scholarly journals Effect of miR-195-5p on cardiomyocyte apoptosis in rats with heart failure by regulating TGF-β1/Smad3 signaling pathway

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Chun Xie ◽  
Huaxin Qi ◽  
Lei Huan ◽  
Yan Yang
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Reporter ◽  
Rat Cardiomyocytes ◽  
Smad 3 ◽  
Tgf Β1

Abstract Purpose: The present study set out to investigate the effect of miR-195-5p on cardiomyocyte apoptosis in rats with heart failure (HF) and its mechanism. Methods: HF rat model and hypoxia/reoxygenation (H/R) cardiomyocyte model were established. miR-195-5p expression and transforming growth factor-β1 (TGF-β1)/signal transduction protein (Smad)3 signaling pathway in HF rats and H/R cardiomyocytes were interfered. miR-195-5p expression was tested by Rt-PCR, TGF-β1/Smad3 signaling pathway related proteins were detected by Western Blot, apoptosis of HF rat cardiomyocytes was tested by TUNEL, and apoptosis of cardiomyocytes induced by H/R was checked by flow cytometry. Results: miR-195-5p was lowly expressed in myocardium of HF rats, while TGF-β1 and Smad3 proteins were high-expressed. Up-regulating miR-195-5p expression could obviously inhibit cardiomyocyte apoptosis of HF rats, improve their cardiac function, and inhibit activation of TGF-β1/Smad3 signaling pathway. Up-regulation of miR-195-5p expression or inhibition of TGF-β1/Smad3 signaling pathway could obviously inhibit H/R-induced cardiomyocyte apoptosis. Dual-luciferase reporter enzyme verified the targeted relationship between miR-195-5p and Smad3. Conclusion: miR-195-5p can inhibit cardiomyocyte apoptosis and improve cardiac function in HF rats by regulating TGF-β1/Smad3 signaling pathway, which may be a potential target for HF therapy.

scholarly journals The miR-130a-3p/TGF-βRII Axis Participates in Inhibiting the Differentiation of Fibroblasts Induced by TGF-β1

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanhong Liu ◽  
Yan Ding ◽  
Yapeng Hou ◽  
Tong Yu ◽  
Hongguang Nie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Immunofluorescence Assay ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Mouse Lung ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease that has a poor prognosis. Abnormal activation of transforming growth factor-β1 (TGF-β1) plays a crucial role in fibroblast differentiation. Mesenchymal stem cells (MSCs) are currently being considered for the treatment of PF, but the regulatory mechanisms are poorly understood. We co-cultured bone marrow-derived MSCs and mouse lung fibroblasts (MLg) in the presence of TGF-β1, and studied the protein/mRNA expression of fibrosis markers and related signaling pathways. The effects of miR-130a-3p and TGF-β receptor II (TGF-βRII) on the differentiation of MLg induced by TGF-β1 were studied using immunofluorescence assay, Western blot, and quantitative real-time PCR techniques, respectively. Our results showed that MSCs reversed the overexpression of fibrosis markers and TGF-β1/Smad signaling pathway proteins and mRNAs after TGF-β1 treatment and increased the level of miR-130a-3p. TGF-βRII was identified as a target of miR-130a-3p and was evaluated by dual-luciferase reporter assay. The miR-130a-3p/TGF-βRII axis could suppress the differentiation of lung fibroblasts via the TGF-β1/Smad signaling pathway, thereby reducing the process of PF.

scholarly journals Human trophoblast-derived exosomes attenuate doxorubicin-induced cardiac injury by regulating miR-200b and downstream Zeb1

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Jie Ni ◽  
Yihai Liu ◽  
Lina Kang ◽  
Lian Wang ◽  
Zhonglin Han ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Reporter ◽  
Human Trophoblast ◽  
Trophoblast Stem

AbstractHuman trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell-derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox)-induced injury remains unclear. In the present study, TSC-Exos were isolated from the supernatants of human trophoblasts using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. In vitro, primary cardiomyocytes were subjected to Dox and treated with TSC-Exos, miR-200b mimic or miR-200b inhibitor. Cellular apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then, different groups of mice were administered either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exos via tail vein injection. Then, the cardiac function, cardiac fibrosis and cardiomyocyte apoptosis in each group were evaluated, and the downstream molecular mechanism was explored. TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocyte apoptosis. Similarly, mice receiving TSC-Exos and AAV-miR-200b inhibitor exhibited improved cardiac function, accompanied by reduced apoptosis and inflammation. The bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b and had an antiapoptotic effect. TSC-Exos attenuated doxorubicin-induced cardiac injury by playing antiapoptotic and anti-inflammatory roles. The underlying mechanism could be an increase in Zeb1 expression by the inhibition of miR-200b expression. In summary, this study sheds new light on the application of TSC-Exos as a potential therapeutic tool for heart failure.

scholarly journals Ursolic Acid Attenuates TGF-β1-Induced Epithelial‐Mesenchymal Transition in NSCLC by Targeting Integrin αVβ5/MMPs Signaling

2019 ◽  
Vol 27 (5) ◽  
pp. 593-600 ◽  
Author(s):  
Jun Shan Ruan ◽  
Huan Zhou ◽  
Lin Yang ◽  
Ling Wang ◽  
Zong Sheng Jiang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ursolic Acid ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Nsclc Cell Line ◽  
Mesenchymal Transition ◽  
New Findings ◽  
Underlying Mechanisms ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced epithelial‐mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC) may contribute to tumor metastasis. TGF-β1-induced EMT in H1975 cells (a human NSCLC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-β1‐integrin signaling pathway. Ursolic acid has been previously reported to inhibit tumor growth and metastasis in several cancers. However, whether ursolic acid can attenuate TGF-β1-induced EMT in H1975 cells and its underlying mechanisms remain unknown. In this study, ursolic acid significantly attenuated the TGF-β1-induced decrease in E-cadherin level and elevated the level of N-cadherin. Furthermore, ursolic acid inhibited the mesenchymal-like responses in H1975 cells, including cell migration, invasion, and activity of matrix metallopeptidase (MMP)-2 and -9. Finally, our new findings provided evidence that ursolic acid could inhibit EMT in NSCLC through TGF-β1 signaling pathway-mediated integrin αVβ5 expression, and this might be the potential mechanism of resveratrol on the inhibition of invasion and metastases in NSCLC. We conclude that ursolic acid attenuated TGF-β1-induced EMT in H1975 cells and thus might be a promising therapeutic agent for treating NSCLC.

scholarly journals Transforming growth factor-β1 impairs CFTR-mediated anion secretion across cultured porcine vas deferens epithelial monolayer via the p38 MAPK pathway

2013 ◽  
Vol 305 (8) ◽  
pp. C867-C876 ◽  
Author(s):  
Sheng Yi ◽  
Fernando Pierucci-Alves ◽  
Bruce D. Schultz
Keyword(s):  
Cystic Fibrosis ◽  
Growth Factor ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Vas Deferens ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Anion Secretion ◽  
Tgf Β1

The goal of this study was to determine whether transforming growth factor-β1 (TGF-β1) affects epithelial cells lining the vas deferens, an organ that is universally affected in cystic fibrosis male patients. In PVD9902 cells, which are derived from porcine vas deferens epithelium, TGF-β1 exposure significantly reduced short-circuit current ( Isc) stimulated by forskolin or a cell membrane-permeant cAMP analog, 8-pCPT-cAMP, suggesting that TGF-β1 affects targets of the cAMP signaling pathway. Electrophysiological results indicated that TGF-β1 reduces the magnitude of current inhibited by cystic fibrosis transmembrane conductance regulator (CFTR) channel blockers. Real-time RT-PCR revealed that TGF-β1 downregulates the abundance of mRNA coding for CFTR, while biotinylation and Western blot showed that TGF-β1 reduces both total CFTR and apical cell surface CFTR abundance. These results suggest that TGF-β1 causes a reduction in CFTR expression, which limits CFTR-mediated anion secretion. TGF-β1-associated attenuation of anion secretion was abrogated by SB431542, a TGF-β1 receptor I inhibitor. Signaling pathway studies showed that the effect of TGF-β1 on Isc was reduced by SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK). TGF-β1 exposure also increased the amount of phospho-p38 MAPK substantially. In addition, anisomycin, a p38 MAPK activator, mimicked the effect of TGF-β1, which further suggests that TGF-β1 affects PVD9902 cells through a p38 MAPK pathway. These observations suggest that TGF-β1, via TGF-β1 receptor I and p38 MAPK signaling, reduces CFTR expression to impair CFTR-mediated anion secretion, which would likely compound the effects associated with mild CFTR mutations and ultimately would compromise male fertility.

Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model

2011 ◽  
Vol 300 (5) ◽  
pp. H1814-H1821 ◽  
Author(s):  
Kazuhisa Kitamura ◽  
Rei Shibata ◽  
Yukiomi Tsuji ◽  
Masayuki Shimano ◽  
Yasuya Inden ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Eicosapentaenoic Acid ◽  
Transforming Growth Factor ◽  
Rabbit Model ◽  
Transforming Growth Factor Β1 ◽  
Atrial Remodeling ◽  
Atrial Fibrosis ◽  
Erk Phosphorylation ◽  
Tgf Β1

Atrial fibrillation (AF) is associated with morbidity and mortality of heart failure. Eicosapentaenoic acid (EPA), which is contained in fish oil, was shown to reduce the risk of cardiovascular diseases. We investigated the effects of EPA on AF associated with heart failure in a rabbit model. Rabbits were subjected to ventricular tachypacing (VTP) for 4 wk with or without EPA treatment. Continuous VTP induced heart failure status in these rabbits. The duration of AF (DAF) induced by burst pacing was analyzed by electrophysiological studies. VTP resulted in increased DAF following burst pacing. EPA treatment attenuated increased DAF. Atrial fibrosis increased in response to VTP, accompanied by extracellular signal-regulated kinase (ERK) phosphorylation and transforming growth factor-β1 (TGF-β1) expression in the atrium. Treatment with EPA attenuated atrial fibrosis, ERK phosphorylation, and TGF-β1 expression in response to VTP. EPA treatment increased adiponectin as an anti-inflammatory adipokine and decreased tumor necrosis factor-α as a proinflammatory adipokine in the atrium and epicardial adipose tissues. EPA attenuated VTP-induced AF promotion and atrial remodeling, which was accompanied by modulating the profiles of adipokine production from epicardial adipose tissue. EPA may be useful for prevention and treatment of AF associated with heart failure.

Activation of Transforming Growth Factor β1 (TGF-β1) Released by Platelets Is Enhanced by Shear and Occurs in Platelet-Rich Thrombi In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3632-3632
Author(s):  
Jasimuddin Ahamed ◽  
Nathalie Burg ◽  
Christin Janczak ◽  
Jihong Li ◽  
Barry S. Coller
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Thrombus Formation ◽  
Transforming Growth Factor Β1 ◽  
Sharp Contrast ◽  
Luciferase Reporter ◽  
Plasminogen Activator Inhibitor 1 ◽  
Total N ◽  
Tgf Β1

Abstract Platelets contain 40–100 times as much transforming growth factor β1 (TGF-β1) as other cells, and release it as an inactive (latent) complex. Although several TGF-β1 activating factors have been identified in various cell types, it is still not known whether and how platelet TGF-β1 becomes activated in vivo. In the present study, cell-free human washed platelet releasates (supernatant after stimulation with thrombin 0.125U/ml for 5 min) or serum samples were subjected to either stirring (1,200 rpm) in an aggregometer or a shear stress of 1800 s−1 in a cone and plate device at 37°C. Activation of TGF-β1 was analyzed by ELISA and selectively confirmed using a cell-based plasminogen activator inhibitor 1 (PAI-1) luciferase reporter assay. TGF-β1 was maximally released within 5 min after stimulation of platelets with thrombin (80 ± 23 ng/ml; n=3), but only 0.2% was active. TGF-β1 activity increased slowly and progressively under shear, reaching a maximum of ∼5% of total TGF-β1 (4.1 ± 1.5 ng/ml) after 1 h. In sharp contrast, in two experiments conducted without shear, active TGF-β1 constituted 0.04 and 0.2% of total at 0 time and remained nearly the same (0.1 and 0.2% of total) after 2 h. Activation of TGF-β1 in serum under shear occurred more slowly, but also reached a maximum of ∼5% of total at 2 h (4.1 ± 1.3 ng/ml active; 76 ± 14 ng/ml total; n=6). Without shear at 0 time, active TGF-β1 constituted 0.02 and 0.06% of total and at 2 h it was still only 0.05 and 0.07% of total. To asses whether TGF-β1 becomes activated in vivo during thrombosis, we induced thrombi in the carotid arteries of C57/BL mice with ferric chloride (8%) for 3 min and then removed the platelet-rich thrombi that formed after 5 or 120 min. The arteries were excised (∼4 mm) and the thrombi were removed and dispersed in buffer (200 μl) on ice for 1 h. Total TGF-β1 recovered from 5 min thrombi was 3.4 and 4.8 ng/ml and total TGF-β1 recovered from 120 min thrombi was 3.7 and 0.7 ng/ml. Active TGF-β1 could be detected in thrombi after 5 min and constituted 1.7 ± 1.1% of the total TGF-β1 recovered (n=3). After 120 min, active TGF-β1 could also be detected in thrombi and it constituted 5.1 ± 3.0% of the total recovered (p=0.14 compared to 5 min value; n=3). In sharp contrast, only 0.05% of TGF-β1 released by thrombin from mouse platelets in vitro was active without stirring or shear (n=3). These data indicate that shear can dramatically enhance TGF-β1 activation after release from platelets. Moreover, TGF-β1 activation occurs in vivo during platelet-rich thrombus formation and thus platelets may be an important source of active TGF-β1 in cardiovascular disease and wound healing.

scholarly journals Poricoic acid A as a modulator of TPH-1 expression inhibits renal fibrosis via modulating protein stability of β-catenin and β-catenin-mediated transcription

2020 ◽  
Vol 11 ◽  
pp. 204062232096264
Author(s):  
Dan-Qian Chen ◽  
Xia-Qing Wu ◽  
Lin Chen ◽  
He-He Hu ◽  
Yan-Ni Wang ◽  
...  
Keyword(s):  
Protein Stability ◽  
Signaling Pathway ◽  
Renal Fibrosis ◽  
Cell Injury ◽  
Tryptophan Hydroxylase ◽  
Transforming Growth Factor ◽  
Lentiviral Vector ◽  
Luciferase Reporter ◽  
Key Enzyme ◽  
Tgf Β1

Background: Renal fibrosis is the common feature of chronic kidney disease (CKD). However, few drugs specifically target fibrogenesis due to the lack of an effective therapeutic target. Hence, it is urgent to find a therapeutic strategy that inhibits renal fibrosis. Here, we identified that poricoic acid A (PAA) as the modulator of tryptophan hydroxylase-1 (TPH-1), the key enzyme in tryptophan metabolism, exerted potent anti-fibrotic effects in the kidney. Methods: Lentiviral vector, luciferase reporter activity assay and co-immunoprecipitation were used. The animal model of unilateral ureteral obstruction and adenine-induced chronic renal failure as well as transforming growth factor (TGF)-β1-treated epithelial cells NRK-52E and fibroblasts NRK-49F were used. Results: TPH-1 was gradually decreased during CKD progression, while PAA treatment significantly increased TPH-1 expression to suppress renal fibrosis. Pharmacological overexpression of TPH-1 by PAA treatment exhibited anti-fibrosis and was linked to Wnt/β-catenin signaling activity. TPH-1 exhibited anti-fibrotic effects by suppressing epithelial cell injury and fibroblast activation, and PAA promoted TPH-1 expression and then suppressed the Wnt/β-catenin signaling pathway via regulating the protein stability of β-catenin and β-catenin-mediated transcription. TPH-1 overexpression enhanced the anti-fibrotic effects of PAA, while TPH-1 deficiency weakened the anti-fibrotic effects of PAA, indicating that TPH-1 was required for the anti-fibrotic effects of PAA. Conclusion: PAA as a modulator of TPH-1 expression attenuated renal fibrosis through regulating the Wnt/β-catenin signaling pathway by acting on the protein stability of β-catenin and β-catenin-mediated transcription. TPH-1 was required for PAA to exert anti-fibrosis.

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