Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Keratoconus is a noninflammatory corneal disorder characterized by gradual stromal thinning and astigmatism. Altered degradation of corneal extracellular matrix is a suggested etiology for this disorder. In the present study we established keratocyte cultures from normal and keratoconus corneas and investigated the roles that matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP, TIMP-2) may play. After chemical modification (reduction and alkylation) to remove the inhibitor and activation of enzyme with p-aminophenylmercuric acetate (APMA), keratoconus-conditioned media displayed a significant increase (p < 0.05) in the total potential gelatinolytic activity when compared with normal culture media treated in a similar manner. Basal levels of gelatinolytic activity in keratoconus culture media (no reduction, alkylation, or APMA treatment), determined by two different assay methods, tended to be about twice that of normal cell cultures. By zymography, both keratoconus and normal cultures showed identical enzyme patterns, which represented MMP-2 (72 kDa) in its proform and, depending on the treatment of the media, varying amounts of activated MMP-2 (65 kDa). This suggests that the increased gelatinolytic activity in keratoconus was not correlated with an increased appearance of either the 65-kDa-activated form of MMP-2 or a new MMP species. In addition, no differences in the amount of MMP-2 were detected that could account for the increased activities in keratoconus cultures. However, a relative decline in the detectable TIMP levels in keratoconus cultures resulted in an apparent three-fold increase in the ratio of MMP-2/TIMP. Northern blots showed no significant changes in mRNA levels for MMP-1, MMP-2, MMP-3, TIMP, or TIMP-2. These data suggest that a possible alteration in the interaction between MMP-2 and TIMP may play a role in the increased gelatinolytic activity seen in keratoconus tissues.
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PMID:Increased gelatinolytic activity in keratoconus keratocyte cultures. A correlation to an altered matrix metalloproteinase-2/tissue inhibitor of metalloproteinase ratio. 815 82

The aim of the study was to investigate the location of the expression of 72-kd metalloproteinase (MMP-2) in relation to the distribution of type IV collagen in untreated prostatic adenocarcinoma (PAc). Twenty formalin-fixed, paraffin-embedded PAc cases, in which high grade prostatic intraepithelial neoplasia (PINhigh) was occasionally present, were immunohistochemically examined. Type IV collagen immunoreactivity showed the presence of a basement membrane (BM) at the epithelial-stromal junction. In cribriform and solid/trabecular PAc, the staining was focally disrupted. In acinar PAc, the BM immunostained by anti-type IV collagen was observed around the individual acini, with occasional thinning and fragmentation. Immunostaining for MMP-2 was heterogeneous in intensity and location. Cribriform and solid/trabecular PAc showed weak cytoplasmic immunostaining for MMP-2; both moderately and intensely stained cells were seen in the cell layer adjacent to the stroma; intense immunostaining was shown by small clusters of neoplastic cells or single neoplastic cells located in the stroma which also showed thinning and fragmentation of BM staining. In acinar PAc, weak cytoplasmic immunostaining for MMP-2 was seen throughout most areas of the tumours, whereas moderately and intensely stained cells were observed less frequently than in cribriform and solid/trabecular adenocarcinoma. Intense immunostaining of single or small clusters of neoplastic cells located in the stroma was rarely observed and, as for cribriform and solid/trabecular PAc, mainly located towards the periphery of the tumour nodules. BM stained by anti-type IV collagen was preserved in normal prostate and in PIN, some thinning being present in the latter. The pattern and intensity of immunoreactivity for MMP-2 in PIN was similar to that of cribriform and solid/trabecular PAc, whereas normal ducts and acini showed weak immunostaining in most of the secretory cells and moderate to strong immunoreactivity in scattered basal cells. Thus, MMP-2 appeared basically expressed in cells which lie in direct contact with the stroma. This underlined the importance of evaluating the MMP-2 location in relation to basement membrane degradation and tumour invasion.
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PMID:Location of 72-kd metalloproteinase (type IV collagenase) in untreated prostatic adenocarcinoma. 882 16

Myocardial infarction (MI), leads to cardiac remodeling, thinning of the ventricle wall, ventricular dilation, and heart failure, and is a leading cause of death. Interactions between the contractile elements of the cardiac myocytes and the extracellular matrix (ECM) help maintain myocyte alignment required for the structural and functional integrity of the heart. Following MI, reorganization of the ECM and the myocytes occurs, contributing to loss of heart function. In certain pathological circumstances, the ECM is modulated such that the structure of the tissue becomes damaged. The matrix metalloproteinases (MMPs) are a family of enzymes that degrade molecules of the ECM. The present experiments were performed to define the time-course, isozyme subtypes, and cellular source of increased MMP expression that occurs following MI in an experimental rabbit model. Heart tissue samples from infarcted and sham animals were analyzed over a time-course of 1-14 days. By zymography, it was demonstrated that, unlike the sham controls, MMP-9 expression was induced within 24 hours following MI. MMP-3 expression, also absent in sham controls, was induced 2 days after MI. MMP-2 expression was detected in both the sham and infarcted samples and was modestly up-regulated following MI. Tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was evaluated and shown to be down-regulated following MI, inverse of MMP-9 and MMP-3 expression. Further, MMP-9 and MMP-3 expression was detected by immunohistochemistry in myocytes within the infarct. Additional studies were conducted in which cultured rat cardiac myocytes were exposed to a hypoxic environment (2% O2) for 24 hours and the media analyzed for MMP expression. MMP-9 and MMP-3 were induced following exposure to hypoxia. It is speculated that the net increase in proteolytic activity by myocytes is a contributing factor leading to myocyte misalignment and slippage. Additional studies with a MMP inhibitor would elucidate this hypothesis.
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PMID:Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. 1120 71

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP-2 and MMP-9. Matrix metalloproteinase-2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP-9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, alpha-1-proteinase inhibitor and alpha-2-macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane-bound MT1-MMP (MMP-14), which activates latent MMP-2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP-3 and MMP-10, were not.
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PMID:Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? 1177

The matrix metalloproteinases (MMPs) and endothelin-1, a potent vasoconstrictor and mitogen for smooth muscle cells, have been shown to be involved in the pathogenesis of various vascular disorders. However, the expression of endothelin-1 and the activation of MMPs have not been fully evaluated in plexogenic pulmonary arteriopathy (PPA). Immunohistochemical and confocal microscopic studies were conducted to evaluate the reactivity of lung tissue from six patients with pulmonary hypertension for alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, factor VIII, endothelin-1, various types of MMPs (MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9), membrane type-MMPs (MT-MMPs), tissue inhibitors of MMPs (TIMPs), and type IV collagen. Four major arterial morphological abnormalities were recognized in PPA: muscularization of pulmonary arterioles, onion-skin lesions, cellular and mature plexiform lesions, and atheromas in elastic pulmonary arteries. Reactivity for MMP-2 and MT-1-MMP was found in endothelial cells and, to a lesser extent, in myofibroblasts proliferating in various lesions of PPA. Increased expression of endothelin-1 was observed in the latter cells and in endothelial cells. Some myofibroblasts were positive for MMP-3 and MMP-7 in the vascular lesions except for mature plexiform lesions. MMP-1, MMP-9 and TIMP-2 tended to be positive only in the atheromatous lesions. Staining for type IV collagen showed focal thinning and discontinuities of the endothelial basement membrane in plexiform lesions. This study demonstrates colocalization of MMP-2 with MT-1-MMP and increased expression of endothelin-1 in various arterial lesions of PPA. These changes may play important roles in the remodeling of arterial structures, particularly of basement membranes, in this disorder.
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PMID:Immunohistochemical study of endothelin-1 and matrix metalloproteinases in plexogenic pulmonary arteriopathy. 1216 97

Study of surgical specimens and direct observation by angioscopy has revealed that the varicose venous wall, the valvular annulus, and the valves themselves undergo profound changes. Morphologic investigations have shown dilation of the valve annulus, bulging valve leaflets, commissural dilation, leaflet stretching, and eventually complete destruction of the valves. The venous wall has been seen to undergo changes of thickening in some segments and thinning in others. Our investigations show that inflammation and subsequent remodeling of the venous valves and wall are the fundamental mechanisms underlying the observed lesions. Hemodynamic forces, such as blood pressure changes in the wall and sheer stress, as well as varying planes of laminar and turbulent flow, induce activation of leukocytes and endothelial cells. Integrins appear to act as intermediaries and expression of adhesion molecules has been observed. Breakdown of extracellular matrix of the media and adventitia through activation of matrix metalloproteases (MMP) has been observed. In particular, expressions of MMP-1, MMP-2, MMP-9, and tissue inhibitor of metalloproteinase have been studied. Telangiectasias, reticular veins, and true varicose veins appear to be a consequence of the changes induced by venous hypertension and sheer stress.
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PMID:Causes of telengiectasias, reticular veins, and varicose veins. 1579 45

Keratoconus is an ocular condition that causes corneal thinning, cone formation and scarring. In view of a hypothesis that activated MMP-2 may initiate or facilitate disease progression, the MMP-2/TIMP systems of stromal cells derived from normal and keratoconic corneas have been compared. To achieve this, stromal cell cultures were established from normal, clear keratoconic (KCS-1) and scarred keratoconic (KCS-2) corneas. The secreted MMP-2 was assayed using [(3)H]Type IV collagen and analysed by zymography. Optimally maintained and nutrient deprived cells were subsequently incubated with [(3)H]lysine. The secreted radiolabelled macromolecules were separated and quantified. The results obtained indicated that optimally maintained KCS-1 stromal cells produced more MMP-2 than normal stromal cells but not TIMP. Nutrient deprivation induced MMP-2 activation and cell death. Surviving cells upregulated TIMP-1 synthesis and in this respect became similar to the KCS-2 stromal cells that did not excessively generate activated MMP-2 or die as a consequence of nutrient deprivation. From these results, it was concluded that KCS-1 stromal cells over-expressed MMP-2 without increasing TIMP production. This may facilitate MMP-2 activation in vivo and hence advance the keratoconic condition. KCS-2 cultures over-expressed both MMP-2 and TIMP-1. Because TIMP-1 inhibits MMP-2 activity and protects against cell death it may be of significance in initiating repair processes and curtailing keratoconus.
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PMID:Keratoconus: matrix metalloproteinase-2 activation and TIMP modulation. 1651 44

In order to understand the effect of mechanical strain on scleral extracellular matrix remodeling, human scleral fibroblasts were subjected to equibiaxial stretch in vitro and the expression of proteoglycans, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were evaluated. Isolated human scleral fibroblasts were seeded onto flexible bottom culture plates, and subjected to a cyclic stretch regimen of 15% equibiaxial stretch for 45 s followed by 15s of rest for 6-48 h in the presence of 35SO4. Newly synthesized proteoglycans were measured in the medium by CPC precipitation of radiolabelled glycosaminoglycans. MMP-2 activity and expression levels were measured in the medium by, Western blot, gel zymography and real-time PCR. Steady state levels of TIMP-2 mRNA and membrane-type MMP, MT1-MMP (MMP-14) mRNA were measured in the cell layer using real-time PCR. The predominant gelatinolytic enzyme secreted by scleral fibroblasts was the pro-enzyme form of MMP-2 (ProMMP-2). Mechanical stretch resulted in a significant increase of ProMMP-2 after 12 and 48 h (+76.28%, p<0.05; +19.56%, p<0.01, respectively). Mechanical stretch significantly increased the production of the active form of MMP-2 (ActiveMMP-2) after 48 h (+59.72%, p<0.05) and decreased levels of TIMP-2 mRNA (-22%, p<0.05). The rate of scleral proteoglycan synthesis and the steady state levels of MMP-2 and MMP-14 mRNA were not significantly affected by mechanical stretch. These results suggest that mechanical strain stimulates the activation of MMP-2 by scleral fibroblasts, possibly through increased levels of ProMMP-2 and reduced levels of TIMP-2. Increased levels of ActiveMMP-2 in the sclera would be expected to contribute to scleral extracellular matrix degradation, scleral thinning and possible ocular ectasia.
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PMID:Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts. 1712 15

To investigate if increased activation of matrix metalloproteinases (MMPs) may contribute to the large cardiovascular risk associated with obesity-related insulin resistance, we examined the effects of physiologically elevated levels of insulin and free fatty acid (FFA) on three MMPs and their physiologic inhibitors (tissue inhibitors of MMP ) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping. Hyperinsulinemia increased the active forms of MMP-2 (approximately sixfold), MMP-9 (approximately 13-fold), and membrane type 1-MMP (MT1-MMP; approximately eightfold) (all Western blots), and the gelatinolytic activity (zymography) of MMP-2 (twofold); it did not affect TIMP-1 and TIMP-2. FFA augmented the insulin-mediated increases in MMP-2 (from approximately six- to approximately 11-fold), MMP-9 (from approximately 13- to approximately 23-fold), MT1-MMP (from approximately eight- to approximately 20-fold), and MMP-2 gelatinolytic activity (from two- to threefold). FFA also increased JNK and p38 mitogen-activated protein kinase activities. The insulin- and FFA-induced hyperactivity of three proatherogenic MMPs in vascular tissues may promote degradation of extracellular matrix over time, leading to thinning of atherosclerotic capsules and acute vascular problems.
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PMID:Effects of insulin and free fatty acids on matrix metalloproteinases. 1862 23

Cerebral aneurysm (CA) has a high prevalence and causes a fatal subarachnoid hemorrhage. Although CA is a socially important disease, there are currently no medical treatments for CA, except for surgical procedures, because the detailed mechanisms of CA formation remain unclear. From recent studies, we propose that CA is a chronic inflammatory disease of the arterial walls and various inflammation-related factors participate in its pathogenesis. Mast cells are well recognized as major inflammatory cells related to allergic inflammation. Mast cells have numerous cytoplasmic granules that contain various cytokines. Recent studies have revealed that mast cells contribute to various vascular diseases through degranulation and release of cytokines. In the present study, we examined the role of mast cells in the pathogenesis of CA using an experimental rat model. The number of mast cells was significantly increased in CA walls during CA formation. Inhibitors of mast cell degranulation effectively inhibited the size and medial thinning of induced CA through the inhibition of chronic inflammation, as evaluated by nuclear factor-kappa B activation, macrophage infiltration, and the expression of monocyte chemoattractant protein-1, matrix metalloproteinases (MMPs), and interleukin-1beta. Furthermore, an in vitro study revealed that the degranulation of mast cells induced the expression and activation of MMP-2, -9, and inducible nitric oxide synthase in primary cultured smooth muscle cells from rat intracranial arteries. These results suggest that mast cells contribute to the pathogenesis of CA through the induction of inflammation and that inhibitors of mast cell degranulation can be therapeutic drugs for CA.
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PMID:Contribution of mast cells to cerebral aneurysm formation. 2033 12


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