Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Yan, Zhankui; Shen, Daifei; Liao, Jilin; Zhang, Yanmei; Chen, Yicun; Shi, Guo‐Ming; Gao, Fenfei

doi:10.1159/000486771

Cited by 16 publications

(13 citation statements)

References 37 publications

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“…Interestingly, this inhibitory effect of sI/R on the increase of α-SMA levels induced by TGF-β1 or spontaneous differentiation in CF has not been previously described. A similar effect has been observed in H9c2 cardiomyocytes and in corneal keratocytes, where hypoxia prevented the transformation to myofibroblasts induced by, an effect which was associated with changes in TGF-β1 signaling pathways [49,50]. Further studies are necessary to elucidate the effects of the A/D/N association on signaling pathways implicated in the effects of differentiation of CF to MCF induced by TGF-β1 after sI/R.…”

Section: Discussionsupporting

confidence: 54%

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

Parra-Flores

Riquelme

Valenzuela-Bustamante

et al. 2019

Antioxidants

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Acute myocardial infarction is one of the leading causes of death worldwide and thus, an extensively studied disease. Nonetheless, the effects of ischemia/reperfusion injury elicited by oxidative stress on cardiac fibroblast function associated with tissue repair are not completely understood. Ascorbic acid, deferoxamine, and N-acetylcysteine (A/D/N) are antioxidants with known cardioprotective effects, but the potential beneficial effects of combining these antioxidants in the tissue repair properties of cardiac fibroblasts remain unknown. Thus, the aim of this study was to evaluate whether the pharmacological association of these antioxidants, at low concentrations, could confer protection to cardiac fibroblasts against simulated ischemia/reperfusion injury. To test this, neonatal rat cardiac fibroblasts were subjected to simulated ischemia/reperfusion in the presence or absence of A/D/N treatment added at the beginning of simulated reperfusion. Cell viability was assessed using trypan blue staining, and intracellular reactive oxygen species (ROS) production was assessed using a 2′,7′-dichlorofluorescin diacetate probe. Cell death was measured by flow cytometry using propidium iodide. Cell signaling mechanisms, differentiation into myofibroblasts and pro-collagen I production were determined by Western blot, whereas migration was evaluated using the wound healing assay. Our results show that A/D/N association using a low concentration of each antioxidant increased cardiac fibroblast viability, but that their separate administration did not provide protection. In addition, A/D/N association attenuated oxidative stress triggered by simulated ischemia/reperfusion, induced phosphorylation of pro-survival extracellular-signal-regulated kinases 1/2 (ERK1/2) and PKB (protein kinase B)/Akt, and decreased phosphorylation of the pro-apoptotic proteins p38- mitogen-activated protein kinase (p38-MAPK) and c-Jun-N-terminal kinase (JNK). Moreover, treatment with A/D/N also reduced reperfusion-induced apoptosis, evidenced by a decrease in the sub-G1 population, lower fragmentation of pro-caspases 9 and 3, as well as increased B-cell lymphoma-extra large protein (Bcl-xL)/Bcl-2-associated X protein (Bax) ratio. Furthermore, simulated ischemia/reperfusion abolished serum-induced migration, TGF-β1 (transforming growth factor beta 1)-mediated cardiac fibroblast-to-cardiac myofibroblast differentiation, and angiotensin II-induced pro-collagen I synthesis, but these effects were prevented by treatment with A/D/N. In conclusion, this is the first study where a pharmacological combination of A/D/N, at low concentrations, protected cardiac fibroblast viability and function after simulated ischemia/reperfusion, and thereby represents a novel therapeutic approach for cardioprotection.

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Section: Discussionsupporting

confidence: 54%

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

Parra-Flores

Riquelme

Valenzuela-Bustamante

et al. 2019

Antioxidants

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“…Previous studies have demonstrated that α-SMA is elevated in leiomyoma compared to myometrium [38]. Yan et al also found that the expression of α-SMA was significantly increased at 5 ng/ml TGFβ1 compared with the control in cardiac myocyte H9c2 cells [39]. In addition, fibronectin mRNA expression was higher in leiomyoma than in autologous myometrium, and the increase caused by TGFβ3 was markedly higher than the one caused by TGFβ1 [9].…”

Section: Discussionmentioning

confidence: 92%

Fucoidan Inhibits the Proliferation of Leiomyoma Cells and Decreases Extracellular Matrix-Associated Protein Expression

Chen

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Uterine leiomyomas (ULs) are benign uterine tumors, and the most notable pathophysiologic feature of ULs is excessive accumulation of extracellular matrix (ECM). Fucoidan is a polysaccharide extracted from brown seaweeds that has a wide range of pharmacological properties, including anti-fibrotic effects. We aimed to study the effect of fucoidan on the growth of ULs activated by transforming growth factor beta (TGFβ). Methods: We used ELT-3 (Eker rat leiomyoma tumor-derived cells) and HUtSMC (human uterine smooth muscle cells) as in vitro models. Cell viability was determined by the MTT assay. Cell colony formation was stained using crystal violet. The side population, cell cycle and apoptosis were analyzed using flow cytometry. Protein expression was assayed by western blot analysis. We also conducted in vivo experiments to confirm the inhibitory effects of fucoidan in nude mouse xenograft models. Tumor tissues were assayed by immunohistochemistry analysis. Results: In our study, fucoidan caused a 50% growth inhibition using a dose of 0.5 mg/ml and decreased the stem cell activity after 48 h. In addition, fucoidan induced sub-G1 cell cycle arrest and apoptosis. Fucoidan down-regulated fibronectin, vimentin, α-SMA and the COL1A1 protein levels in TGFβ3-induced ELT-3 cells. In the cellular mechanism, fucoidan abrogated TGFβ3-induced levels of p-Smad2 and p-ERK1/2, as well as β-catenin translocation into the nucleus. Furthermore, fucoidan suppressed xenograft tumor growth in vivo. Conclusion: Fucoidan displays anti-proliferation and anti-fibrotic effects and exerts protective effects against ULs development.

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“…A recent study reported that in TGF-β treated malignant glioma, MTDH protein was increased via Smad2/3 phosphorylation [ 30 ]. In activated TGF-β/Smad signaling pathway, the p-Smad2 and p-Smad3 form oligomeric complexes with Smad4, translocated into the nucleus and regulated genes transcription [ 35 , 36 ]. However, in our study, we demonstrated that TGF-β treatment perform functions on translational regulation of MTDH rather than transcriptional repression.…”

Section: Discussionmentioning

confidence: 99%

miR-145 and miR-497 suppress TGF-β-induced epithelial–mesenchymal transition of non-small cell lung cancer by targeting MTDH

et al. 2018

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BackgroundMicroRNAs (miRNAs) have been reported to play crucial roles in multiple cancers including non-small cell lung cancer (NSCLC). Here, we investigated the role of miR-145 and miR-497 in TGF-β-induced epithelial–mesenchymal transition (EMT) process of NSCLC.MethodsWe performed quantitative real time PCR (qRT-PCR) to detect the expression level of miR-145 and miR-497 in NSCLC cell lines. Then in the presence/absence of TGF-β, we transfected miRNA mimics or inhibitor into A549 and H1299 cells and investigated the role of miR-145 and miR-497 in cell migration and invasion using transwell and wound-healing assay. The regulation role of miR-145 and miR-497 on Metadherin (MTDH) was determined by luciferase assay. The expression level of MTDH and EMT markers E-cadherin and vimentin were detected on mRNA and protein level.ResultsIn our study, our results showed that miR-145 and miR-497 were downregulated in NSCLC cell lines. Overexpression of miR-145 and miR-497 inhibited TGF-β-induced EMT and suppressed cancer cell migration and invasion, while the opposite results were observed in cells transfected with miR-145 or miR-497 inhibitor. Moreover, the luciferase assay confirmed that miR-145 and miR-497 attenuated MTDH expression by directly binding 3′-UTR of MTDH mRNA and exert the tumor-suppression role.ConclusionsOverall, we demonstrated that miR-145 and miR-497 functioned as EMT-suppressor in NSCLC by targeting MTDH, provided new evidence that miR-145 and miR-497 as potential therapeutic targets.

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Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Cited by 16 publications

References 37 publications

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

Fucoidan Inhibits the Proliferation of Leiomyoma Cells and Decreases Extracellular Matrix-Associated Protein Expression

miR-145 and miR-497 suppress TGF-β-induced epithelial–mesenchymal transition of non-small cell lung cancer by targeting MTDH

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