been shown to bind to active MMPs and to regulate the MMP activational process. The goal of this study was to determine whether deletion of the TIMP-1 gene in mice, which in turn would remove TIMP-1 expression in LV myocardium, would produce time-dependent effects on LV geometry and function. Age-matched sibling mice (129Sv) deficient in the TIMP-1 gene (TIMP-1 knock-out (TIMP-1 KO), n=10) and wild-type mice (n=10) underwent comparative echocardiographic studies at 1 and 4 months of age. LV catheterization studies were performed at 4 months and the LV harvested for histomorphometric studies. LV end-diastolic volume and mass increased (18+/-4 and 38+/-3%, respectively, P<0.05) at 4 months in the TIMP-1 KO group; a significant increase compared to wild-type controls (P<0.05). At 4 months, LV and end-diastolic wall stress was increased by over two-fold in the TIMP-1 KO compared to wild type (P<0.05). However, LV systolic pressure and ejection performance were unchanged in the two groups of mice. LV myocyte cross-sectional area was unchanged in the TIMP-1 KO mice compared to controls, but myocardial fibrillar collagen content was reduced. Changes in LV geometry occurred in TIMP-1 deficient mice and these results suggest that constitutive TIMP-1 expression participates in the maintenance of normal LV myocardial structure.
J Mol Cell Cardiol 2000 Jan
PMID:Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice. 1065 95

The cellular mechanisms underlying fetal membrane repair are poorly understood. Matrix metalloproteinases (MMP) and the endogenous tissue inhibitors of metalloproteinases (TIMP) play a key role in the control of turnover of extracellular matrix in fetal membranes at normal parturition and preterm prelabour rupture of the fetal membranes (PPROM). The time course of secretion of MMP-2 (72 kDa, gelatinase A) and MMP-9 (92 kDa, gelatinase B) and TIMP into extra-embryonic coelomic, allantoic and amniotic fluids in a rabbit model was examined. Furthermore, to evaluate their role in fetal membrane repair, the changes induced by fetoscopy at mid-gestation (23 days; gestation length is 32 days) were investigated. Zymography showed predominantly secretion of latent MMP-2 at 18, 23 and 30 days of gestation in all gestational compartments. Reverse zymography detected a broad range of TIMP activity with molecular weights of 27-30 kDa (TIMP-1, glycosylated TIMP-3 and TIMP-4), 24 kDa (unglycosylated TIMP-3) and 21 kDa (TIMP-2). Following fetoscopy, both MMP-2 and TIMP increased significantly in amniotic fluid and extra-embryonic coelomic fluid, but not in allantoic fluid, as demonstrated by densitometric analyses. These findings indicate a modulating role for MMP and TIMP in the repair processes following a surgically induced fetal membrane defect.
Mol Hum Reprod 2000 May
PMID:Matrix metalloproteinases -2 and -9 and their endogenous tissue inhibitors in fetal membrane repair following fetoscopy in a rabbit model. 1077 54

The N-terminal, matrix metalloproteinase (MMP)-inhibitory fragment of recombinant, human tissue inhibitor of metalloproteinases (TIMP-1) exhibits varied backbone dynamics and rigidity. Most striking is the presence of chemical exchange in the MMP-binding ridge reported to undergo conformational change upon MMP binding. Conformational exchange fluctuations in microseconds to milliseconds map to the sites of MMP-induced fit at residues Val29 through Leu34 of the AB loop and to the Ala65 and Cys70 "hinges" of the CD loop of TIMP-1. Slow chemical exchange is also present at the type I turn of the EF loop at the base of the MMP-binding ridge. These functional slow motions and other fast internal motions are evident from backbone (15)N spin relaxation at 500 and 750 MHz, whether interpreted by the model-free formalism with axial diffusion anisotropy or by the reduced spectral density approach. The conformational exchange is confirmed by its deviation from the trend between R(2) and the cross-correlation rate eta. The magnetic field-dependence indicates that the chemical exchange broadening in the AB and CD loops is fast on the time-scale of chemical shift differences. The conformational exchange rates for most of these exchanging residues, which can closely approach MMP, appear to be a few thousand to several thousand per second. The slow dynamics of the TIMP-1 AB loop contrast the picosecond to nanosecond dynamics reported in the longer TIMP-2 AB loop.
J Mol Biol 2000 Aug 11
PMID:Tissue inhibitor of metalloproteinases-1 undergoes microsecond to millisecond motions at sites of matrix metalloproteinase-induced fit. 1092 26

Endothelial cells were isolated from bovine thoracic aorta and cultured. Bovine aortic endothelial cells (BAEC) were incubated with radiolabeled arachidonic acid (3H-AA) or eicosapentaenoic acid (14C-EPA) (1 microM) for 3 hr. Both fatty acids were predominantly incorporated into phosphatidylcholine (57 +/- 2% and 62 +/- 2% respectively) and slightly into phosphatidylethanolamine (11 +/- 0.5% and 12 +/- 0.6% respectively). phosphatidylinositol (26 +/- 1.5% and 10 +/- 0.5% respectively) and neutral lipids (6 +/- 0.5% and 15 +/- 1% respectively). After BAEC incubation with 3H-AA for 24 hr with or without EPA (1 microM), the release of radioactive metabolites of AA induced by thrombin (5.5 U/ml) was strongly reduced by the preliminary treatment with EPA (72 +/- 5%). After BAEC incubation with AA, EPA or vehicle (control), endothelin-1 levels were measured by RIA in the culture medium and we observed that: 1) the basal production of endothelin-1 was not modified after either AA or EPA treatment, 2) the thrombin-evoked release of endothelin-1 was significantly reduced by EPA (5.8 +/- 0.82 and 3.8 +/- 0.50 pg/microg proteins in control and EPA-treated cells, respectively); 3) by contrast, AA had no significant effect on the thrombin-evoked release of endothelin-1. In conclusion, EPA reduces strongly the endothelin-1 release but AA is ineffective. This reduction of endothelin-1 release may account partly for some of the vascular effects of EPA.
Res Commun Mol Pathol Pharmacol 1999
PMID:Eicosapentaenoic acid reduces thrombin-evoked release of endothelin-1 in cultured bovine endothelial cells. 1095 31

Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? 1095 32

We investigated possible polymorphisms in the promoter regions of the TIMP-1, 2 and 3 genes (tissue inhibitor of metalloproteinases) to establish their frequencies in the Caucasian population. Polymorphisms were analysed by means of heteroduplex analysis and fragments with altered mobility were sequenced. No polymorphisms were found in the promoters for TIMP-1 and 2 but three novel polymorphisms (-899T/A, -915A/G and -1296T/C) were identified in the promoter region of the TIMP-3. Allele frequencies in a sample of healthy Caucasian subjects (n=95) were determined by PCR followed by restriction analyses with specific endonucleases. Allele frequencies of the -899A, -915G and -1296C polymorphisms were 0.05, 0.39 and 0. 40, respectively. We conclude that the -915A/G and -1296T/C variants of the TIMP-3 gene appear to be common polymorphisms in the Caucasian Czech population.
Mol Cell Probes 2000 Aug
PMID:Identification of novel common polymorphisms in the promoter region of the TIMP-3 gene in Czech population. 1097 Jul 32

Studies in our laboratory have shown that structural changes in cervical biopsied fetal membranes, prior to labour, coincide with differences in the expression of the gelatinase enzyme, latent matrix metalloproteinase-9 (MMP-9). Concurrently, in vivo, there is an increase in the expression of prostaglandins, notably prostaglandin E(2) (PGE(2)), which has been shown to regulate the expression of MMPs in other systems. The aim of this study was to test the hypothesis (using an in-vitro culture model) that endogenously produced PGE(2) has a role in the elevation of MMP-9 described in vivo. Non-infected fetal membranes sampled from women undergoing elective Caesarean section were stimulated with 10% (v/v) fetal bovine serum (FBS), a known inducer of prostaglandins. This activation resulted in a time-dependent increase in the secretion of PGE(2) into the media, as determined by enzyme-linked immunosorbent assay (day 1: 19 +/- 9 pg/ml/24 h to 358 +/- 54 pg/ml/24 h by day 4). A similar pattern of secretion of latent MMP-9 was observed in parallel with the increase in PGE(2) in the same culture media (day 1: 1.63 +/- 0.17 ng/ml/24 h to 4.2 +/- 1.4 ng/ml/24 h by day 4). When both molecules were compared, a significant (P: < 0.01) positive correlation (r = 0.623) was observed. Secretion of the tissue inhibitor of MMPs-9 (TIMP-1) was not significantly different between untreated (3.07 +/- 0.266 microg/ml/24 h) and FBS-treated (3. 85 +/- 0.24 microg/ml/24 h) cultures during the first 4 days in culture. Prostaglandin synthesis inhibition studies using indomethacin (100 micromol/l) resulted in a 70-80% reduction in the activated secretion of latent MMP-9. Direct PGE(2) stimulation of cultures resulted in the bell shaped dose-response curve with concentrations of 1-100 nmol/l (which are within the range secreted in culture in response to FBS), stimulating significant latent MMP-9 secretion. These results suggest a link between endogenous PGE(2) and latent MMP-9 production in human fetal membranes, raising the possibility that PGE(2) has a role in the mechanism of fetal membrane structural changes and, hence, in parturition-associated membrane rupture.
Mol Hum Reprod 2000 Nov
PMID:Prostaglandin E(2)-dependent production of latent matrix metalloproteinase-9 in cultures of human fetal membranes. 1104 67

Although there are numerous methods available to hydrolyze glycans utilizing strong acids, it all requires lengthy steps to obtain quantitative yield. We have developed a new simple one-step method for analysis of amino and neutral monosaccharides of glycoproteins quantitatively. Free monosaccharides were found to be stable during hydrolysis of glycans with 6 N HCI at 80 degrees C up to 2 h. Using this condition, analysis of free monosaccharides hydrolyzed from the bovine fetuin showed sugar composition of Gal: Man: GlcN: GaIN = 13.2: 11.0: 15.5: 2.6, which is closely matched with the reported value of 12.4: 9.6: 17.2: 2.7 (Townsend et al., ABRF News 8: 14, 1997). This method was shown to be applicable to varieties of well-characterized glycoproteins, erythropoietin, fibrinogen and soybean agglutinin. The amounts of sugars released under the condition were very close to the experimental values by other procedures or to the theoretical ones. This condition was found to be suitable for direct sugar analysis of fetuin, which have been immobilized onto polyvinylidene difluoride membrane. Based on these results, it support that the 6 N HCl/80 degrees C/2 h is the simplest method for quantitative analysis of monosaccharide composition of glycoproteins.
Exp Mol Med 2000 Sep 30
PMID:An improved method for quantitative sugar analysis of glycoproteins. 1104 45

During lung injury, fibroblasts migrate into the alveolar spaces where they can be exposed to pulmonary surfactant. We examined the effects of Survanta and surfactant protein A (SP-A) on fibroblast growth and apoptosis and on type I collagen, collagenase-1, and tissue inhibitor of metalloproteinase (TIMP)-1 expression. Lung fibroblasts were treated with 100, 500, and 1,000 microg/ml of Survanta; 10, 50, and 100 microg/ml of SP-A; and 500 microg/ml of Survanta plus 50 microg/ml of SP-A. Growth rate was evaluated by a formazan-based chromogenic assay, apoptosis was evaluated by DNA end labeling and ELISA, and collagen, collagenase-1, and TIMP-1 were evaluated by Northern blotting. Survanta provoked fibroblast apoptosis, induced collagenase-1 expression, and decreased type I collagen affecting mRNA stability approximately 10-fold as assessed with the use of actinomycin D. Collagen synthesis and collagenase activity paralleled the gene expression results. SP-A increased collagen expression approximately 2-fold and had no effect on collagenase-1, TIMP-1, or growth rate. When fibroblasts were exposed to a combination of Survanta plus SP-A, the effects of Survanta were partially reversed. These findings suggest that surfactant lipids may protect against intraluminal fibrogenesis by inducing fibroblast apoptosis and decreasing collagen accumulation.
Am J Physiol Lung Cell Mol Physiol 2000 Nov
PMID:Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression. 1105 32

Neointima formation after arterial de-endothelialization refers not only to smooth muscle cell (SMC) migration and proliferation, but also involves extracellular matrix (ECM) metabolism. Most studies regarding the role of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in neointima have focused on the early phase of vascular remodeling. In this study, we examined the expression of MMP and TIMP in rabbit aortic neointima at a relatively late stage of lesion development, between 4 and 12 weeks after initial de-endothelialization. Northern blot analysis revealed expression of steady-state MMP-9 mRNA was increased up to the 4th week and MMP-2 mRNA to the 12th week after de-endothelialization. In situ hybridization shown that MMP positive cells were predominantly distributed in arterial neointima. Expression of TIMP-1 mRNA was continuously up-regulated up to the 12th week and TIMP-1 positive cells, primarily SMCs, were also localized to the neointimal tissue. Alteration at mRNA level was accompanied by that at protein level, as assessed by SDS-PAGE zymography for MMPs and immunoblotting for TIMP-1. The profile of alteration at protein level correlated well with that at mRNA level. These data suggest that synthesis of MMPs and TIMP is a prolonged process and arterial SMC is a major source of MMP production in arterial neointima. Enhanced synthesis of MMPs and TIMPs at late stage of neointimal development may contribute to arterial ECM metabolism.
Int J Mol Med 2001 Jan
PMID:Expression of metalloproteinases and its inhibitor in later stage of rabbit neointima development. 1111 18


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