scholarly journals miR-15a-5p regulates myocardial fibrosis in atrial fibrillation by targeting Smad7

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12686
Author(s):  
Dan He ◽  
Zhong-bao Ruan ◽  
Gui-xian Song ◽  
Ge-cai Chen ◽  
Fei Wang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Myocardial Fibrosis ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Transforming Growth Factor Β1 ◽  
Collagen I ◽  
Cell Counting ◽  
H9c2 Cell ◽  
Expression Levels ◽  
Tgf Β1

Background At present, there is no effective treatment for myocardial fibrosis in atrial fibrillation (AF). It is reported that miR-15a-5p is abnormally expressed in AF patients but its specific role remains unclear. This study aims to investigate the effect of miR-15a-5p in myocardial fibrosis. Methods Left atrial appendage (LAA) tissues were collected from AF and non-AF patients. In lipopolysaccharide (LPS) stimulated H9C2 cells, miR-15a-5p mimic, inhibitor, pcDNA3.1-Smad7 and small interfering RNA-Smad7 (siRNA-Smad7) were respectively transfected to up-regulate or down-regulate the intracellular expression levels of miR-15a-5p and Smad7. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) were used to determine the expression levels of miR-15a-5p, Smad7, transforming growth factor β1 (TGF-β1) and collagen I. Cell counting kit-8 (CCK-8) and ethylene deoxyuridine (EdU) were used to determine cell viability and proliferation capacity, respectively. Dual-luciferase was used to detect whether miR-15a-5p interacted with Smad7, hydroxyproline (HYP) and Hematoxylin-Eosin (HE) staining were used to detect tissue fibrosis. Results The expression levels of miR-15a-5p, TGF-β1 and collagen I were up-regulated, while Smad7 was down-regulated in AF tissues and LPS-stimulated cells. MiR-15a-5p mimic can inhibit the expression of Smad7, and the dual-luciferase experiment confirmed their interaction. MiR-15a-5p inhibitor or pcDNA3.1-Smad7 can inhibit LPS-induced fibrosis and cell proliferation, while siRNA-Smad7 can reverse the changes caused by miR-15a-5p inhibitor. Conclusion We combined clinical studies with LPS-stimulated H9C2 cell model to validate the role of miR-15a-5p in the regulation of Smad7 and fibrosis. Taken together, the miR-15a-5p/Smad7 pathway might be a potential target for AF therapy.

scholarly journals A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation

2021 ◽  
Vol 10 (19) ◽  
pp. 4430
Author(s):  
Grażyna Sygitowicz ◽  
Agata Maciejak-Jastrzębska ◽  
Dariusz Sitkiewicz
Keyword(s):  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Signalling Pathways ◽  
Ang Ii ◽  
Atrial Fibrosis ◽  
Genes Encoding ◽  
Tgf Β1

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

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.

scholarly journals Tumor-Suppressing STF cDNA 3 Overexpression Suppresses Renal Fibrosis by Alleviating Anoikis Resistance and Inhibiting the PI3K/Akt Pathway

2021 ◽  
pp. 1-13
Author(s):  
Fei Xiao ◽  
Xinghong Liu ◽  
Yan Chen ◽  
Huanzi Dai
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Cell Model ◽  
Cell Counting ◽  
Akt Pathway ◽  
Renal Interstitial Fibrosis ◽  
Anoikis Resistance ◽  
Matrigel Invasion ◽  
Tgf Β1

<b><i>Background:</i></b> Myofibroblast (MF) activation is the key event of irreversible renal interstitial fibrosis. Anoikis resistance is the hallmark of active MFs, which is conferred by continuous activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway. Our previous study found that tumor-suppressing STF cDNA 3 (TSSC3) enhances the sensitivity of cells to anoikis via the PI3K/Akt pathway. Therefore, we hypothesized that TSSC3 might suppress renal interstitial fibrosis by inducing anoikis via the PI3K/Akt pathway. <b><i>Methods:</i></b> Cell anoikis was induced by the exogenous addition of RGD-containing peptides or by culturing cells in suspension. MFs were established by stimulating HK-2 renal tubular epithelial cells with transforming growth factor beta 1 (TGF-β1). Lentivirus vectors were to construct a TSSC3 overexpression cell model. The effects of TSSC3 on the anoikis, growth, migration, invasion, and contraction of MFs were determined using annexin V-fluorescein isothiocyanate assays, cell counting kit-8 assays, wound healing migration assays, matrigel invasion assays, and collagen-based contraction assays. <b><i>Results:</i></b> The results demonstrated that TGF-β1, simultaneous with the induction of MF differentiation, confers significant protection against anoikis-induced cell death, which could be partly reversed by treatment with the PI3K/Akt pathway inhibitor, LY294002. Moreover, overexpression of TSSC3 obviously impaired cell growth, cell migration, cell invasion, contraction, and anoikis resistance of MFs, and decreased the activity of the PI3K/Akt pathway and the production of extracellular matrix molecules, all of which could be attenuated by treatment with the PI3K/Akt pathway activator, 740Y-P. Taken together, this study suggested that TSSC3 attenuates the anoikis resistance and profibrogenic ability of TGF-β1-induced MF by regulating the PI3K-Akt pathway. <b><i>Conclusion:</i></b> These findings provide a biological basis for further exploration of the therapeutic significance of targeting MF via TSSC3 in renal interstitial fibrosis.

scholarly journals Platelets Promote Ang II (Angiotensin II)-Induced Atrial Fibrillation by Releasing TGF-β1 (Transforming Growth Factor-β1) and Interacting With Fibroblasts

Hypertension ◽  
2020 ◽  
Vol 76 (6) ◽  
pp. 1856-1867
Author(s):  
Yang Liu ◽  
Haichen Lv ◽  
Ruopeng Tan ◽  
Xiangbo An ◽  
Xiao-Hui Niu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Platelet Activation ◽  
Transforming Growth Factor ◽  
Platelet Inhibition ◽  
Transforming Growth Factor Β1 ◽  
Ang Ii ◽  
Atrial Fibrosis ◽  
Electrical Transmission ◽  
Platelet Accumulation ◽  
Tgf Β1

Hypertension is a risk factor of atrial fibrillation (AF), and a certain number of patients with hypertension were found with an enlarged left atrium. Platelet activation is found in patients with hypertension or pressure overload/Ang II (angiotensin II)-induced hypertensive animal models and contribute to ventricular fibrosis. Whether hypertension-induced atrial fibrosis is mediated by platelets remains unknown. Our previous experimental data showed that platelet-derived TGF-β1 (transforming growth factor-β1) was reduced in patients with hypertensive AF. The present study is to investigate whether platelet-derived TGF-β1 promotes Ang II-induced atrial fibrosis and AF. Platelet activation and atrial platelet accumulation were measured in sinus rhythm controls, normotensive AF, and patients with hypertensive AF. Ang II (1500 ng/kg per minute, 3 weeks) infused mice with pharmacological (clopidogrel) and genetic platelet inhibition (TGF-β1 deletion in platelets) were used. Platelet activation, atrial structural remodeling, atrial electrical transmission, AF inducibility, inflammation, and fibrosis were measured in mice. We found that circulating platelets were activated in patients with hypertensive AF. A large amount of platelet was accumulated in the atriums of patients with hypertensive AF. Both clopidogrel treatment and platelet-specific deletion of TGF-β1 attenuated Ang II-induced structural remodeling, atrial electrical transmission, AF inducibility, as well as atrial inflammation and fibrosis than mice without interventions. Furthermore, clopidogrel blocked atrial platelet accumulation and platelet-fibroblast conjugation. Platelets promoted atrial fibroblast differentiation in cell culture. Profibrotic actions of platelets are largely via activation of atrial fibroblasts by releasing TGF-β1 and inducing platelet-fibroblast conjugation, and platelet inhibition is sufficient to inhibit atrial fibrosis and AF inducibility.

Targeted inhibition of β-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-β1

2020 ◽  
Author(s):  
Rujie Huo ◽  
Xinli Tian ◽  
Qin Chang ◽  
Dai Liu ◽  
Chen Wang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Airway Remodeling ◽  
Inhibitory Effect ◽  
Transforming Growth Factor Β1 ◽  
Alveolar Type ◽  
Anti Inflammatory ◽  
Targeted Inhibition ◽  
Tgf Β1

Abstract Background and objective TGF-β1 is a key cytokine involved in airway inflammation and airway remodeling in asthma, owing to its anti-inflammatory and profibrotic effects. In our previous study, we found that the knockdown of cytosolic β-catenin mitigated the profibrogenic effect of TGF-β1 without affecting its anti-inflammatory effect. However, the exact role of targeting β-catenin in asthma is not yet fully demonstrated. In the present study, we investigated the effect and mechanism of targeting β-catenin in OVA-challenged asthmatic rats with airway inflammation and remodeling features. Methods We integrated experimental asthma model and asthma related cell model to explore the effect of targeting β-catenin on airway inflammation and remodeling of asthma. Results Blocking β-catenin with ICG001, a small molecule inhibitor of β-catenin/TCF via binding to CBP, attenuated airway inflammation by increasing the level of the anti-inflammatory cytokines IL-10, IL-35, and reducing the level of proinflammation cytokine IL-17. Suppressing β-catenin with ICG001 has an inhibitory effect on airway remodeling via reducing the level of TGF-β1 and the expression of MMP-7 and Snail, upregulating expression of E-cadherin, downregulating expressions of α-SMA and Fn. Inhibiting β-catenin with ICG001 suppressed TGF-β1-induced proliferation and activation of lung fibroblast (CCC-REPF-1) cells, and blocked TGF-β1-induced, blocked TGF-β1 induced EMT of alveolar type II epithelial (RLE-6TN) cells. Conclusions Blockade of β-catenin/TCF not only prevents TGF-β1 induced EMT and profibrogenic effects involved in pathological remodeling of airway, but also alleviates airway inflammation in asthma by balancing proinflammatory and anti-inflammatory cytokine.

scholarly journals Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

2021 ◽  
Vol 8 ◽  
Author(s):  
Yajun Yao ◽  
Shanqing He ◽  
Youcheng Wang ◽  
Zhen Cao ◽  
Dishiwen Liu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Transforming Growth Factor ◽  
Canine Model ◽  
Transforming Growth Factor Β1 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Atrial Pacing ◽  
Atrial Fibrosis ◽  
Exosome Biogenesis ◽  
Underlying Mechanisms ◽  
Tgf Β1

Background: Clinical studies have shown that exosomes are associated with atrial fibrillation (AF). However, the roles and underlying mechanisms remain unclear. Hence, this study aimed to investigate the function of exosomes in AF development.Methods: Twenty beagles were randomly divided into the sham group (n = 6), the pacing group (n = 7), and the pacing + GW4869 group (n = 7). The pacing and GW4869 groups underwent rapid atrial pacing (450 beats/min) for 7 days. The GW4869 group received intravenous GW4869 injection (an inhibitor of exosome biogenesis/release, 0.3 mg/kg, once a day) during pacing. Electrophysiological measurements, transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT-PCR, Masson's staining, and immunohistochemistry were performed in this study.Results: Rapid atrial pacing increased the release of plasma and atrial exosomes. GW4869 treatment markedly suppressed AF inducibility and reduced the release of exosomes. After 7 days of pacing, the expression of transforming growth factor-β1 (TGF-β1), collagen I/III, and matrix metalloproteinases was enhanced in the atrium, and the levels of microRNA-21-5p (miR-21-5p) were upregulated in both plasma exosomes and the atrium, while the tissue inhibitor of metalloproteinase 3 (TIMP3), a target of miR-21-5p, showed a lower expression in the atrium. The administration of GW4869 abolished these effects.Conclusions: The blockade of exosome release with GW4869 suppressed AF by alleviating atrial fibrosis in a canine model, which was probably related to profibrotic miR-21-5p enriched in exosomes and its downstream TIMP3/TGF-β1 pathway.

scholarly journals Tangshen Formula Improves Diabetes-Associated Myocardial Fibrosis by Inhibiting TGF-β/Smads and Wnt/β-Catenin Pathways

2021 ◽  
Vol 8 ◽  
Author(s):  
Lin Hu ◽  
Yuyang Wang ◽  
Yuzhou Wan ◽  
Liang Ma ◽  
Tingting Zhao ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Myocardial Fibrosis ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Primary Mouse ◽  
Tangshen Formula ◽  
Tgf Β1

Cardiovascular disease has become the main cause of death among complications of diabetes. Myocardial fibrosis is a crucial pathological change of cardiovascular disease. Tangshen Formula (TSF) shows a good clinical effect in the treatment of diabetic kidney disease (DKD). However, whether TSF alleviates diabetes-associated myocardial fibrosis is still unknown. In the present research, we studied the effect and mechanism of TSF in the treatment of myocardial fibrosis in vivo and in vitro. We found that TSF treatment significantly downregulates myocardial fibrosis-related markers, including collagens I and III, and α-SMA. TSF also protects primary mouse cardiac fibroblast (CF) from transforming growth factor-β1- (TGF-β1-) induced damage. Moreover, TSF decreased the expression levels of TGF-β/Smad-related genes (α-SMA, collagens I and III, TGF-β1, and pSmad2/3), and increased Smad7 gene expression. Finally, TSF decreased the expressions of wnt1, active-β-catenin, FN, and MMP7 to regulate the Wnt/β-catenin pathway. Taken together, TSF seems to attenuate myocardial fibrosis in KKAy mice by inhibiting TGF-β/Smad2/3 and Wnt/β-catenin signaling pathways.

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