Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroids in humans whose low levels are related to aging, greater incidence of various cancers, immune dysfunction, atherosclerosis, and osteoporosis. It has been shown that collagen and collagenase gene expression decreases in fibroblasts taken from more aged donors. In this paper, to investigate the relationship between DHEA and skin aging, we examined the effects of DHEA on the regulation of collagen, collegians and stromelysin-1 genes in cultured human skin fibroblasts. In collagen assay, DHEA slightly increased collagen production in a dose-related fashion, its maximal effect occurred at 10(-5) M DHEA (P>0.05). In the presence of DHEA, steady-state levels of alpha1 (I) procollagen mRNA increased to 1. 6-fold of the non-treated group, while those of fibronectin were not. Interestingly, DHEA differently regulated collagenase and stromelysin-1 gene expression. The steady-state levels of collagenase mRNA decreased in response to DHEA by 40%, whereas those of stromelysin-1 mRNA increased up to 2.4-fold, compared to controls. Similar results were obtained for chloramphenicol acetyltransferase assay (CAT); maximal promoter activation of stromelysin-1 gene occurred at 10(-6) M DHEA, 4.5-fold higher than control. CAT assay revealed that treatment with 10(-5) M DHEA resulted in a strong ( approximately 70%) inhibition of the collagenase promoter activity. In our experiments, the effects of DHEA on these gene expressions were higher at pharmacologic concentration (>/=10(-5) M) than those at physiologic concentration (10(-8)-10(-6) M). This study suggests that the level of DHEA may be related to the process of skin aging through the regulation of production and degradation in extracellular matrix.
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PMID:Effects of dehydroepiandrosterone on collagen and collagenase gene expression by skin fibroblasts in culture. 1080 27

A common variant in the promoter of the human stromelysin gene, causing reduced enzyme expression, has been associated with the progression of coronary atherosclerosis. On the other hand, increased stromelysin activity may promote plaque rupture. The present study was undertaken to investigate the relationship between the genetic variation in the human stromelysin gene promoter and common carotid geometry. Forty-two healthy male subjects without major coronary heart disease risk factors were investigated. The polymorphism in the stromelysin gene promoter was studied through polymerase chain reaction amplification with the use of mutagenic primers. Age, blood pressure, lipids, glucose, viscosity, and body mass index were similar in homozygotes for the 5A allele (5A/5A), heterozygotes (5A/6A), and homozygotes for the 6A allele (6A/6A). Serum matrix metalloproteinase-3 levels did not differ significantly among genotypes. Common carotid diameters and intima-media thickness, measured by noninvasive ultrasonography, were significantly larger in 6A/6A subjects (for respective 6A/6A, 5A/6A, and 5A/5A subjects, diameter at the R wave was 0.63+/-0.09, 0.55+/-0.06, and 0.53+/-0.04 cm [mean+/-SD], P<0.005 by ANOVA; intima-media thickness was 765+/-116, 670+/-116, and 630+/-92 microm [mean+/-SD], P<0.05 by ANOVA). Wall shear stress, calculated as blood velocityxblood viscosity/internal diameter, was significantly lower in 6A/6A subjects (for respective 6A/6A, 5A/6A, and 5A/5A subjects, mean wall shear stress was 10.4+/-2.9, 13.5+/-3.5, and 12.6+/-1.9 dyne/cm(2) [mean+/-SD], P<0.05 by ANOVA). The results demonstrate that the gene polymorphism in the promoter region of stromelysin is associated with structural and functional characteristics of the common carotid artery in healthy male subjects without major risk factors for atherosclerosis. Individuals with the 6A/6A genotype (associated with lower enzyme activity) show a triad of events, namely, increased wall thickness, enlarged arterial lumen, and local reduction of wall shear stress, which might predispose them to atherosclerotic plaque localization.
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PMID:Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects. 1084 78

The matrix metalloproteinase (MMP) family has been implicated in the process of a variety of diseases such as arthritis, atherosclerosis, and tumor cell metastasis. We have been designing single-stranded peptides (SSPs) and triple-helical peptides (THPs) as potential discriminatory MMP substrates. Edman degradation sequence and matrix-assisted laser desorption/ionization mass spectrometric (MALDI-MS) analyses of proteolytic activity have been utilized to aid in further substrate design. THP models of the alpha1(I)772-786 sequence from type I collagen were synthesized to examine the triple-helical substrate specificity of MMP family members. Sequence and MALDI-MS analyses were used in conjunction with a fluorometric assay to determine the exact point of cleavage by each MMP. MMP-1 (interstitial collagenase) cleaved the substrates at a single Gly-Ile bond, analogous to the cleavage site in type I collagen. MMP-2 (Mr 72 000 type IV collagenase; gelatinase A) was found to cleave the substrates at two sites, a Gly-Ile bond and a Gly-Gln bond. MMP-3 (stromelysin 1) was found to cleave only one of the substrates after reaction for 48 h. Ultimately, sequence and MALDI-MS analyses allowed us to detect an additional cleavage site for MMP-2 in comparison to MMP-1, while MMP-3 was found to cleave a substrate after an extended time period. The second cleavage site would cause the kinetic parameters for MMP-2 to be overestimated by the fluorometric assay. Further design variations for these substrates need to consider the presence of more stable triple-helical conformation (to eliminate MMP-3 binding) and the removal of Gly-Gln bonds that may be susceptible to MMP-2.
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PMID:Use of Edman degradation sequence analysis and matrix-assisted laser desorption/ionization mass spectrometry in designing substrates for matrix metalloproteinases. 1097 99

The functional 5A/6A polymorphism of the stromelysin-1 promoter has been implicated as a potential genetic marker for the progression of angiographically determined atherosclerosis in patients with coronary artery disease. Recently, a novel interleukin-6 (IL-6) gene functional G/C polymorphism at -174 in the promoter has also been reported. In this study, we analyzed the relation of these two polymorphisms with carotid artery atherosclerosis in 109 randomly selected, middle-aged men without exercise-induced ischemia. Atherosclerosis was quantified as intima-media thickness (IMT) by high-resolution ultrasonography. Univariately, stromelysin genotype was significantly (P:=0.015) associated with IMT, and this relation remained (P:=0.033) after adjustments for age, cardiorespiratory fitness, body mass index, smoking, LDL cholesterol, and systolic blood pressure and for sonographers. The 5A/6A polymorphism independently explained 7% of the variance in carotid bifurcation IMT. The IL-6 polymorphism was also significantly associated (P:=0. 036) with increased IMT, with men homozygous for the G allele having IMT that was 11% greater than men homozygous for the C allele. Men who were homozygous for both the 6A and G alleles had an covariate adjusted IMT that was 36% greater than men who were homozygous for neither allele (P:<0.003). These data suggest that genetic factors that predispose to reduced matrix remodeling (stromelysin 6A allele) and to increased inflammation (IL-6 G allele) combine to increase susceptibility for intima-media thickening in the carotid bifurcation, a predilection site for atherosclerosis.
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PMID:Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. 1111 68

To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and their tissue inhibitos (TIMPs) in patients with premature coronary atheroscrelosis, we studied 53 consecutive male patients with angiographically defined premature (<65 years) and stable coronary artery disease. Plasma levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 were determined in peripheral blood by a sandwich enzyme immunoassay, and the results were compared with those from 133 age-matched control males. There were significant differences in all the MMPs and TIMPs (p<0.001) between patients and controls. In the patient group, the levels of MMP-9 (mean +/- SD (ng/ml) 27.2 +/- 15.2/21.8 +/- 15.2) and TIMP-1 (130.4 +/- 55.7/94.5 +/- 26.3) were significantly higher, and the levels of MMP-2 (632.5 +/- 191.6/727.6 +/- 171.4), MMP-3 (53.1 +/- 31.2/79.6 +/- 29.9), and TIMP-2 (24.7 +/- 15.2/35.4 +/- 16.4) were significantly lower than those of controls. We found significant positive correlation between plasma MMP-9 levels and low-density lipoprotein (LDL)-cholesterol levels (Rs = 0.168, p = 0.022), and significant negative correlation between plasma MMP-9 levels and high-density lipoprotein (HDL)-cholesterol levels (Rs = -0.164, p = 0.026) by Spearman rank correlation test. In contrast, plasma MMP-2 (Rs = 0.181, p = 0.014) and MMP-3 (Rs = 0.260, p = 0.0004) levels were positively correlated with HDL-cholesterol levels. TIMP-2 levels were negatively correlated with total cholesterol (Rs = -0.197, p = 0.007) and LDL-cholesterol (Rs = -0.168, p=0.022) levels. These results suggest that the circulating levels of MMPs and TIMPs are altered in patients with premature coronary atherosclerosis and that plasma lipoprotein cholesterol levels correlate with these, possibly as a result of the lipoprotein-vessel wall interactions.
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PMID:Circulating matrix metalloproteinases and their inhibitors in premature coronary atherosclerosis. 1143 85

Long-term patency of human saphenous vein bypass grafts is low because of intimal thickening and superimposed atherosclerosis. Matrix-degrading metalloproteinases (MMPs) and changes in vascular smooth muscle cell (VSMC) phenotype are thought to be essential for the VSMC migration that contributes to intimal thickening. We examined VSMC phenotype and MMP activity in saphenous veins obtained before and after surgical manipulation. Surgical preparation of the veins significantly increased pro-MMP-1 expression by 2-fold and significantly reduced tissue inhibitor of MMPs (TIMP)-2 expression, whereas MMP-3 and TIMP-1 were unaffected. Furthermore, caseinolytic and gelatinolytic activities measured by in situ zymography were dramatically elevated by injury. The expression of desmin and smoothelin was significantly decreased by injury, whereas vimentin expression was significantly increased. In addition, these changes in phenotype and MMP activity were localized to a subpopulation of VSMCs, the circumferential medial VSMCs. Our data show that surgical preparative injury induces phenotypic modulation of a subpopulation of medial VSMCs to a synthetic phenotype and increases MMP activity. This may favor matrix degradation, VSMC migration, and the subsequent intimal thickening that leads to graft failure.
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PMID:Injury induces dedifferentiation of smooth muscle cells and increased matrix-degrading metalloproteinase activity in human saphenous vein. 1145 43

Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems can degrade most ECM components. The availability of mice models with deficiency of main components of both systems has allowed to study their contribution to vascular remodeling in several biological processes. In mouse models of atherosclerosis, urokinase-mediated plasmin generation plays a role in activation of several macrophage-derived MMPs (MMP-3, -9, -12 and -13), triggering elastolysis and collagenolysis, resulting in media destruction and aneurysm formation. Neointima formation after vascular injury, a process that depends on smooth muscle cell migration, is reduced in mice with plasminogen or urokinase deficiency and enhanced in mice with deficiency of TIMP-1 (type 1 tissue inhibitor of MMPs). Also in allograft transplant arteriosclerosis and in abdominal aortic aneurysm both proteolytic systems contribute to matrix degradation. In a mouse model of myocardial infarction, urokinase deficiency protects totally and MMP-9 deficiency partially against cardiac rupture, but these animals suffer cardiac failure. Thus, the plasminogen/plasmin and MMP systems, in concert, contribute to vascular remodeling in the setting of cardiovascular disease.
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PMID:Plasmin and matrix metalloproteinases in vascular remodeling. 1148 21

1. Large artery stiffness is a principal determinant of pulse pressure and both are related to cardiovascular mortality independently of other major risk factors. A clearer understanding of the structural and genetic processes that contribute to large artery properties may provide novel approaches to therapy. 2. Age, atherosclerosis and gender are three important factors that contribute to large artery stiffening. Each influences the artery elastic matrix and its relationship to medial smooth muscle cells. Genetic and hormonal modulation of the extracellular matrix proteins and their regulators, including matrix metalloproteinases (MMPs), may account for some interindividual differences. 3. In a study of 213 healthy individuals and 105 patients with coronary artery disease (CAD), we examined whether stromelysin-1 (MMP-3) genotype, determined by the 5A/6A promoter polymorphism, influences large artery stiffening. In healthy individuals, the 5A/5A genotype was linked with stiffer large arteries and higher systolic blood pressure compared with other genotypes. 4. Genetic variation in the extracellular matrix protein fibrillin-1, using a pentanucleotide repeat polymorphism, was assessed as a potential determinant of large artery stiffness in patients with CAD. The 2-3 genotype was associated with stiffer large arteries, higher pulse pressure and more severe CAD than other genotypes. 5. Females experience a greater increase in large artery stiffness with age than males, with a time-course suggestive of sex steroid modulation. The mechanisms mediating such gender differences have not been established, but the known regulatory role of sex steroids with respect to MMPs likely contributes. 6. The demonstration that genetic and hormonal modulation of extracellular matrix components and MMPs contributes to age, atherosclerotic and gender-related differences in large artery mechanical properties suggests these proteins may be important targets for therapy.
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PMID:Large artery stiffness: structural and genetic aspects. 1190 11

Clinical complications of atherosclerosis are often triggered by the rupture of unstable plaques, while thinning of the atherosclerotic vessel wall owing to elastin and collagen degradation and media necrosis may result in aneurysm formation and bleeding. Proteolysis, mediated via the plasminogen/plasmin and/or matrix metalloproteinase (MMP) systems may contribute to neovascularization and rupture of plaques, or to ulceration and rupture of aneurysms. In an in vivo model of atherosclerosis, using mice that had a combined deficiency of apolipoprotein E (ApoE) and urokinase-type plasminogen activator (u-PA) and that were maintained on a cholesterol-rich diet, it was observed that u-PA deficiency protects against aneurysm formation. This was explained by the findings that plasmin, generated from plasminogen by u-PA, activates several macrophage-secreted proMMPs (e.g. proMMP-3, -9, -12 and -13), which in turn cause extracellular matrix degradation. A potential role for MMP-3 (stromelysin-1) was confirmed in a subsequent study using mice with a combined deficiency of ApoE and MMP-3, that were kept on a cholesterol-rich diet. The results suggest that MMP-3 contributes to plaque destabilization, possibly by degrading extracellular matrix components, but also promotes aneurysm formation by degrading the elastic lamina. These effects may be mediated by MMP-3 directly or by activation of other proMMPs or other (proteolytic) systems. A functional role of MMPs is further supported by the finding that deficiency in TIMP-1 (tissue inhibitor of MMPs type 1) reduces atherosclerotic plaque size but enhances aneurysm formation. Taken together, these results suggest that u-PA has an important role in the structural integrity of the atherosclerotic vessel wall, which is likely to involve triggering the activation of MMPs and, furthermore, they suggest that increased u-PA levels are a risk factor for aneurysm formation.
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PMID:Extracellular proteolysis in the development and progression of atherosclerosis. 1202 44

Platelet-derived growth factor (PDGF) stimulates expression of matrix metalloproteinases (MMPs), including stromelysin-1 (MMP-3). Induction of these expressions is known to occur during the course of atherosclerosis, tumor invasion, and metastasis. We investigated PDGF-alpha receptor (alphaR)- and beta receptor (betaR)-mediated signaling pathways for the expression of MMP-3 and invasion activity using porcine aortic endothelial (PAE) cells with stable expression of normal or mutated PDGF receptors. RT-PCR and Western blot analyses revealed that PDGF-BB induces MMP-3 expression in PAE cells that exclusively express either the PDGF-alphaR or the -betaR, but not in non-transfected control cells. To identify the signals necessary for PDGF receptor-mediated induction of MMP-3 expression, several lines of PAE cells expressing mutant PDGF receptors were further analyzed. Cells expressing mutant PDGF receptors unable to associate with Src or PLCgamma, retained the ability to induce MMP-3 expression as a result of PDGF-BB stimulation. However, incubation with PDGF-BB did not induce MMP-3 expression in cells expressing a mutant PDGF-betaR unable to associate with phosphatidylinositol 3(')-kinase (PI3K). LY294002, a PI3K inhibitor, reduced PDGF-BB-stimulated MMP-3 expression in PAE cells expressing wild-type PDGF receptors. In contrast, PDGF-BB induced MMP-3 expression in the presence of U-73122, a PLCgamma inhibitor. Moreover, PDGF-BB enhanced the invasiveness of cells expressing wild type PDGF-beta receptors, but not of cells expressing mutant PDGF-betaRs impaired in their ability to associate with PI3K. In light of these results, it appears that PDGF-BB is capable of inducing MMP-3 expression through both the PDGF-alphaR and the -betaR, and the effects are contributed by the PI3K-mediated transduction pathways.
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PMID:Functional analysis of aortic endothelial cells expressing mutant PDGF receptors with respect to expression of matrix metalloproteinase-3. 1205 99


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