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)

Vascular lesion development is associated with an accumulation of extracellular matrix proteins within the vessel wall. Matrix metalloproteinases (MMPs) degrade these proteins. Conversely, oxidized low density lipoprotein (LDL) is implicated in atherogenesis through, amongst other cellular effects, a stimulation of the deposition of collagen within the vascular lesion. The present study investigated the potential for an interaction between oxidized LDL and MMP levels. Within the vessel wall fibroblasts, smooth muscle, endothelial and infiltrating cells have been reported to secrete MMPs into the extracellular space to effect remodeling of the extracellular matrix. A consequence of angioplasty and atherosclerotic disease is the loss of endothelial cells or endothelial function, respectively. We have investigated the effects of chronic incubation of cultured vascular smooth muscle cells from rabbit thoracic aorta with oxidized LDL and its influence on MMP levels in the extracellular space. Our data indicate that a low concentration of minimally oxidized LDL (0.005 mg/mL) significantly depressed the levels of MMP-2 and MMP-9 present in the culture medium. Native LDL exerted the same effect but exhibited reduced potency. The effects were not attributable to cytotoxicity exerted by the oxidized LDL. The reduction in MMP secretion into the extracellular medium was a result of decreased enzyme synthesis within the smooth muscle cell. Our results demonstrate that an important atherogenic moiety, oxidized LDL, can reduce MMP activity and hence has the potential to increase the deposition of extracellular matrix proteins within SMC-rich vascular lesions.
Mol Cell Biochem 2003 Jul
PMID:Native and minimally oxidized low density lipoprotein depress smooth muscle matrix metalloproteinase levels. 1295 9

The matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) have been associated with ovarian tissue remodelling and development of ovarian tumours. With respect to ovarian cancer, the majority of previous studies were performed on serous and mucinous tumours, and little is known about clear cell carcinoma, which shows unique characteristics among ovarian cancers. In the present study, we assessed the differences in the levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the normal ovary and ovarian tumours of different histology, including clear cell carcinoma, using specific enzyme-linked immunosorbent assays. In malignant tumours, a prominent increase in pro-MMP-9 levels was observed compared with those of normal ovary and benign tumours, and pro-MMP-2 and TIMP-1 levels were moderately increased. In contrast, TIMP-2 levels were markedly decreased in malignant tumours compared with normal ovary with the exception of clear cell carcinoma, in which they were significantly elevated. Similar results were obtained by the organ culture of carcinoma tissue and normal ovary as well as in the cyst fluids of the tumours. Increased expression of TIMP-2 in clear cell carcinoma was also confirmed by Western blot analysis. Immunohistochemistry showed that TIMP-2 immunoreactivity was localized predominantly in epithelial cancer cells in clear cell carcinoma, while it was present mainly in stromal cells in the other histological types. Taken together, the present study shows that TIMP-2 expression is markedly increased in clear cell carcinoma of the ovary, suggesting a role of TIMP-2 in its unique characteristics among ovarian cancers.
Mol Hum Reprod 2003 Oct
PMID:Increased expression of tissue inhibitor of metalloproteinase-2 in clear cell carcinoma of the ovary. 1297 Mar 94

The dose-dependent effect of a 24 h treatment with estradiol (E(2)) (1, 2, 5, 10 nM) and raloxifene (Rx) (1, 5, 10, 20 microM) on ER alpha and ER beta mRNA expression, collagen bio-synthesis, prolidase activity, MMP-2, MMP-9, insulin-like growth factor I receptor expression (IGF-1R) and beta1-integrin expressions in cultured fibroblasts obtained from postmenopausal women were examined. Both ligands increased mRNA expression of ER compared to control. Rx at 5 and 10 microM concentrations had greater stimulative effect on collagen biosynthesis, prolidase activity and IGF-1R expression compared to E(2) at 2 and 5 nM concentration. Both studied ER ligands had no effect on beta1-integrin receptor expressions. MMP-2 expression was not detected in human skin fibroblast culture. In contrast to estradiol raloxifene inhibited the expression of MMP-9. Raloxifene had stronger positive stimulative effects on collagen biosynthesis, through different biochemical mechanisms, than estradiol in human skin fibroblasts and might reverse some of the postmenopausal changes in skin or connective tissue. Increase of collagen synthesis induced by raloxifene may be activated by both estrogen receptor dependent and independent pathways such as up-regulation of estrogen receptors, up-regulation of IGF receptor, transcriptional regulation of collagen genes by estrogen receptor-raloxifene complex, increasing of prolidase activity or finally by inhibition of MMP-9 expression.
Int J Mol Med 2003 Nov
PMID:Differential effects of estradiol and raloxifene on collagen biosynthesis in cultured human skin fibroblasts. 1453 13

Cell invasion and angiogenesis are crucial processes in cancer metastasis that require extracellular matrix (ECM) degradation. Proteolytic degradation of the ECM components is a central event of invasion and angiogenesis processes. During these processes, matrix metalloproteinases (MMPs) seem to be primarily responsible for much of the ECM degradation. Disulfiram is frequently used in the treatment of alcoholism and has been reported to possess antiretroviral activity and can eject intrinsic zinc out of human immunodeficiency virus (HIV) nucleocapsid protein. In this report, we show that disulfiram inhibited invasion and angiogenesis in both tumor and endothelial cells at nontoxic concentrations. The 3H-labeled type IV collagen degradation assay suggested that disulfiram has type IV collagenase inhibitory activity, and this inhibition was responsible for blocking invasion and angiogenesis through cell-mediated and non-cell-mediated pathways. However, the mechanisms underlying cell-mediated signal pathways are not fully characterized. Our data demonstrate that the non-cell-mediated pathway is dominant. Thus, disulfiram could directly interact with MMP-2 and MMP-9 and inhibit their proteolytic activity through a zincchelating mechanism. Addition of zinc could reverse the inhibition of invasiveness and collagenase inhibition through disulfiram treatment. This finding implies that MMP-2 and MMP-9 may be the inhibitory targets for a potential disulfiram treatment. These observations raise the possibility clinical therapeutic applications for disulfiram used as a potential inhibitor of metastatic cell invasion and angiogenesis.
Mol Pharmacol 2003 Nov
PMID:Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram. 1457 56

Enhanced cardiac generation of peroxynitrite contributes to septic cardiomyopathy. Since matrix metalloproteinases (MMPs) are activated in vitro by peroxynitrite, we hypothezised that MMPs may contribute to cardiac mechanical dysfunction in sepsis. Rats were injected (i.p.) with either lipopolysaccharide (LPS, 4 mg/kg) or vehicle. MMP inhibitors, either Ro 31-9790 (20 mg/kg), doxycycline (4 mg/kg), or vehicle were administered i.p. 30 min after LPS. At 6 h, when the symptoms of endotoxemia peak, hearts were excised and perfused as working hearts with Krebs-Henseleit buffer at 37 degrees C. Cardiac work (cardiac output x peak systolic pressure product) was measured. Perfusate and ventricle samples were analyzed by gelatin zymography to quantify MMP activity. Cardiac function was significantly depressed in LPS-treated rats compared to control rats (control: 55 +/- 4, LPS: 26 +/- 6 mmHg*mL*min(-1)). LPS also caused a loss of 72 kDa MMP-2 activity in the ventricles and the perfusate. Although MMP-9 activity was not detected in the ventricles, LPS resulted in an increase in perfusate 92 kDa MMP-9 activity. The MMP inhibitors significantly improved cardiac function of LPS-treated rats (Ro 31-9790: 38 +/- 3, doxycycline: 51 +/- 3 mmHg*mL*min(-1)), had no effect on the loss of MMP-2 activity, and significantly reduced the MMP-9 activity in the perfusate. These results demonstrate, for the first time, that LPS induced cardiac dysfunction is associated with a loss in ventricular MMP-2 activity and the release of MMP-9 from the heart. MMP inhibitors can significantly preserve cardiac mechanical function during septic shock.
Mol Cell Biochem 2003 Sep
PMID:Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9. 1457 5

Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is an integral part of physiological processes such as embryonic development, the female reproductive cycle and wound healing. Angiogenesis is also central to a variety of pathologies including cancer, where it is recognised as being crucial for the growth of solid tumours. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, most notably MMP-2 and -9 and membrane-type-1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, liberation of angiogenic factors, production of endogenous angiogenic inhibitors, and the unmasking of cryptic biologically relevant sites in ECM components. This review brings together what is currently known about the functions of the MMPs and the closely related adamalysin metalloproteinase (ADAM) family in angiogenesis, and discusses how this information might be useful in manipulation of the angiogenic process, with a view to controlling aberrant neovascularisation.
Expert Rev Mol Med 2003 Sep 22
PMID:Metalloproteinases and their inhibitors in angiogenesis. 1458 70

Our purpose was to investigate the expression of matrix metalloproteinase (MMP)-2 and -9 in all types of abdominal aortic aneurysms (AAA): symptomatic, asymptomatic, and ruptured. MMP-2 and -9 activity was investigated in surgical samples from the arterior wall of 46 AAA, using a standard immunohistochemical technique. The MMP-9 activity was significantly higher in large AAA (>6 cm), but there was no relation between AAA size and MMP-2 activity. Neither MMP-2 nor MMP-9 were related with AAA rupture, other complications or symptoms. The MMP-9 activity in AAA is a determinant of the aneurysm size, but it is not related to clinical manifestations.
Int J Mol Med 2003 Dec
PMID:Immunohistochemical expression of metalloproteinases MMP-2 and MMP-9 in abdominal aortic aneurysms: correlation with symptoms and aortic diameter. 1461 75

Matrix metalloproteinases (MMPs) belong to a super family of endopeptidases which have been implicated as crucial mediators of angiogenesis and tumour invasion in brain tumours. This study was undertaken in an attempt to establish the relationship between 2 specific MMPs and the main classical subtypes of meningioma. We examined the expression of MMP-2 and -9 (gelatinase-A and -B respectively), by gelatin zymography, in a series of 18 cell cultures derived from human meningiomas of a range of histological subtypes and grades of malignancy, including 7 meningothelial, 6 transitional, 2 fibroblastic and 3 atypical meningiomas. Our findings indicate that generally, the meningothelial subtype, had the weakest expression, the transitional subtype had an intermediate expression whereas the fibroblastic subtype had the strongest expression of both MMP-2 and -9. There was no correlation between other clinicopathological features (age, sex, site of tumour) and the level of MMP-2 and -9 expression. Although, the number of samples in this study is limited, these findings suggest that there may be a trend for association between the expression of these 2 MMPs and the main classical histological subtypes of meningioma.
Int J Mol Med 2003 Dec
PMID:Expression of MMP-2 and -9 in short-term cultures of meningioma: influence of histological subtype. 1461 77

Breast cancer patients frequently develop metastases. This process requires the degradation of extracellular matrix proteins which act as a barrier to tumour cell passage. These proteins can be degraded by proteases, mainly the matrix metalloproteinases (MMPs). MMP-2 and -9 which are frequently detected in breast cancer tissues. ProMMPs are released from cancer cells, and their activation is considered to be a crucial step in metastases development. In breast cancer, estrogen metabolism is altered favouring the accumulation of 2- and 4-hydroxyestradiol (2- and 4-OHE(2)). These estradiol metabolites can generate free radicals. Since reactive species are known activators of proMMPs, this study was designed to determine if the free radicals generated by 2- and 4-OHE(2) can activate proMMP-2 and -9. Activation of MMPs by hydroxyestradiol was determined by monitoring the cleavage of a fluorogenic peptide and by zymography analysis. Both estradiol metabolites activated the MMP-2 and -9. 4-OHE(2) was a more potent activator than 2-OHE(2), which reflects its higher capacity to generate free radicals. ProMMPs activation was mainly mediated through O(2)*-, although the free radical HO* also activated the proMMPs but to a lesser extent. ProMMPs activation was not observed with estrogens that cannot generate free radicals, i.e. estradiol, estrone, 2- and 4-methoxyestradiol, and 16alpha-hydroxyestrone. These results demonstrate that 2- and 4-OHE(2) at a concentration as low as 10(-8)M can activate the proMMP-2 and -9 and might play an important role in the invasion of breast cancer cells.
J Steroid Biochem Mol Biol 2003 Oct
PMID:Activation of matrix metalloproteinase-2 and -9 by 2- and 4-hydroxyestradiol. 1463 92

Matrix metalloproteinases (MMPs) are an at least 23 member family of calcium and zinc dependent enzymes implicated in many physiological and pathological processes. Asthma, chronic obstructive pulmonary disease (COPD) and emphysema are diseases associated with an inflammation of the airways and lung parenchyma. In this review, we focus on the role played by MMPs in the pathogenesis of inflammation, airway remodelling and alveolar destruction, depicting the observational studies in humans and the experimental studies in animal models. During the course of asthma, MMP-2,-8,-9 and TIMP-1 are expressed at baseline and the allergen exposure or exacerbations of the disease lead to an increase of MMP-9 secretion being at this time much higher than that of TIMP-1, allowing temporarily a matrix damage, possibly followed by abnormal repair. Animal models suggest a predominant role for MMP-9 and MMP-12 in the pathogenesis of pulmonary inflammation and link an absence of MMP-2 to an increased parenchymal inflammation. In COPD and emphysema, human studies indicate an over-secretion of MMP-2,-8,-9 and animal models pointout MMP-1 and MMP-12 as being key players in the pathogenesis of emphysema. Taken together, these data identify specific MMP inhibition as appropriate target for therapeutic intervention in asthma or COPD/emphysema They also strongly argue against the widespread use of large spectrum non specific inhibitors that could be detrimental.
Cell Mol Biol (Noisy-le-grand) 2003 Sep
PMID:Pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix metalloproteases inhibitors. 1465 45


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