Endothelial-specific deletion of <i>Ets-1</i> attenuates Angiotensin II-induced cardiac fibrosis via suppression of endothelial-to-mesenchymal transition

Xu, Lixin; Fu, Mengxia; Chen, Dongrui; Han, Weiqing; Ostrowski, Michael C.; Grossfeld, Paul; Gao, Pingjin; Ye, Maoqing

doi:10.5483/bmbrep.2019.52.10.206

Cited by 27 publications

(23 citation statements)

References 23 publications

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“…In addition, the pathologic process of cardiomyocyte hypertrophy is highly related to the expression of ETS-1. Ang II infusion induced an increase in heart size and ventricular wall thickness in mice, but these effects were significantly diminished in global ETS-1 knockout mice ( Zhan et al, 2005 ; Xu et al, 2019 ). Our current research shows that adding H 2 O 2 to cultured cardiomyocytes can increase the levels of PUMA and ETS-1 and that inhibiting PUMA and ETS-1 can reduce apoptosis and hypertrophy, respectively.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-221/222 Mediates ADSC-Exosome-Induced Cardioprotection Against Ischemia/Reperfusion by Targeting PUMA and ETS-1

Lai

Lee

Chang

et al. 2020

Front. Cell Dev. Biol.

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Cardiovascular disease is a major health problem in industrialized and developing countries and is the leading cause of death and disability. Myocardial ischemia/reperfusion (I/R) causes cardiomyocyte damage such as apoptosis and hypertrophy. The purpose of this study was to investigate the effects of exosomes from adipose-derived stem cells (ADSC-Exo) on hearts from I/R mice and to explore the underlying mechanisms. ADSC-Exo significantly decreased I/R-induced cardiomyocyte apoptosis and hypertrophy, as detected by TdT-mediated dUTP nick end-labeling (TUNEL) and wheat germ agglutinin (WGA) staining, respectively. In addition, the expression of apoptosis-related proteins p-p53 and PUMA and hypertrophy-related proteins ETS-1 and ANP were significantly reduced in the cardiomyocytes of ADSC-Exo-treated I/R mice compared to those of control mice. Both PUMA and ETS-1 are reported to be target genes for miR-221/222. I/R operation significantly reduced miR-221/222 expression, while ADSC-Exo treatment increased miR-221/222 expression, as detected by RT-qPCR. We also observed that cardiac I/R operation markedly increased cell apoptosis and hypertrophy in miR-221/222 knockout (KO) mice, while ADSC-Exo reduced the effects of I/R operation. Furthermore, ADSC-Exo protected H9c2 cardiomyocytes from H2O2-induced damage by reducing apoptosis and hypertrophy in vitro. H2O2 treatment significantly reduced miR-221/222 expression, while ADSC-Exo treatment reversed this effect in H9c2 cells. ADSC-Exo treatment decreased H2O2-induced PUMA and ETS-1 expression. Compared with control treatment, I/R treatment significantly reduced p-AKT and increased p-p65, while ADSC-Exo and miR-221/222 mimics attenuated these effects. The AKT activator SC79 and p65 inhibitor Bay 11-7082 reduced H2O2-induced cell apoptosis and hypertrophy. Based on these findings, ADSC-Exo prevents cardiac I/R injury through the miR-221/miR-222/PUMA/ETS-1 pathway. Therefore, ADSC-Exo is an effective inhibitor of I/R-induced heart injury.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-221/222 Mediates ADSC-Exosome-Induced Cardioprotection Against Ischemia/Reperfusion by Targeting PUMA and ETS-1

Lai

Lee

Chang

et al. 2020

Front. Cell Dev. Biol.

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“…In addition, ETS-1 upregulation mediates angiotensin II-induced cardiac fibrosis 6 . ETS-1 participates in this process by regulating the expression of fibrotic matrix genes, such as collagen 1, collagen 3, and fibronectin 23 . Consistent with previous observations, we demonstrated that I/R induced increases in oxidative stress, myocardial apoptosis and fibrosis, as shown by DHE staining, TUNEL assay and Masson's trichrome staining, respectively.…”

Section: Discussionmentioning

confidence: 99%

Conditioned medium from adipose-derived stem cells attenuates ischemia/reperfusion-induced cardiac injury through the microRNA-221/222/PUMA/ETS-1 pathway

et al. 2021

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Rationale: Cardiovascular diseases, such as myocardial infarction (MI), are the leading causes of death worldwide. Reperfusion therapy is the common standard treatment for MI. However, myocardial ischemia/reperfusion (I/R) causes cardiomyocyte injury, including apoptosis and fibrosis. We aimed to investigate the effects of conditioned medium from adipose-derived stem cells (ADSC-CM) on apoptosis and fibrosis in I/R-treated hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes and the underlying mechanisms. Methods: ADSC-CM was collected from ADSCs. The effects of intramuscular injection of ADSC-CM on cardiac function, cardiac apoptosis, and fibrosis examined by echocardiography, Evans blue/TTC staining, TUNEL assay, and Masson's trichrome staining in I/R-treated mice. We also examined the effects of ADSC-CM on apoptosis and fibrosis in H/R-treated H9c2 cells by annexin V/PI flow cytometry, TUNEL assay, and immunocytochemistry. Results: ADSC-CM treatment significantly reduced heart damage and fibrosis of I/R-treated mice and H/R-treated cardiomyocytes. In addition, the expression of apoptosis-related proteins, such as p53 upregulated modulator of apoptosis (PUMA), p-p53 and B-cell lymphoma 2 (BCL2), as well as the fibrosis-related proteins ETS-1, fibronectin and collagen 3, were significantly reduced by ADSC-CM treatment. Moreover, we demonstrated that ADSC-CM contains a large amount of miR-221/222, which can target and regulate PUMA or ETS-1 protein levels. Furthermore, the knockdown of PUMA and ETS-1 decreased the induction of apoptosis and fibrosis, respectively. MiR-221/222 overexpression achieved similar results. We also observed that cardiac I/R markedly increased apoptosis and fibrosis in miR-221/222 knockout (KO) mice, while ADSC-CM decreased these effects. The increased phosphorylation of p38 and NF‐κB not only mediated myocardial apoptosis through the PUMA/p53/BCL2 pathway but also regulated fibrosis through the ETS-1/fibronectin/collagen 3 pathway. Conclusions: Overall, our results show that ADSC-CM attenuates cardiac apoptosis and fibrosis by reducing PUMA and ETS-1 expression, respectively. The protective effect is mediated via the miR-221/222/p38/NF-κB pathway.

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“…Although, most studies were performed in peritoneal effluents, serum of patients undergoing PD or in animal experimental models, one study developed in peritoneal membrane biopsies from pediatric patients, showed an increase in miR-21 levels associated with fibrotic stages [ 34 ]. Alternatively, studies using primary/immortalized and microvascular/aortic endothelial cells reported the participation of various miRNAs in the regulation of high glucose-induced EndMT [ 76 , 77 , 78 ]. However, the extrapolation of in vitro findings to human diseases using an extended diversity of endothelial cells should be carefully considered.…”

Section: Discussionmentioning

confidence: 99%

Increased miR-7641 Levels in Peritoneal Hyalinizing Vasculopathy in Long-Term Peritoneal Dialysis Patients

Díaz

Sandoval

Rodrigues-Díez

et al. 2020

IJMS

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Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. Clinical data were collected and lesions were evaluated by immunohistochemistry. In selected biopsies a microRNA (miRNA)-sequencing analysis was performed. Only fifteen patients (15%) showed PHV at different degrees. PHV prevalence was significantly lower among patients using PD fluids containing low glucose degradation products (GDP) (5.9% vs. 24.5%), angiotensin converting enzyme inhibitors (ACEIs) (7.5% vs. 23.4%), statins (6.5% vs. 22.6%) or presenting residual renal function, suggesting the existence of several PHV protective factors. Peritoneal biopsies from PHV samples showed loss of endothelial markers and induction of mesenchymal proteins, associated with collagen IV accumulation and wide reduplication of the basement membrane. Moreover, co-expression of endothelial and mesenchymal markers, as well as TGF-β1/Smad3 signaling activation were found in PHV biopsies. These findings suggest that an endothelial-to-mesenchymal transition (EndMT) process was taking place. Additionally, significantly higher levels of miR-7641 were observed in severe PHV compared to non-PHV peritoneal biopsies. Peritoneal damage by GDPs induce miRNA deregulation and an EndMT process in submesothelial vessels, which could contribute to collagen IV accumulation and PHV.

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Endothelial-specific deletion of Ets-1 attenuates Angiotensin II-induced cardiac fibrosis via suppression of endothelial-to-mesenchymal transition

Cited by 27 publications

References 23 publications

MicroRNA-221/222 Mediates ADSC-Exosome-Induced Cardioprotection Against Ischemia/Reperfusion by Targeting PUMA and ETS-1

MicroRNA-221/222 Mediates ADSC-Exosome-Induced Cardioprotection Against Ischemia/Reperfusion by Targeting PUMA and ETS-1

Conditioned medium from adipose-derived stem cells attenuates ischemia/reperfusion-induced cardiac injury through the microRNA-221/222/PUMA/ETS-1 pathway

Increased miR-7641 Levels in Peritoneal Hyalinizing Vasculopathy in Long-Term Peritoneal Dialysis Patients

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