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1.
Life Sci ; 241: 117109, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31786195

RESUMO

AIMS: This study aimed to identify interstitial molecules that were responsible for the deterioration of the esiantimated glomerular filtration rate (eGFR) in diabetic nephropathy (DN). MATERIALS AND METHODS: Weighted gene co-expression network analysis (WGCNA) was used to link the tubulointerstitial gene expression profile of DN to eGFR values. The relationship of eGFR with each sub-domain regulator in the network was analyzed with the linear regression model. Gene sets enrichment analysis (GSEA) was applied to detect the molecular changes mostly relating to the essential regulators. KEY FINDINGS: Four co-expression modules were found strongly correlating with eGFR values. Genes from these modules were over-represented in fibrosis-related biological processes (extracellular matrix (ECM) organization and cell adhesion) and pathways (integrin signaling and ECM-receptor interaction). Of sub-domains in the gene interaction network, the expression of hypoxia-inducible factor 1A (HIF1A) was most negatively correlated with eGFR (R2 = 0.417, P = 0.026). The positive correlations between HIF1A and its target genes were found, indicating an enhanced transcriptional activity of HIF1A. We also found that HIF1A positively correlated with CCAAT enhancer binding protein delta (CEBPD) (r = 0.731, P = 0.011), an activator of HIF1A transcription. Moreover, GSEA showed that samples with high HIF1A expression were enriched with fibrosis associated signaling, like ECM-receptor interaction and cell adhesion. Intriguingly, vascular epithelial growth factor A (VEGFA) expression decreased while HIF1A increased (R2 = 0.733, P = 0.001), suggesting VEGFA loss may exacerbate hypoxia and stimulate HIF1A induction. SIGNIFICANCE: The present study suggested that interstitial HIF1A may be involved in renal interstitial fibrosis in DN.


Assuntos
Nefropatias Diabéticas/genética , Fibrose/fisiopatologia , Taxa de Filtração Glomerular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Rim/patologia , Adulto , Idoso , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/fisiopatologia , Feminino , Fibrose/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Taxa de Filtração Glomerular/fisiologia , Humanos , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/genética
2.
Nat Cell Biol ; 21(12): 1490-1503, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768046

RESUMO

Tendon injuries cause prolonged disability and never recover completely. Current mechanistic understanding of tendon regeneration is limited. Here, we use single-cell transcriptomics to identify a tubulin polymerization-promoting protein family member 3-expressing (Tppp3+) cell population as potential tendon stem cells. Through inducible lineage tracing, we demonstrate that these cells can generate new tenocytes and self-renew upon injury. A fraction of Tppp3+ cells expresses platelet-derived growth factor receptor alpha (Pdfgra). Ectopic platelet-derived growth factor-AA (PDGF-AA) protein induces new tenocyte production while inactivation of Pdgfra in Tppp3+ cells blocks tendon regeneration. These results support Tppp3+Pdgfra+ cells as tendon stem cells. Unexpectedly, Tppp3-Pdgfra+ fibro-adipogenic progenitors coexist in the tendon stem cell niche and give rise to fibrotic cells, revealing a clandestine origin of fibrotic scars in healing tendons. Our results explain why fibrosis occurs in injured tendons and present clinical challenges to enhance tendon regeneration without a concurrent increase in fibrosis by PDGF application.


Assuntos
Moléculas de Adesão Celular/metabolismo , Fibrose/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Regeneração/fisiologia , Células-Tronco/metabolismo , Tendões/metabolismo , Adipogenia/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Traumatismos dos Tendões/metabolismo , Traumatismos dos Tendões/fisiopatologia , Tendões/fisiopatologia , Tenócitos/metabolismo , Tenócitos/fisiologia
4.
J Biomed Sci ; 26(1): 86, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31656195

RESUMO

Chronic inflammation is the underlying pathological condition that results in fibrotic diseases. More recently, many forms of cancer have also been linked to chronic tissue inflammation. While stromal immune cells and myofibroblasts have been recognized as major contributors of cytokines and growth factors that foster the formation of fibrotic tissue, the endothelium has traditionally been regarded as a passive player in the pathogenic process, or even as a barrier since it provides a physical divide between the circulating immune cells and the inflamed tissues. Recent findings, however, have indicated that endothelial cells in fact play a crucial role in the inflammatory response. Endothelial cells can be activated by cytokine signaling and express inflammatory markers, which can sustain or exacerbate the inflammatory process. For example, the activated endothelium can recruit and activate leukocytes, thus perpetuating tissue inflammation, while sustained stimulation of endothelial cells may lead to endothelial-to-mesenchymal transition that contributes to fibrosis. Since chronic inflammation has now been recognized as a significant contributing factor to tumorigenesis, it has also emerged that activation of endothelium also occurs in the tumor microenvironment. This review summarizes recent findings characterizing the molecular and cellular changes in the vascular endothelium that contribute to tissue fibrosis, and potentially to cancer formation.


Assuntos
Endotélio Vascular/fisiopatologia , Fibrose/fisiopatologia , Neoplasias/fisiopatologia , Animais , Fibrose/etiologia , Humanos , Camundongos , Neoplasias/etiologia
5.
BMC Complement Altern Med ; 19(1): 283, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653214

RESUMO

BACKGROUND: A potato protein hydrolysate, APPH is a potential anti-obesity diet ingredient. Since, obesity leads to deterioration of liver function and associated liver diseases, in this study the effect of APPH on high fat diet (HFD) associated liver damages was investigated. METHODS: Six week old male hamsters were randomly separated to six groups (n = 8) as control, HFD (HFD fed obese), L-APPH (HFD + 15 mg/kg/day of APPH), M-APPH (HFD + 30 mg/kg/day), H-APPH (HFD + 75 mg/kg/day of APPH) and PB (HFD + 500 mg/kg/day of probucol). HFD fed hamsters were administered with APPH 50 days through oral gavage. The animals were euthanized and the number of apoptotic nuclei in liver tissue was determined by TUNEL staining and the extent of interstitial fibrosis was determined by Masson's trichrome staining. Modulation in the molecular events associated with apoptosis and fibrosis were elucidated from the western blotting analysis of the total protein extracts. RESULTS: Hamsters fed with high fat diet showed symptoms of liver damage as measured from serum markers like alanine aminotransferase and aspartate aminotransferase levels. However a 50 day long supplementation of APPH effectively ameliorated the effects of HFD. HFD also modulated the expression of survival and apoptosis proteins in the hamster liver. Further the HFD groups showed elevated levels of fibrosis markers in liver. The increase in fibrosis and apoptosis was correlated with the increase in the levels of phosphorylated extracellular signal-regulated kinases (pERK1/2) revealing a potential role of ERK in the HFD mediated liver damage. However APPH treatment reduced the effect of HFD on the apoptosis and fibrosis markers considerably and provided hepato-protection. CONCLUSION: APPH can therefore be considered as an efficient therapeutic agent to ameliorate high fat diet related liver damages.


Assuntos
Caspase 3/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Obesidade/dietoterapia , Proteínas de Plantas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Solanum tuberosum/metabolismo , Animais , Apoptose , Caspase 3/genética , Cricetinae , Dieta Hiperlipídica/efeitos adversos , Fibrose/dietoterapia , Fibrose/genética , Fibrose/metabolismo , Fibrose/fisiopatologia , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Mesocricetus , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Proteínas de Plantas/química , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Solanum tuberosum/química
6.
Med Sci Monit ; 25: 7182-7190, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31550244

RESUMO

BACKGROUND The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly understood. This study aimed to use a mouse model of carbon tetrachloride (CCL4)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-ß1) and SMADs pathway. MATERIAL AND METHODS Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl4. BM-MSCs were transplanted after 12 weeks of CCl4 treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (alpha-SMA), TGF-ß1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1alpha), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction. RESULTS Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson's trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1alpha and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-ß1, collagen I, alpha-SMA, and SMAD3 (p<0.05). CONCLUSIONS BM-MSC transplantation reduced CCl4-induced murine liver fibrosis, indicating that in a hypoxic microenvironment, BM-MSCs may inhibit the TGFß-1/SMADs pathway.


Assuntos
Fibrose/metabolismo , Cirrose Hepática/terapia , Células-Tronco Mesenquimais/fisiologia , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Medula Óssea/metabolismo , Tetracloreto de Carbono/farmacologia , Hipóxia Celular/fisiologia , China , Modelos Animais de Doenças , Fibrose/fisiopatologia , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Smad/metabolismo , Proteínas Smad/fisiologia , Fator de Crescimento Transformador beta/metabolismo
7.
Reprod Domest Anim ; 54 Suppl 3: 46-52, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31512314

RESUMO

Inflammation and fibroproliferative diseases may be modulated by epigenetic changes. Therefore, we suggest that epigenetic mechanisms could be involved in equine endometrosis pathogenesis. DNA methylation is one of the methods to evaluate epigenetics, through the transcription of methyltransferases (DNMT1, DNMT3A, DNMT3B). The correlation between DNMTs and collagen (COL) transcripts was assessed for the different Kenney and Doig's (Current Therapy in Theriogenology. Philadelphia: WB Saunders; 1986) endometrium categories. Endometrial biopsies were randomly collected from cyclic mares. Histological classification (category I, n = 13; II A, n = 17; II B, n = 12; and III, n = 7) and evaluation of COL1A2, COL3A1 and DNMTs transcripts by qPCR, were performed. Data were analysed by one-way analysis of variance (ANOVA), Kruskal-Wallis test and Pearson correlation. As mares aged, there was an increase in endometrium fibrosis (p < .01), and in DNMT1 mRNA (p < .001). Considering DNMT3B transcripts for each category, there was an increase with fibrosis (p < .05). No changes were observed for DNMT1 and DNMT3A transcripts. However, DNMT3A mRNA levels were the highest in all categories (p < .01). In category I endometrium, a positive correlation was observed for transcripts of all DNMTs in both COLs (p < .01). In category IIA, this correlation was also maintained for all DNMTs transcripts in COL1A2 (p < .05), but only for DNMT3B in COL3A1 (p < .05). In category IIB, there was a positive correlation between DNMT3B and COL3A1 (p < .05). In category III, a positive correlation was only observed between DNMT3B and COL3A1 (p < .05). Our results suggest that there is a disturbance in COLs and DNMTs correlation during fibrosis.


Assuntos
Colágeno/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Endometrite/veterinária , Doenças dos Cavalos/metabolismo , Envelhecimento/fisiologia , Animais , Colágeno/genética , Metilação de DNA , Endometrite/genética , Endometrite/metabolismo , Endométrio/patologia , Feminino , Fibrose/fisiopatologia , Doenças dos Cavalos/genética , Cavalos , RNA Mensageiro
8.
Genes Dev ; 33(21-22): 1491-1505, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31558567

RESUMO

Cardiac fibroblasts (CFs) respond to injury by transitioning through multiple cell states, including resting CFs, activated CFs, and myofibroblasts. We report here that Hippo signaling cell-autonomously regulates CF fate transitions and proliferation, and non-cell-autonomously regulates both myeloid and CF activation in the heart. Conditional deletion of Hippo pathway kinases, Lats1 and Lats2, in uninjured CFs initiated a self-perpetuating fibrotic response in the adult heart that was exacerbated by myocardial infarction (MI). Single cell transcriptomics showed that uninjured Lats1/2 mutant CFs spontaneously transitioned to a myofibroblast cell state. Through gene regulatory network reconstruction, we found that Hippo-deficient myofibroblasts deployed a network of transcriptional regulators of endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) consistent with elevated secretory activity. We observed an expansion of myeloid cell heterogeneity in uninjured Lats1/2 CKO hearts with similarity to cells recovered from control hearts post-MI. Integrated genome-wide analysis of Yap chromatin occupancy revealed that Yap directly activates myofibroblast cell identity genes, the proto-oncogene Myc, and an array of genes encoding pro-inflammatory factors through enhancer-promoter looping. Our data indicate that Lats1/2 maintain the resting CF cell state through restricting the Yap-induced injury response.


Assuntos
Fibroblastos/citologia , Fibrose/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Fibroblastos/patologia , Fibrose/fisiopatologia , Deleção de Genes , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/fisiopatologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-31327400

RESUMO

Intestinal fibrosis with stricture formation affects up to half of patients with Crohn's disease (CD), resulting in impaired quality of life, increased risk of surgical intervention, and associated patient morbidity. The underlying pathophysiologic mechansisms responsible for initiating and perpetuating intestinal fibrosis are complex, dynamic, and implicate both inflammation-dependent and independent pathways. Previously thought to be an irreversible complication of long-standing inflammation unresponsive to medical therapy, fibrostenotic CD has been traditionally managed with endoscopic or surgical approaches. However, recent advances in our understanding of the humoral, cellular, and environmental pathways driving intestinal fibrosis has the potential to fundamentally change these management paradigms for CD-related strictures. Furthermore, the promise of fibrosis treatments in other organ systems has encouraged hope that anti-fibrotic treatment approaches for CD may be within reach. Here, we summarize the key breakthroughs in our molecular understanding of intestinal fibrosis, review current medical, endoscopic, and surgical treatment approaches to CD-related strictures, propose future directions for anti-fibrotic therapy in CD, and identify crucial research questions in this field that require additional investigation.


Assuntos
Doença de Crohn/fisiopatologia , Fibrose/fisiopatologia , Intestinos/patologia , Doença de Crohn/terapia , Humanos
10.
Curr Opin Ophthalmol ; 30(5): 314-318, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31313749

RESUMO

PURPOSE OF REVIEW: Congenital fibrosis of the extraocular muscles (CFEOM) is caused by abnormal development of the innervation of extraocular muscles. We update the recent literature regarding the clinical, anatomic, genetic, and molecular characteristics of CFEOM. Surgical considerations are addressed. RECENT FINDINGS: CFEOM is broken down into three main subtypes, CFEOM1, CFEOM2, and CFEOM3. Several recent reports of individuals, as well as family pedigrees, highlight the phenotypic heterogeneity of CFEOM. Intracranial and intraorbital radiologic findings have enhanced our understanding of the disease pathophysiology. Molecular genetics research has increased our understanding of the development of extraocular muscles and their innervation as well as pathophysiology of CFEOM. SUMMARY: Our understanding of the pathophysiology of CFEOM has increased with the recent contributions from neuroimaging, molecular genetics, and pedigree analysis. Surgical management of patients with CFEOM continues to be challenging.


Assuntos
Fibrose , Oftalmoplegia , Blefaroptose/fisiopatologia , Blefaroptose/cirurgia , Oftalmopatias Hereditárias/fisiopatologia , Oftalmopatias Hereditárias/cirurgia , Fibrose/classificação , Fibrose/fisiopatologia , Fibrose/cirurgia , Humanos , Transtornos da Motilidade Ocular/fisiopatologia , Transtornos da Motilidade Ocular/cirurgia , Oftalmoplegia/classificação , Oftalmoplegia/fisiopatologia , Oftalmoplegia/cirurgia , Fenótipo
12.
Basic Res Cardiol ; 114(5): 33, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31312919

RESUMO

Leukocyte-mediated inflammation is central in atherothrombosis and ST-segment elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) have been shown to enhance atherothrombosis and stimulate fibroblast function. We analyzed the effects of NETs on cardiac remodeling after STEMI. We measured double-stranded (ds)DNA and citrullinated histone H3 (citH3) as NET surrogate markers in human culprit site and femoral blood collected during primary percutaneous coronary intervention (n = 50). Fibrocytes were characterized in whole blood by flow cytometry, and in culprit site thrombi and myocardium by immunofluorescence. To investigate mechanisms of fibrocyte activation, isolated NETs were used to induce fibrocyte responses in vitro. Enzymatic infarct size was assessed using creatine-phosphokinase isoform MB area under the curve. Left ventricular function was measured by transthoracic echocardiography. NET surrogate markers were increased at the culprit site compared to the femoral site and were positively correlated with infarct size and left ventricular dysfunction at follow-up. In vitro, NETs promoted fibrocyte differentiation from monocytes and induced fibrocyte activation. Highly activated fibrocytes accumulated at the culprit site and in the infarct transition zone. Our data suggest that NETs might be important mediators of fibrotic remodeling after STEMI, possibly by stimulating fibrocytes.


Assuntos
Armadilhas Extracelulares , Fibroblastos/patologia , Leucócitos/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Remodelação Ventricular/fisiologia , Adulto , Idoso , Feminino , Fibrose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia
13.
Knee ; 26(4): 914-922, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174979

RESUMO

BACKGROUND: To establish proof of principle of a link between phenotypic expression and stiffness after TKR. METHODS: From 100 patients, genetic expression of markers of fibrosis was performed for 15 synovial samples from patients categorised as 'best post-operative range of movement (ROM)' and 15 samples from patients with 'worst ROM'. These markers included Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteinases with Thrombospondin (ADAMTS) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs). Genetic marker data were compared to Oxford Knee Scores (OKS) and Pain Catastrophizing Scores (PCS). RESULTS: Quantitative markers for gene expression demonstrated more outliers in stiff compared to non-stiff knees, suggesting a greater imbalance in pro- and anti-fibrotic markers in stiff knees. Whilst there was a significant difference in the range of post-operative knee flexion (p = 0.001) and extension (p = 0.001), there was no statistically significant difference between stiff and non-stiff knees in pre-operative or post-operative OKS (p ≥ 0.06). There was no difference in the individual components of the individual PCS score items nor the PCS total scores when stiff and non-stiff knees were compared (p > 0.05). CONCLUSION: Biological factors, namely gene expression of MMPs, TIMPs and ADAMTS, may contribute towards post-TKR stiffness. This now warrants further investigation to better understand this relationship based on larger, multi-centre, cohorts. LEVEL OF EVIDENCE: Level 3.


Assuntos
Artroplastia do Joelho/efeitos adversos , Articulação do Joelho/patologia , Articulação do Joelho/fisiopatologia , Amplitude de Movimento Articular/fisiologia , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Idoso , Biomarcadores/metabolismo , Feminino , Fibrose/metabolismo , Fibrose/fisiopatologia , Humanos , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Complicações Pós-Operatórias , RNA/metabolismo , Líquido Sinovial/metabolismo , Inibidores Teciduais de Metaloproteinases/genética , Inibidores Teciduais de Metaloproteinases/metabolismo
14.
Urologiia ; (2): 103-107, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31162910

RESUMO

The results of recent studies on the mechanisms of kidney damage are presented in the review of literature. The role of the immune system in the occurrence, development and outcome of damage to the epithelium of the renal tubules, as well as molecular, genetic and metabolic changes which determine the extent and consequences of renal trauma are described in details. The mechanisms of restoration of the renal parenchyma and the development of fibrosis following the cessation of injury are given.


Assuntos
Nefropatias/fisiopatologia , Túbulos Renais/fisiopatologia , Rim/fisiopatologia , Urotélio/fisiopatologia , Fibrose/fisiopatologia , Humanos , Rim/lesões , Nefropatias/etiologia , Túbulos Renais/lesões , Urotélio/lesões
15.
Medicina (Kaunas) ; 55(5)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126142

RESUMO

Background and objectives: Cardiac remodeling in pregnancy and postpartum is poorly understood. The aim of this study was to evaluate changes in cardiac fibrosis (pericardial, perivascular, and interstitial), as well as the expression of matrix metalloproteinases (MMP-1, MMP-2, and MMP-9) and their inhibitors (Tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-4) during late pregnancy and postpartum in rat left ventricle. Materials and Methods: Female Sprague-Dawley rats were used for this study. Rats were divided three groups: non-pregnant, late pregnancy, and postpartum. The heart was weighed and cardiac fibrosis was studied by conventional histological procedures. The expression and transcript level of target proteins were evaluated using immunoblot techniques and quantitative PCR. Results: The experiments showed an increase of perivascular, pericardial, and interstitial fibrosis in heart during pregnancy and its reversion in postpartum. Moreover, in late pregnancy, MMP-1, MMP-2, and MMP-9 metalloproteinases were downregulated and TIMP-1 and TIMP-4 were upregulated in left ventricle. Conclusions: Our data suggest that the metalloproteinases system is involved in the cardiac extracellular matrix remodeling during pregnancy and its reversion in postpartum, this improves the knowledge of the adaptive cardiac remodeling in response to a blood volume overload present during pregnancy.


Assuntos
Fibrose/complicações , Ventrículos do Coração/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Fibrose/fisiopatologia , Ventrículos do Coração/enzimologia , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 1 da Matriz/fisiologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/fisiologia , Metaloproteinases da Matriz/fisiologia , Período Pós-Parto , Gravidez , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/fisiologia , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-2/fisiologia
17.
Rev. chil. cardiol ; 38(1): 37-45, abr. 2019. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1003636

RESUMO

Resumen: Introducción: Atletas altamente entrenados muestran cambios cardíacos estructurales como adaptación a la sobrecarga, producto del ejercicio repetitivo y extenuante. Se han evidenciado elevación de biomarcadores de remodelado y fibrosis miocárdica posterior al ejercicio intenso en atletas. Sin embargo, el comportamiento de estos biomarcadores según el nivel de entrenamiento previo no se ha evaluado. Objetivo: Investigar biomarcadores de fibrosis y función ventricular derecha en maratonistas con distinto nivel de entrenamiento previo. Métodos: Se incluyeron 36 maratonistas hombres, sanos, que completaron 42 km en la maratón de Santiago. Se dividieron según entrenamiento previo en dos grupos, Grupo 1 (G1): ≥100 km/semana y Grupo 2 (G2): <100 km/semana. Se realizó ecocardiografía transtorácica y se evaluaron niveles plasmáticos de galectina-3 y del propéptido amino terminal del procolágeno tipo III (PIIINP) en la semana previa a la carrera e inmediatamente posterior a ésta. Resultados: Posterior a la maratón, la función sistólica del ventrículo derecho disminuyó en el grupo G2 junto con un aumento significativo de los niveles plasmáticos de PIIIPNP (61±16 a 94±24 ng/mL, p=0,01). Estos cambios no se observaron en el grupo G1 (65 ± 11 a 90±29 ng/mL, p=0,10). Los niveles plasmáticos de galectina-3 aumentaron significativamente en ambos grupos posterior al ejercicio (6,8±2,2 a 19,7±4,9 ng/mL, p 0,012 y 6,0±1,1 a 19,4 ± 5,9 ng/mL, p 0,01) en los grupos G1 y G2, respectivamente). Conclusiones: Atletas con menor grado de entrenamiento, presentan posterior a una maratón un significativo aumento de productos de degradación del colágeno (PIIIPNP) asociado a disminución de la función del ventrículo derecho. Los niveles de galectina-3 plasmática aumentan significativamente en ambos grupos post-esfuerzo independiente del entrenamiento previo.


Abstracts: Introduction: Highly trained athletes show structural cardiac changes as adaptation to overload. Rise in remodeling biomarkers and myocardial fibrosis after intense exercise in athletes has been evidenced; however, the behavior of these biomarkers according to pre-competition training level has not been evaluated. Objective: To evaluate fibrosis biomarkers levels and right ventricle function in marathon runners according to their previous training level, in the period prior to a marathon race and immediately after it. Methods: Thirty-six healthy male marathon runners were included. Subjects were grouped according to their previous training level: Group 1 (G1): ≥100 km/week and Group 2 (G2): <100 km/week. Transthoracic echocardiography along with plasmatic levels of galectin-3 and amino terminal propeptide of type III procollagen (PIIINP) were measured one week previous and immediately after the marathon. Results: Post-effort right ventricle systolic function decreased in G2, together with a significant elevation of PIIIPNP (61±16 to 94±24 ng/mL, p=0.01). These changes were not observed in G1 (from 65±11 to 90±29 ng/mL, p=0.10). Plasma galectin-3 increased significantly in both groups immediately post-exercise (6.8±2.2 to 19.7±4.9 ng/mL, p=0.012, and 6.0±1.1 to 19.4±5.9 ng/mL, p=0.01, in G1 and G2. respectively). Conclusion: Less trained athletes evidenced higher post marathon levels of PIIIPNP which is associated with a decreased global right ventricle function. Plasma galectin-3 levels increased significantly after intense exertion regardless of the intensity of previous training.


Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Corrida/fisiologia , Fibrose/sangue , Biomarcadores/sangue , Função Ventricular Direita , Traumatismos Cardíacos/sangue , Fragmentos de Peptídeos/sangue , Fibrose/fisiopatologia , Exercício/fisiologia , Método Simples-Cego , Chile , Estudos Prospectivos , Estudos Longitudinais , Função Ventricular Esquerda , Pró-Colágeno/sangue , Galectina 3/sangue , Atletas
18.
J Biosci ; 44(1)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30837367

RESUMO

Atrial fibrillation (AF) is the most frequently diagnosed cardiac arrhythmia worldwide. Patients with permanent atrial fibrillation are at an increased risk of developing valvular heart disease. Atrial fibrosis occurs in this pathophysiological setting. LIM kinase 1 (LIMK1) is a serine/threonine kinase that regulates microtubule stability and actin polymerization in fibroblasts. LIMK1 has been implicated in the pathogenesis of atrial fibrillation. Clinical data and biopsies of the right atrial appendage were collected from 50 patients with valvular heart disease who underwent heart valve replacement surgery. Data from patients with permanent atrial fibrillation (AF) and patients with sinus rhythm (SR) were compared. We found that AF patients had upregulated expression of LIMK1 as well as higher fibrosis. Transforming growth factor-ß (TGF-ß) stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts as well as upregulated expression of LIMK1. Downregulation of LIMK1 by siRNA inhibited TGF-ß induced fibroblast-myofibroblast transition, as evidenced by the downregulation of the expression of several differentiation markers, namely alpha-smooth muscle actin and type I and III collagen. Our findings revealed that increased LIMK1 protein levels may contribute to atrial fibrosis, and suggested that LIMK1 might be involved in AF development by promoting fibrogenesis associated with TGF-ß.


Assuntos
Fibrilação Atrial/genética , Fibrose/genética , Doenças das Valvas Cardíacas/genética , Quinases Lim/genética , Actinas/genética , Animais , Fibrilação Atrial/complicações , Fibrilação Atrial/fisiopatologia , Biópsia , Colágeno Tipo I/genética , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , RNA Interferente Pequeno/farmacologia , Fator de Crescimento Transformador beta/farmacologia
19.
Cell Mol Biol Lett ; 24: 10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906331

RESUMO

This study was designed to investigate the potential role of microRNA-29c (miR-29c) in biliary atresia-related fibrosis. The expression of miR-29c was determined in 15 pairs of peripheral blood samples from infants with biliary atresia (BA) and infants with non-BA neonatal cholestasis using quantitative real-time PCR. EMT was established by induction with TGF-ß1 in HIBEpiC cells. MiR-29c was inhibited by lipofectamine transfection. The expressions of proteins related to epithelial-mesenchymal transition (EMT), i.e., E-cadherin, N-cadherin and vimentin, were determined using quantitative real-time PCR and western blotting. Direct interaction between miR-29c and DNMT3A and DNMT3B was identified using a luciferase reporter assay. The expressions of DNMT3A and DNMT3B were suppressed by treatment with SGI-1027. Patients with BA showed significantly lower miR-29c levels in peripheral blood samples than the control subjects. In vitro, TGF-ß1-induced EMT significantly decreased the expression of miR-29c. Downregulation of miR-29c had a promotional effect on BA-related fibrosis in HIBEpiC cells, as confirmed by the decrease in E-cadherin and increase in N-cadherin and vimentin levels. MiR-29c was found to target the 3'UTR of DNMT3A and DNMT3B and inhibit their expression. Suppression of DNMT3A and DNMT3B reversed the effects of miR-29c downregulation on BA-related fibrosis in HIBEpiC cells. These data suggest that BA-related fibrosis is closely associated with the occurrence of EMT in HIBEpiC cells. MiR-29c might be a candidate for alleviating BA-related fibrosis by targeting DNMT3A and DNMT3B.


Assuntos
Atresia Biliar/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Transição Epitelial-Mesenquimal , Fibrose/metabolismo , MicroRNAs/metabolismo , Atresia Biliar/complicações , Atresia Biliar/fisiopatologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Fibrose/etiologia , Fibrose/fisiopatologia , Regulação da Expressão Gênica , Humanos , Lactente , MicroRNAs/genética
20.
Transfusion ; 59(S1): 884-892, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30737822

RESUMO

Scarring is a result of the wound healing response and causes tissue dysfunction after injury. This process is readily evident in the skin, but also occurs internally across organ systems in the form of fibrosis. Stem cells are crucial to the innate tissue healing response and, as such, present a possible modality to therapeutically promote regenerative healing while minimizing scaring. In this review, the cellular basis of scaring and fibrosis is examined. Current stem cell therapies under exploration for skin wound healing and internal organ fibrosis are discussed. While most therapeutic approaches rely on the direct application of progenitor-type cells to injured tissue to promote healing, novel strategies to manipulate the scarring response are also presented. As our understanding of developmental and stem cell biology continues to increase, therapies to encourage regeneration of healthy functional tissue after damage secondary to injury or disease will continue to expand.


Assuntos
Fibrose/terapia , Transplante de Células-Tronco/métodos , Cicatrização/fisiologia , Fibrose/fisiopatologia , Humanos
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