Menstrual blood derived mesenchymal cells ameliorate cardiac fibrosis via inhibition of endothelial to mesenchymal transition in myocardial infarction

2013 ◽  
Vol 168 (2) ◽  
pp. 1711-1714 ◽  
Author(s):  
Zhaocai Zhang ◽  
Jian-an Wang ◽  
Yinchuan Xu ◽  
Zhi Jiang ◽  
Rongrong Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Mesenchymal Cells ◽  
Menstrual Blood ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

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 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 Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1

Theranostics ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 3905-3924 ◽  
Author(s):  
Tim Wilhelmi ◽  
Xingbo Xu ◽  
Xiaoying Tan ◽  
Melanie S. Hulshoff ◽  
Sabine Maamari ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

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 Author response: Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

2020 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Ana Paredes ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Author Response ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Abstract 352: MicroRNAs Play A Crucial Role In The Induction Of Endothelial-to-Mesenchymal Transition-Mediated Cardiac Fibrosis.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Varun Nagpal ◽  
Mesut Eren ◽  
Marissa A Michaels ◽  
Douglas E Vaughan
Keyword(s):  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Human Heart ◽  
Cardiac Fibrosis ◽  
Primary Cultures ◽  
Human Myocardium ◽  
Tgf Beta ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Introduction: Fibroblast-like cells derived from aberrant activation of endothelial-to-mesenchymal transition (EndMT) are an important contributor to cardiac fibrosis. TGF-beta signaling plays a pivotal role in the induction of EndMT and cardiac fibrosis. Our recent studies have shown that specific miRNAs are differentially regulated during TGF-beta-induced EndMT and blocking TGF-beta-receptor I (TbetaR1) kinase inhibits TGF-beta-induced EndMT. Hypothesis: We hypothesize that miRNAs that promote EndMT will potentially exacerbate cardiac fibrosis, and knockdown of these miRNAs will attenuate EndMT-mediated cardiac fibrosis. Results and Methods: We investigated the levels of miRNAs and profibrotic markers in the failing human myocardium compared to healthy human heart tissue. Our results indicate that miRNAs upregulated during EndMT were significantly elevated in the failing human myocardium. In addition, failing human myocardium exhibited significant upregulation of profibrotic markers including alpha-SMA, Col1 and PAI-1. Next, primary cultures of mouse cardiac endothelial cells treated with TGF-beta or SB431542 (TbetaR1 kinase inhibitor) were evaluated for EndMT markers using bright field microscopy, fluorescence microscopy, western blot analysis and qRT PCR. We observed that blocking TbetaR1 kinase by SB431542 inhibits specific miRNAs which were upregulated during TGF-beta-induced EndMT. In addition, in silico analysis revealed that these miRNAs target key TGF-beta effectors, which was further confirmed by western blot analysis. Furthermore, overexpression of specific miRNAs using mimics resulted in the induction of EndMT. Next, miRNA mimics in combination with TGF-beta substantially potentiated TGF-beta-induced EndMT. Finally, knockdown of these miRNAs using inhibitors or Cy3-tagged antagomiRs significantly attenuated TGF-beta-induced cardiac EndMT. Conclusions: Our results indicate that TbetaR1 kinase-induced expression of miRNAs is involved in cardiac EndMT. Thus, miRNAs may promote profibrotic signaling in EndMT-derived fibroblast-like cells, which may contribute to fibrogenesis in the human heart.

scholarly journals Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 865 ◽  
Author(s):  
Tsai ◽  
Lin ◽  
Hang ◽  
Chen
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Umbilical Vein ◽  
Active Form ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Umbilical Vein Endothelial Cells

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes.

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