scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

2020 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
Vanessa Núñez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

ABSTRACTMacrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Ana Paredes ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

scholarly journals Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Valentin Platel ◽  
Sébastien Faure ◽  
Isabelle Corre ◽  
Nicolas Clere
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Therapy Resistance ◽  
Experimental Conditions ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Cancer cells evolve in a very complex tumor microenvironment, composed of several cell types, among which the endothelial cells are the major actors of the tumor angiogenesis. Today, these cells are also characterized for their plasticity, as endothelial cells have demonstrated their potential to modify their phenotype to differentiate into mesenchymal cells through the endothelial-to-mesenchymal transition (EndoMT). This cellular plasticity is mediated by various stimuli including transforming growth factor-β (TGF-β) and is modulated dependently of experimental conditions. Recently, emerging evidences have shown that EndoMT is involved in the development and dissemination of cancer and also in cancer cell to escape from therapeutic treatment. In this review, we summarize current updates on EndoMT and its main induction pathways. In addition, we discuss the role of EndoMT in tumorigenesis, metastasis, and its potential implication in cancer therapy resistance.

Transcriptional regulation of endothelial-to-mesenchymal transition in cardiac fibrosis: role of myocardin-related transcription factor A and activating transcription factor 3

2017 ◽  
Vol 95 (10) ◽  
pp. 1263-1270 ◽  
Author(s):  
Vibhuti Sharma ◽  
Nilambra Dogra ◽  
Uma Nahar Saikia ◽  
Madhu Khullar
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Cardiac Fibrosis ◽  
Activating Transcription Factor 3 ◽  
Mesenchymal Transition ◽  
Related Transcription Factor ◽  
Endothelial To Mesenchymal Transition ◽  
Activating Transcription Factor ◽  
Transcription Factor 3

The etiology of cardiac fibrogenesis is quite diverse, but a common feature is the presence of activated fibroblasts. Experimental evidence suggests that a subset of cardiac fibroblasts is derived via transition of vascular endothelial cells into fibroblasts by endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype. Molecular mechanisms and the transcriptional mediators controlling EndMT in heart during development or disease remain relatively undefined. Myocardin-related transcription factor A facilitates the transcription of cytoskeletal genes by serum response factor during fibrosis; therefore, its specific role in cardiac EndMT might be of importance. Activation of activating transcription factor 3 (ATF-3) during cardiac EndMT is speculative, since ATF-3 responds to a transforming growth factor β (TGF-β) stimulus and controls the expression of the primary epithelial-to-mesenchymal transition markers Snail, Slug, and Twist. Although the role of TGF-β in EndMT-mediated cardiac fibrosis has been established, targeting of the TGF-β ligand has not proven to be a viable anti-fibrotic strategy owing to the broad functional importance of this ligand. Thus, targeting of downstream transcriptional mediators may be a useful therapeutic approach in attenuating cardiac fibrosis. Here, we discuss some of the transcription factors that may regulate EndMT-mediated cardiac fibrosis and their involvement in type 2 diabetes.

scholarly journals Curcumin Blunts IL-6 Dependent Endothelial‐to‐Mesenchymal Transition to Alleviate Renal Allograft Fibrosis Through Autophagy Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiajun Zhou ◽  
Mengtian Yao ◽  
Minghui Zhu ◽  
Mengchao Li ◽  
Qiwei Ke ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kidney Transplantation ◽  
Renal Allograft ◽  
Umbilical Vein ◽  
Rat Kidney ◽  
Graft Loss ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Fibrosis contributes to graft loss in chronic renal allograft injury. Endothelial‐to‐mesenchymal transition (EndMT) plays an important role in the development of fibrosis following kidney transplantation. Autophagy plays an important role in the homeostasis of diverse cell types including endothelial cells. Here we demonstrate that inhibition of autophagy by treatment with 3-methyladenine (3-MA) or by silencing autophagy-related (ATG)5 promoted interleukin (IL)-6–dependent EndMT in human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs), and autophagy inactivation was associated with EndMT in patients with chronic allograft dysfunction. IL-6 level was significantly higher in the culture medium of HUVECs transfected with ATG5 siRNA or treated with 3-MA compared to the respective control groups. IL-6 application induced EndMT in HUVECs and HRGECs, whereas antibody-mediated neutralization of IL-6 suppressed EndMT induced by ATG5 silencing. The protective role of curcumin (Cur) against allograft fibrosis was confirmed in a rat kidney transplantation model of F344 donors to Lewis recipients. Curcumin—a natural polyphenol compound with known antifibrotic effects in various tissues—alleviated IL-6–induced EndMT and promoted autophagy in the allografted organ and in HUVECs. This is the first demonstration of the role of autophagy in renal allograft fibrosis; our findings indicate that curcumin can alleviate chronic renal allograft injury by suppressing IL-6–dependent EndMT via activation of autophagy.

Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction through promoting endothelial to mesenchymal transition

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Q Qin ◽  
J.H Chen ◽  
J.B Jia ◽  
J.Y Qian ◽  
J.B Ge
Keyword(s):  
Myocardial Infarction ◽  
Nuclear Receptor ◽  
Cardiac Fibrosis ◽  
Vascular Endothelial Cells ◽  
Funding Source ◽  
Orphan Nuclear Receptor ◽  
Mesenchymal Transition ◽  
National Budget ◽  
Endothelial To Mesenchymal Transition ◽  
Public Grant

Abstract Background Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Methods and results Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. Results suggested that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22α, Snail and decreased expression of PECAM-1 and eNOS compared with WT mice after MI. Then we found overexpression Nur77 in HCAECs significantly inhibited IL-1β and TGFβ2 induced EndMT, as shown by reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT through inhibiting NF-κB-dependent pathway Conclusion Nur77 plays a role in cardiac fibrosis through inhibition of EndMT, and may be a promising target for therapy of cardiac fibrosis after MI. Nur77 inhibited EndMT Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China

scholarly journals MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis

2021 ◽  
Vol 22 (16) ◽  
pp. 8629
Author(s):  
Nina P. Jordan ◽  
Samuel J. Tingle ◽  
Victoria G. Shuttleworth ◽  
Katie Cooke ◽  
Rachael E. Redgrave ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Heart Tissue ◽  
Lineage Tracing ◽  
Ischaemic Injury ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Over Expression ◽  
Endothelial To Mesenchymal Transition

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.

P3115Effect of calcitriol attenuates doxorubicin-induced cardiac dysfunction in mice model: focus on endothelial-to-mesenchymal transition

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T H Tsai ◽  
W Y Chen
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Cell Damage ◽  
Active Form ◽  
Smad Pathway ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Abstract Objective Doxorubicin (DOX) is an effective anti-neoplasm drug, but the early and late cardiac toxicity limits its clinical use. The Endothelial-to-mesenchymal transition (EndMT) has been found to involve in the process of heart failure. It's unclear whether EndMT plays a role in DOX-induced cardiomyopathy (DoIC). Calcitriol is an active form Vitamin D3, which blocks the growth of cancer cells via inhibiting Smad pathway. This study investigated the cardiac protective effect of calcitriol via inhibiting of EndMT in DoIC. Methods/Findings C57BL/6 mice and endothelial-specific labeled mice were administered Dox twice weekly for 4 weeks [intraperitoneally (i.p.), 32 mg/kg cumulative dose]and were subsequently treated with/without calcitriol for 12 weeks. The cardiac echography revealed diastolic dysfunction at 13 weeks following the first DOX treatment and was accompanied by increased of myocardial fibrosis and up-regulated pro-fibrotic proteins.(Figure A-C) Calcitriol attenuated DOX-induced myocardial fibrosis, down-regulated pro-fibrotic proteinsand diastolic function. Endothelial fate tracing revealed that endothelium-derived cells contributed DOX-induced cardiac remodelling through EndMT and Calcitriol attenuated this process without attenuating Dox-induced cardiac myocyte and endothelial cell damage.(Figure D) In vitro, we examined if calcitriol would inhibit EndMT and fibroblast-to-myofibroblast transition (FMT) through the Smad pathway. Human umbilical vein endothelial cells (HUVECs) and mouse cardiac fibroblasts were treated with TGF-beta with or without calcitriol. Morphological, immunofluorescence staining, and western blot analyses were carried out to evaluate EndMT and FMT. Calcitriol attenuated EndMT and FMT by inhibiting the Smad2 pathway. Taken together, calcitriol didn't reduced Doxorubicin induced damage of cardiomocyte and endothelial cells. But calcitriol inhibit doxorubicin induced heart failure by attenuating cardiac fibrosis through inhibiting Smad pathway. Conclusion Calcitriol attenuated DOX-induced cardiomyopathy partial through inhibiting EndMT process. Acknowledgement/Funding CMRPG8E0661-3

scholarly journals Autophagy attenuates endothelial-to-mesenchymal transition by promoting Snail degradation in human cardiac microvascular endothelial cells

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Jin Zou ◽  
Yanhua Liu ◽  
Bingong Li ◽  
Zeqi Zheng ◽  
Xuan Ke ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanism ◽  
Cardiac Fibrosis ◽  
Microvascular Endothelial Cells ◽  
Cardiovascular Development ◽  
Mesenchymal Transition ◽  
Microvascular Endothelial ◽  
Endothelial To Mesenchymal Transition ◽  
Cardiac Microvascular Endothelial Cells

Endothelial-to-mesenchymal transition (EndMT) mainly exists in cardiovascular development and disease progression, and is well known to contribute to cardiac fibrosis. Recent studies indicated that autophagy also participates in the regulation of cardiac fibrosis. However, the precise role of autophagy in cardiac fibrosis and the underlying molecular mechanism remain unclear. The present study aimed to explore the role of autophagy in EndMT, reveal the underlying molecular mechanism, and seek new therapy for cardiac fibrosis. In the present study, we found that EndMT and autophagy were induced simultaneously by hypoxia in human cardiac microvascular endothelial cells (HCMECs). Rapamycin, an autophagy enhancer, attenuated EndMT with promoting angiogenesis, while 3-methyladenine (3-MA) and chloroquine (CQ), agents that inhibit autophagy, accelerated the progression accompanied by the decrease in counts of tube formation under hypoxia conditions. Interestingly, intervening autophagy by rapamycin, 3-MA, or CQ did not affect hypoxia-induced autocrine TGFβ signaling, but changed the expression of Snail protein without alterations in the expression of Snail mRNA. Furthermore, the colocalization of LC3 and Snail indicated that autophagy might mediate Snail degradation under hypoxia conditions in HCMECs. Interaction of p62, the substrate of autophagy, with Snail by co-immunoprecipitation especially in hypoxia-incubated cells confirmed the hypothesis. In conclusion, autophagy serves as a cytoprotective mechanism against EndMT to promote angiogenesis by degrading Snail under hypoxia conditions, suggesting that autophagy targetted therapeutic strategies may be applicable for cardiac fibrosis by EndMT.

Sign in / Sign up

Export Citation Format

Share Document