Dataset Information

Cardiac Chagas Disease: MMPs, TIMPs, Galectins, and TGF-? as Tissue Remodelling Players.

ABSTRACT: A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-? are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibrosis upon infection with Trypanosoma cruzi. Thus, considering that the heart is one of the main target organs in Chagas disease, knowledge regarding the mechanisms of action of these molecules is essential to understand how they interact and trigger local and systemic reactions and, consequently, determine whether they contribute to the development of Chagas' heart disease. In this sense, it is believed that the inflammatory microenvironment caused by the infection alters the expression of these proteins favoring progression of the host-parasite cycle and thereby stimulating cardiac tissue remodeling mechanisms and fibrosis. The aim of this review was to gather information on metalloproteinases and their tissue inhibitors, galectins, and TGF-? and discuss how these molecules and their different interrelationships contribute to the development of Chagas' heart disease.

SUBMITTER: da Costa AWF

PROVIDER: S-EPMC6899287 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cardiac Chagas Disease: MMPs, TIMPs, Galectins, and TGF-<i>β</i> as Tissue Remodelling Players.

da Costa Arthur Wilson Florencio AWF do Carmo Neto Jose Rodrigues JR Braga Yarlla Loyane Lira YLL Silva Beatriz Aquino BA Lamounier Amanda Borges AB Silva Bárbara Oliveira BO Dos Reis Marlene Antônia MA de Oliveira Flávia Aparecida FA Celes Mara Rúbia Nunes MRN Machado Juliana Reis JR

Disease markers 20191125

A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-<i>β</i> are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibro ...[more]

PMID: 31885735

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Project description:BackgroundMatrix metalloproteinases (MMPs) are involved in remodeling of the extracellular matrix (ECM) during pregnancy and parturition. Aberrant ECM degradation by MMPs or an imbalance between MMPs and their tissue inhibitors (TIMPs) have been implicated in the pathogenesis of preterm labor, however few studies have investigated MMPs or TIMPs in maternal serum. Therefore, the purpose of this study was to determine serum concentrations of MMP-3, MMP-9 and all four TIMPs as well as MMP:TIMP ratios during term and preterm labor.MethodsA case control study with 166 singleton pregnancies, divided into four groups: (1) women with preterm birth, delivering before 34 weeks (PTB); (2) gestational age (GA) matched controls, not in preterm labor; (3) women at term in labor and (4) at term not in labor. MMP and TIMP concentrations were measured using Luminex technology.ResultsMMP-9 and TIMP-4 concentrations were higher in women with PTB vs. GA matched controls (resp. p = 0.01 and p<0.001). An increase in MMP-9:TIMP-1 and MMP-9:TIMP-2 ratio was observed in women with PTB compared to GA matched controls (resp. p = 0.02 and p<0.001) as well as compared to women at term in labor (resp. p = 0.006 and p<0.001). Multiple regression results with groups recoded as three key covariates showed significantly higher MMP-9 concentrations, higher MMP-9:TIMP-1 and MMP-9:TIMP-2 ratios and lower TIMP-1 and -2 concentrations for preterm labor. Significantly higher MMP-9 and TIMP-4 concentrations and MMP-9:TIMP-2 ratios were observed for labor.ConclusionsSerum MMP-9:TIMP-1 and MMP-9:TIMP-2 balances are tilting in favor of gelatinolysis during preterm labor. TIMP-1 and -2 concentrations were lower in preterm gestation, irrespective of labor, while TIMP-4 concentrations were raised in labor. These observations suggest that aberrant serum expression of MMP:TIMP ratios and TIMPs reflect pregnancy and labor status, providing a far less invasive method to determine enzymes essential in ECM remodeling during pregnancy and parturition.

Project description:IntroductionBovine papillomaviruses -1/-2 (BPVs) are small non-enveloped double-stranded DNA viruses able to infect the skin of bovids and equids, causing development of neoplastic lesions such as bovine cutaneous fibropapillomas and equine sarcoid. Matrix metalloproteinases (MMPs) are a group of zinc-dependent endopeptidases that degrade basal membrane and extracellular matrix, whose function is essential in physiological processes such as tissue remodeling and wound healing. MMPs activity is finely regulated by a balancing with expression of tissue inhibitors of MMPs (TIMPs), a process that is impaired during tumour development. BPV infection is associated with upregulation of MMPs and /or their unbalancing with TIMPs, contributing to local invasion and impairment of extracellular matrix remodeling in equine sarcoid; however, studies regarding this topic in bovine fibropapillomas are lacking.MethodsThe aim of this study was to perform an immunohistochemical and biochemical analysis on a panel of MMPs and TIMPs in BPV-2 positive bovine cutaneous fibropapillomas vs. normal skin samples.ResultsImmunohistochemistry revealed a cytoplasmic expression of MMP-2 (15/19), a cytoplasmic and perinuclear immunoreactivity of MMP-7 (19/19) and MMP-9 (19/19), along with a cytoplasmic and nuclear pattern of MMP-14 (16/19), accompanied by a cytoplasmic expression of TIMP-1 (14/19) and TIMP-2 (18/19) in tumour samples; western blotting revealed an overexpression of MMP-2 (8/9), MMP-7 (9/9) and MMP-9 (9/9), and a decreased level of MMP-14 (9/9), TIMP-1 (9/9) and TIMP-2 (9/9) in tumour versus normal skin samples. Moreover, gelatine zymography confirmed the expression of pro-active MMP-2 (9/9) and MMP-9 (9/9) and, most importantly, indicated the presence and increased activity of their active forms (82 and 62 kDa, respectively) in tumour samples.DiscussionThis is the first study describing MMPs and TIMPs in bovine cutaneous fibropapillomas and our results suggest that their unbalanced expression in presence of BPV-2 may play a significant role in tumour development. A further analysis of supplementary MMPs and TIMPs could bring new important insights into the papillomavirus induced tumours.

Project description:BackgroundIncisional hernia is a common and important complication of laparotomies. Epidemiological studies allude to an underlying biological cause, at least in a subset of population. Interest has mainly focused on abnormal collagen metabolism. However, the role played by other determinants of extracellular matrix (ECM) composition is unknown. To date, there are few laboratory studies investigating the importance of biological factors contributing to incisional hernia development. We performed a descriptive tissue-based analysis to elucidate the possible relevance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in association with local cytokine induction in human incisional hernia tissues. The expression profiles of MMPs, TIMPs and pro-inflammatory cytokine signalling were investigated in aponeurosis and skeletal muscle specimens taken intraoperatively from incisional hernia (n= 10) and control (n= 10) patients. Semiquantitative RT-PCR, zymography and immunoblotting analyses were done. Incisional hernia samples displayed alterations in the microstructure and loss of ECM, as assessed by histological analyses. Moreover, incisional hernia tissues showed increased MMP/TIMP ratios and de-regulated inflammatory signalling (tumor necrosis factor [TNFA] and interleukin [IL]-6 tended to increase, whereas aponeurosis TNFA receptors decreased). The changes were tissue-specific and were detectable at the mRNA and/or protein level. Statistical analyses showed several associations between individual MMPs, TIMPs, interstitial collagens and inflammatory markers. The increment of MMPs in the absence of a counterbalance by TIMPs, together with an ongoing de-regulated inflammatory signalling, may contribute in inducing a functional defect of the ECM network by post-translational mechanisms, which may trigger abdominal wall tissue loss and eventual rupture. The notable TIMP3 protein down-regulation in incisional hernia fascia may be of pathophysiological significance. We conclude that this study may help to pinpoint novel hypotheses of pathogenesis that can lead to a better understanding of the disease and ultimately to improvement in current therapeutic approaches.

Project description:BACKGROUND:Chronic alcohol consumption has been shown in human and animal studies to result in collagen accumulation, myocardial fibrosis, and heart failure. Cardiac fibroblasts produce collagen and regulate extracellular matrix (ECM) homeostasis through the synthesis and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), with the balance of MMPs/TIMPs determining the rate of collagen turnover. Dynamic changes of MMP and TIMP expression were reported in alcohol-induced hepatic fibrosis; however, the effect of alcohol on MMP/TIMP balance in the heart and cardiac fibroblasts is unknown. We hypothesized that alcohol exposure alters cardiac fibroblast MMP and TIMP expression to promote collagen accumulation in the heart. METHODS:Cardiac fibroblasts isolated from adult rats were cultured in the presence of alcohol (12.5 to 200 mM) for 48 hours. MMP, TIMP, and collagen type I and III expression were assayed by Western blot analysis. Hydroxyproline (HPro) was used as a marker of collagen production. The in vivo cardiac effects of ethanol (EtOH) were determined using rats exposed to EtOH vapor for 2 weeks, resulting in blood alcohol levels of 150 to 200 mg/dl. Cardiac collagen volume fraction (CVF), as well as MMP, TIMP, and collagen expression, was assessed. RESULTS:EtOH-exposed rats exhibited up-regulation of TIMP-1, TIMP-3 and TIMP-4 in the heart, with no significant increases in MMPs. Cardiac fibroblasts exhibited transformation to a profibrotic phenotype following exposure to alcohol. These changes were reflected by increased ?-smooth muscle actin and collagen I and III expression, as well as increased collagen secretion. In vivo EtOH exposure also produced fibrosis, indicated by increased CVF and expression of collagens. CONCLUSIONS:Alcohol exposure modulates cardiac fibroblast MMP/TIMP expression favoring a profile associated with collagen accumulation. Our data suggest that this disrupted MMP/TIMP profile may contribute to the development of myocardial fibrosis and cardiac dysfunction resulting from chronic alcohol abuse.

Project description:The association between matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and obesity as well as obesity-related disease including metabolic syndrome is not fully explored. Our aims are that: (i) to evaluate the plasma levels of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2 and their ratios in non-obese people, overweight and obese people with or without metabolic syndrome, (ii) to investigate correlations between MMPs or TIMPs levels and several anthropometric parameters, blood pressure, endothelial function. Anthropometric and biochemical parameters were determined in 479 randomly selected participants, subdividing according to body mass index (BMI) and metabolic syndrome status. Plasma MMPs and TIMPs levels were measured. The assessment of endothelial function was characterized in people with obesity, overweight and non-obese, using laser Doppler Flowmetry. Obese people have elevated MMP-1, MMP-2, TIMP-1, TIMP-2 levels and decreased MMP-3/TIMP-1 and MMP-9/TIMP-1 ratios compared with non-obese people. MMP-1 levels and MMP-1/TIMP-1 ratio were positively correlated with BMI and waist circumference (WC) while MMP-2 levels were negatively correlated with BMI and WC values in obese people. MMP-3 levels and MMP-3/TIMP-1 ratio were positively correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP) in obese and metabolic syndrome people. Additionally, MMP-9 levels and MMP-9/TIMP-1 ratio were negatively correlated with endothelium-dependent response in obese and metabolic syndrome people. MMP-1, MMP-2, TIMP-1, TIMP-2 levels were increased in obese subjects. Significant correlations between anthropometric parameters and MMP-1 as well as MMP-1/TIMP-1 ratio supported these results. MMP-3 and -9 levels as well as their ratios with TIMP-1 were associated with blood pressure and endothelial-dependent response, respectively. In conclusion, our results demonstrated that MMP-1, MMP-3 and MMP-9 levels were correlated with several obesity-related parameters including BMI, WC, blood pressure and endothelial-dependent response. Our findings will hopefully provide new aspects for the use of MMPs and TIMPs as clinical biomarkers in obesity-related cardiovascular diseases such as metabolic syndrome and hypertension. The lack of measure of MMPs activity in plasma and relevant organs/tissues in obesity and metabolic syndrome is considered as a limitation in this report.

Project description:TGF-? involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-? signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of T?R1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-? signaling pathway reduced TGF-?/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-? inhibitors.

Dataset Information

Cardiac Chagas Disease: MMPs, TIMPs, Galectins, and TGF-? as Tissue Remodelling Players.

Publications

Cardiac Chagas Disease: MMPs, TIMPs, Galectins, and TGF-<i>β</i> as Tissue Remodelling Players.

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