Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
Cardiovasc Res 1995 Oct
PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to a pericapillary fibrin cuff and plugging of capillaries by white blood cells. On the basis of a previous work, we had assumed that the key event in the pathogenesis of venous leg ulcers is related to inflammation generated by activated white blood cells that accumulate under unrelieved blood pressure, because in ulcer biopsies we had detected the presence of tumor necrosis factor-alpha (TNF-alpha) in intracapillary monocytes, elastase in the polymorphonuclear leukocytes near the vessels, and a pericapillary undegraded fibrin cuff causing a diffusion barrier to oxygen. This concept was developed because TNF-alpha synthesized by activated monocytes is responsible for many deleterious effects. It has a potent mitogenic effect on fibroblasts, leading to new collagen deposition and angiogenesis, it induces an increase in collagenase production, it acts through upregulation of an intracellular adhesion molecule (ICAM-1), leading to leukocyte sequestration and consequently a release of toxic metabolites by the polymorphonuclear cells, an early step in chronic inflammation, it activates the coagulation pathway via a marked increase in monocyte-associated tissue factor (TF) procoagulant activity, and it inhibits fibrinolysis by promoting the release of PAI-1, contributing to undegraded fibrin deposition. Therefore, we were interested in evaluating, in patients with venous leg ulcers, the effect of pentoxifylline administered at 1,200 mg daily (versus placebo) for 2-months, as this drug induces a decrease in TNF-alpha synthesis and also blocks its activity. This pilot assay was performed in blind. Evolution of several parameters in ulcer biopsies are analyzed: TNF-alpha, intact fibrin, fibrin degradation products, ICAM-1, TF, and elastase. Pentoxifylline administration induced a decrease of local elastase and of fibrin deposit. These results support the hypothesis that accumulation of activated leukocytes is the key event in venous leg ulcers.
J Cardiovasc Pharmacol 1995
PMID:Expression of elastase and fibrin in venous leg ulcer biopsies: a pilot study of pentoxifylline versus placebo. 869 46

We investigated the effect of endothelin-1 (ET-1) in normal and systemic sclerosis (SSc) dermal fibroblasts. Collagen type I, collagen type III, and MMP-1 levels in culture supernatants were measured by competition ELISA and cellular mRNA expression was examined by Northern blotting. Mitogenic responses to ET-1 were assessed by [3H]TdR incorporation. ET receptor mRNA expression was examined by RT-PCR analysis of fibroblast RNA and with surface binding studies using radiolabeled ET receptor ligands and specific receptor antagonists. ET-1 enhanced release of collagen types I and III by control and SSc fibroblast strains, but the effects were significantly greater for control cells (p < 0.05). This effect appeared to involve both ETA and ETB receptor subtypes. SSc fibroblasts demonstrated lower constitutive MMP-1 production than control fibroblasts (p < 0.01), but ET-1 treatment decreased MMP-1 in normal fibroblasts to levels observed in SSc. Mitogenic response (percent control [3H]TdR incorporation) to ET-1 for SSc fibroblasts was 130 +/- 34, significantly less (p < 0.01) than that for normal fibroblasts strains (290 +/- 25). This response appeared to be predominantly mediated via the ETA receptor subtype. Surface binding studies suggested a significantly lower level of ETA binding sites in SSc compared with normal fibroblasts (p < 0.05). These data suggest that ET-1 induces a fibrogenic phenotype in normal dermal fibroblasts that resembles that seen in fibroblasts grown from lesional SSc skin. Moreover, SSc cells appear to be refractory to these effects, and this reduced responsiveness is associated with an altered ratio of ETA:ETB receptor expression, supporting a role for ET-1 in the fibrotic pathology of SSc.
J Cardiovasc Pharmacol 1998
PMID:Endothelins: effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts. 959 82

The cardiac fibroblast is the most abundant cell type present in the myocardium and is mainly responsible for the deposition of extracellular matrix (ECM). Important components of cardiac ECM include structural and adhesive proteins such as collagen and fibronectin. Excess deposition of cardiac ECM (fibrosis) has been associated with the pathophysiological mechanical overload of the heart. Therefore, the role of cardiac fibroblasts in "sensing", "integrating" and "responding" to mechanical stimuli is of great interest. The development of in vitro strain apparatuses has allowed scientists to investigate the effects of mechanical stimuli on cardiac fibroblast function. Cardiac fibroblasts express ECM receptors (integrins) which couple mechanical stimuli to functional responses. Mechanical stimulation of cardiac fibroblasts has been shown to result in activation of various signal transduction pathways. The application of defined mechanical stimuli to cultured cardiac fibroblasts has been associated with ECM gene expression, growth factor production, release and/or bioactivity as well as collagenase activity. Ultimately, for fibrosis to develop the overproduction of ECM must overcome any associated increases in collagenase activity. Mechanically induced upregulation of ECM production may follow direct or indirect pathways through the autocrine or paracrine action of growth factors. Given the complex nature of the interstitial milieu of the working heart, additional research is needed to further our understanding of the roles that mechanical stimuli play in excess deposition of myocardial ECM.
Cardiovasc Res 2000 May
PMID:Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. 1077 29

Matrix metalloproteinase-1 (MMP-1) may play an important role in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture. We investigated the effect of the calcium channel blockers amlodipine and nifedipine on the expression of MMP-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in endothelial cells (ECs). MMP-1 and TIMP-1 levels in conditioned media of human vascular ECs were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescence-labeled collagen digestion. The addition of interleukin-1beta (IL-1beta) increased MMP-1 levels in the culture media of ECs. Amlodipine, but not nifedipine, significantly decreased MMP-1 levels in IL-1beta-stimulated ECs. TIMP-1 levels also were significantly increased by IL-1beta, and its expression was slightly decreased by amlodipine, not by nifedipine. Amlodipine significantly inhibited collagenolytic activity in the culture media of IL-1beta-stimulated ECs, whereas nifedipine showed no significant effect on the activity. Our findings revealed that amlodipine, but not nifedipine, inhibits IL-1beta-induced MMP-1 expression in human ECs.
J Cardiovasc Pharmacol 2000 Jun
PMID:Amlodipine inhibits expression of matrix metalloproteinase-1 and its inhibitor in human vascular endothelial cells. 1083 22

We investigated late-onset anastomotic stenosis in an implanted prosthetic graft. Rupture of the pseudointima and hemorrhaging from the vasa vasorum were observed at the border of the collagenous tissue and fibrin layer. An immunohistological study showed that the fibrin layer was positive for tPA, but weakly positive for PAI-1. Some neutrophils and monocyte/macrophages in the fibrin layer were immunostained for tPA, uPA, uPAR, and MMP-1, -2 and -3. Some spindle-shaped cells surrounding the graft were immunostained for uPA, uPAR, MMP-1, -2, -3, -7 and -9, and TIMP-1 and -2. The endothelial cells of some microvessels were positive for MMP-1 and -2, and tPA. Some multi-nucleated giant cells were immunostained for MMP-7 and-9, tPA, PAI-1, uPA, and uPAR. Overexpressed MMPs and PAs possibly caused instability of the pseudointima.
J Cardiovasc Surg (Torino) 2000 Jun
PMID:Rupture of pseudointima in an implanted vascular prosthesis: immunohistological study of plasminogen activators and matrix metalloproteinases. 1095 41

Matrix metalloproteinases (MMPs) are members of a large family of enzymes that can degrade extracellular matrix as well as other molecules. MMPs participate in a broad variety of normal and pathologic states, and recent evidence implicates the MMP family as potential mediators of cardiac dilation and progression to heart failure. This evidence is based on several lines of investigation. First, members of the MMP family are overexpressed in the myocardium in both experimental and human myocardial injury, infarction, and dilation. Second, overexpression of at least one MMP (MMP-1) in the hearts of transgenic mice can cause cardiac hypertrophy, dilation, and systolic dysfunction. Third, studies from multiple laboratories with different experimental models indicate that inhibition of MMPs through small molecules or gene transfer of endogenous inhibitors favorably affects cardiac remodeling. Fourth, targeted deletion of MMP genes in mice attenuates cardiac remodeling. These compelling results appear to fulfill Koch's Postulates as they may be applied to a non-infectious mediator of a disease, and thus current evidence supports MMP inhibition as a promising strategy for preventing heart failure. However, the crucial question of whether MMP inhibition benefits long-term left ventricular function and survival should be answered.
Trends Cardiovasc Med 2001 Jul
PMID:Matrix metalloproteinase inhibition and the prevention of heart failure. 1159 32

Upregulation of angiotensin II receptor, may be involved in the initiation and progression of atherosclerosis. To examine the contribution of AT1 receptor in the expression of matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor (TIMP-2) in lipid-deposited arterial tissues, New Zealand white rabbits were given high-cholesterol chow (with losartan 25 mg/d or vehicle) for 10 weeks. Losartan reduced the areas of sudanophilia in the aorta of rabbits fed high-cholesterol diet (p < 0.01 vs. control). Losartan also significantly decreased the enhanced mRNA expression of MMP-1 and TIMP-2 in aortas of rabbits with high-cholesterol diet. Losartan-treated rabbits revealed a reduction in immunohistochemical expression of MMP-1, whereas TIMP-2 expression became localized to the intima. In addition, losartan treatment reduced the activation of NF-kappa B by inhibiting the degradation of its inhibitor I kappa-B alpha. These observations demonstrate that AT1 receptor blockade with losartan reduces lipid deposition and exerts potent inhibitory effects on NF-kappa B activation and modulates the expression of MMP-1 and TIMP-2 in hypercholesterolemic rabbits.
J Cardiovasc Pharmacol 2002 Mar
PMID:Modulation of matrix metalloproteinase-1, its tissue inhibitor, and nuclear factor-kappa B by losartan in hypercholesterolemic rabbits. 1186 11

In the heart, collagens are the major extracellular matrix (ECM) protein. The fibrillar collagens of the heart surround and interconnect myocytes and muscle fibers to provide for muscle fiber and myocyte alignment which imparts mechanical support to the myocardium and governs tissue stiffness. Loss of collagen fibrils and struts are said to lead to myocyte slippage, ventricular dilation, and progressive contractile dysfunction. Failed human hearts examined either at autopsy or explantation invariably exhibit alterations of the ECM primarily due to changes in collagen. Modulation of the balance between matrix synthesis and degradation is important in the process of ventricular remodeling and in the pathophysiology of chronic heart failure. Support for the importance of the ECM and activity of matrix metalloproteinases (MMP) in the development of chronic heart failure has been demonstrated both in animal models of heart disease and in humans. A causative role for the ECM in this process was recently revealed in experiments using a transgenic mouse model that expresses the specific collagen-degrading enzyme, MMP-1, in the heart. These studies demonstrated that chronic expression of MMP-1 leads to dynamic changes in the heart and ultimately results in systolic dysfunction. Multiple studies in animal models have also shown that inhibition of MMP activity in animal models of heart failure have attenuated the onset of left ventricular dilatation. Future studies will determine whether inhibition of MMP activity improves morbidity and mortality in patients with heart failure.
Trends Cardiovasc Med 2002 Apr
PMID:Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction. 1200 33

High levels of low-density lipoprotein are associated with atherosclerosis, and myocardial and arterial remodeling. We postulated that low-density lipoprotein influences collagen synthesis and degradation in fibroblasts as a potential mechanism of tissue remodeling. Incubation of cultured human skin fibroblasts with low-density lipoproteins resulted in a time-dependent and dose-dependent increase in the secretion of matrix metalloproteinase activity measured by gelatin zymography. Western blot analysis showed a concomitant increase in matrix metalloproteinase-1 protein. Northern blot analysis demonstrated an increase in collagen I messenger RNA after treatment with low-density lipoprotein. The matrix metalloproteinase-1 secretory response of fibroblasts to low-density lipoprotein was attenuated by heparin, which inhibits low-density lipoprotein uptake through the low-density lipoprotein-receptor. These observations suggest that low-density lipoprotein has a regulatory effect on collagen metabolism in fibroblasts.
J Cardiovasc Pharmacol Ther 2003 Jun
PMID:Low density lipoproteins modulate collagen metabolism in fibroblasts. 1280 89


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