scholarly journals Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players

2021 ◽  
Vol 7 ◽  
Author(s):  
Somayeh Saadat ◽  
Mahdi Noureddini ◽  
Maryam Mahjoubin-Tehran ◽  
Sina Nazemi ◽  
Layla Shojaie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Type I ◽  
Receptor Complex ◽  
Fibroblast Proliferation ◽  
Smad Signaling ◽  
Ecm Proteins ◽  
Non Coding Rnas ◽  
Β Receptor

Unintended cardiac fibroblast proliferation in many pathophysiological heart conditions, known as cardiac fibrosis, results in pooling of extracellular matrix (ECM) proteins in the heart muscle. Transforming growth factor β (TGF-β) as a pivotal cytokine/growth factor stimulates fibroblasts and hastens ECM production in injured tissues. The TGF-β receptor is a heterodimeric receptor complex on the plasma membrane, made up from TGF-β type I, as well as type II receptors, giving rise to Smad2 and Smad3 transcription factors phosphorylation upon canonical signaling. Phosphorylated Smad2, Smad3, and cytoplasmic Smad4 intercommunicate to transfer the signal to the nucleus, culminating in provoked gene transcription. Additionally, TGF-β receptor complex activation starts up non-canonical signaling that lead to the mitogen-stimulated protein kinase cascade activation, inducing p38, JNK1/2 (c-Jun NH2-terminal kinase 1/2), and ERK1/2 (extracellular signal–regulated kinase 1/2) signaling. TGF-β not only activates fibroblasts and stimulates them to differentiate into myofibroblasts, which produce ECM proteins, but also promotes fibroblast proliferation. Non-coding RNAs (ncRNAs) are important regulators of numerous pathways along with cellular procedures. MicroRNAs and circular long ncRNAs, combined with long ncRNAs, are capable of affecting TGF-β/Smad signaling, leading to cardiac fibrosis. More comprehensive knowledge based on these processes may bring about new diagnostic and therapeutic approaches for different cardiac disorders.

scholarly journals Mechanisms of Transforming Growth Factor-β Receptor Endocytosis and Intracellular Sorting Differ between Fibroblasts and Epithelial Cells

2001 ◽  
Vol 12 (3) ◽  
pp. 675-684 ◽  
Author(s):  
Jules J.E. Doré ◽  
Diying Yao ◽  
Maryanne Edens ◽  
Nandor Garamszegi ◽  
Elizabeth L. Sholl ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Ligand Binding ◽  
Transforming Growth Factor ◽  
Point Mutations ◽  
Type I ◽  
Receptor Complex ◽  
Type Ii ◽  
Down Regulation ◽  
Β Receptor

Transforming growth factor-βs (TGF-β) are multifunctional proteins capable of either stimulating or inhibiting mitosis, depending on the cell type. These diverse cellular responses are caused by stimulating a single receptor complex composed of type I and type II receptors. Using a chimeric receptor model where the granulocyte/monocyte colony-stimulating factor receptor ligand binding domains are fused to the transmembrane and cytoplasmic signaling domains of the TGF-β type I and II receptors, we wished to describe the role(s) of specific amino acid residues in regulating ligand-mediated endocytosis and signaling in fibroblasts and epithelial cells. Specific point mutations were introduced at Y182, T200, and Y249 of the type I receptor and K277 and P525 of the type II receptor. Mutation of either Y182 or Y249, residues within two putative consensus tyrosine-based internalization motifs, had no effect on endocytosis or signaling. This is in contrast to mutation of T200 to valine, which resulted in ablation of signaling in both cell types, while only abolishing receptor down-regulation in fibroblasts. Moreover, in the absence of ligand, both fibroblasts and epithelial cells constitutively internalize and recycle the TGF-β receptor complex back to the plasma membrane. The data indicate fundamental differences between mesenchymal and epithelial cells in endocytic sorting and suggest that ligand binding diverts heteromeric receptors from the default recycling pool to a pathway mediating receptor down-regulation and signaling.

P5001Acute cardiac fibrogenic response triggered by endotrophin, a type VI collagen signalling molecule

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A L Reese-Petersen ◽  
M Karsdal ◽  
F Genovese
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Cardiac Fibroblasts ◽  
Vehicle Control ◽  
Serum Starvation ◽  
Type I ◽  
Type Vi Collagen ◽  
Ecm Proteins

Abstract Background/Aim Accumulation of extracellular matrix (ECM) proteins is the hallmark of cardiac fibrosis, causing stiffening of the ventricular wall, which can lead to heart failure and ultimately death. Many different cell types and growth factors are involved in this process but fibroblasts are the main source of ECM proteins. Here we present results from an in vitro model indicating that endotrophin (ETP), a collagen type VI fragment, activates cardiac fibroblasts and induces fibrogenesis. Methods The effect of ETP, transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF)-DD on ECM protein synthesis was assessed in a scar-in-a-jar (SiaJ) cell model using human cardiac fibroblasts isolated from the atrium of an adult healthy donor. Cells were seeded in 48-well plates at a density of 30.000 cells/well and incubated for 24H in Dulbecco's Modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS). Serum starvation was done by seeding the cells for further 24H in DMEM + 0.4% FBS. Fresh medium was added at day 0 with 37.5/25mg/mL Ficoll 70/400 and 1% ascorbic acid, containing 11.75 nM human recombinant ETP, 0.04 nM TGF-β, 0.39 nM PDGF-DD or a vehicle control. Medium was changed and collected at day 3 and 6. Biomarkers of type I (PRO-C1), III (PRO-C3), VI (PRO-C6) collagens and fibronectin (FBN-C) formation were assessed in the medium by ELISAs developed at Nordic Bioscience. Results ETP induced a significant increase in PRO-C1, PRO-C3 and FBN-C (comparable to TGF-β and PDGF-DD) within the first three days of the experiment, compared to the vehicle control. The levels remained significantly increased for PRO-C3 and FBN-C throughout the experiment, and non-significantly elevated for PRO-C1, compared to the vehicle control. PDGF-DD significantly induced synthesis of type VI collagen compared to the vehicle control, while TGF-β induced a small increase in synthesis from day 0–3, after which it seemed to inhibit synthesis. Conclusion For the first time, a direct pro-fibrotic effect on fibroblasts induced by ETP has been shown. This novel pathway of activation could play an important role in regulating cardiac fibrosis, and thus prove to be a therapeutic target. This SiaJ model in combination with the investigated biomarkers of ECM formation could be used to further elucidate the mechanisms behind cardiac fibrosis.

scholarly journals Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

2007 ◽  
Vol 282 (14) ◽  
pp. 10405-10413 ◽  
Author(s):  
Jaspreet Pannu ◽  
Sashidhar Nakerakanti ◽  
Edwin Smith ◽  
Peter ten Dijke ◽  
Maria Trojanowska
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor

scholarly journals Repression of transforming growth factor-β receptor type I promoter expression by Sp1 deficiency

Oncogene ◽  
2000 ◽  
Vol 19 (40) ◽  
pp. 4660-4667 ◽  
Author(s):  
Sumudra Periyasamy ◽  
Sudhakar Ammanamanchi ◽  
Manoranjani PM Tillekeratne ◽  
Michael G Brattain
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor

scholarly journals Caveolin-1 Regulates Transforming Growth Factor (TGF)-β/SMAD Signaling through an Interaction with the TGF-β Type I Receptor

2000 ◽  
Vol 276 (9) ◽  
pp. 6727-6738 ◽  
Author(s):  
Babak Razani ◽  
Xiao Lan Zhang ◽  
Markus Bitzer ◽  
Gero von Gersdorff ◽  
Erwin P. Böttinger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Type I ◽  
Smad Signaling ◽  
Caveolin 1

scholarly journals MicroRNA-210-5p Alleviates Cardiac Fibrosis via Targeting Transforming Growth Factor-beta Type I Receptor in Rats on High Salt Diet

2021 ◽  
Author(s):  
Kun Zhao ◽  
Yukang Mao ◽  
Xiaoman Ye ◽  
Jiazheng Ma ◽  
Litao Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Collagen I ◽  
Type I ◽  
High Salt Diet ◽  
Salt Diet ◽  
Growth Factor Beta

Abstract Background: The aim of the present study was to explore whether high salt diet (HSD) caused cardiac fibrosis regardless of blood pressure in rats, and to determine the effects of microRNA (miR)-210-5p on sodium chloride (NaCl)-induced fibrosis in neonatal rat cardiac fibroblasts (NRCFs) and its target. Methods: The rats received 8% HSD in vivo, and NRCFs were treated with NaCl in vitro. Results: The levels of collagen I, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) were increased in the heart of hypertension (HTN), hypertension-prone (HP) and hypertension-resistant (HR) rats on HSD. Middle and high doses (50 mM and 100 mM) of NaCl increased the levels of collagen I, α-SMA and TGF-β in NRCFs. The expression level of miR-210-5p was reduced in NaCl-treated NRCFs by miR high-throughput sequencing. The NaCl-induced increases of collagen I, α-SMA and TGF-β were inhibited by miR-210-5p agomiR, and further enhanced by miR-210-5p antagomiR. Bioinformatics analysis and luciferase reporter assays demonstrated that TGF-β type I receptor (TGFβRI) was a direct target gene of miR-210-5p. These results indicated that HSD resulted in cardiac fibrosis regardless of blood pressure. Conclusion: The upregulation of miR-210-5p could attenuate NRCF fibrosis via targeting TGFβRI. Thus, upregulating miR-210-5p to inhibit TGF-β signaling pathway might be a strategy for the treatment of cardiac fibrosis.

Sign in / Sign up

Export Citation Format

Share Document