scholarly journals The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

2021 ◽  
Vol 22 (4) ◽  
pp. 1861
Author(s):  
Jemima Seidenberg ◽  
Mara Stellato ◽  
Amela Hukara ◽  
Burkhard Ludewig ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Beclin 1 ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

scholarly journals Age-Dependent Expression of Collagen Receptors and Deformation of Type I Collagen Substrates by Rat Cardiac Fibroblasts

2011 ◽  
Vol 17 (4) ◽  
pp. 555-562 ◽  
Author(s):  
Christopher G. Wilson ◽  
John W. Stone ◽  
Vennece Fowlkes ◽  
Mary O. Morales ◽  
Catherine J. Murphy ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Type I ◽  
Β1 Integrin ◽  
Alpha Smooth Muscle Actin ◽  
Collagen Receptors ◽  
Age Dependent ◽  
Adult Cells

AbstractLittle is known about how age influences the ways in which cardiac fibroblasts interact with the extracellular matrix. We investigated the deformation of collagen substrates by neonatal and adult rat cardiac fibroblasts in monolayer and three-dimensional (3D) cultures, and quantified the expression of three collagen receptors [discoidin domain receptor (DDR)1, DDR2, and β1 integrin] and the contractile protein alpha smooth muscle actin (α-SMA) in these cells. We report that adult fibroblasts contracted 3D collagen substrates significantly less than their neonate counterparts, whereas no differences were observed in monolayer cultures. Adult cells had lower expression of β1 integrin and α-SMA than neonate cultures, and we detected significant correlations between the expression of α-SMA and each of the collagen receptors in neonate cells but not in adult cells. Consistent with recent work demonstrating age-dependent interactions with myocytes, our results indicate that interactions between cardiac fibroblasts and the extracellular matrix change with age.

Cryptolepine derivative-6h inhibits liver fibrosis in TGF-β1-induced HSC-T6 cells by targeting the Shh pathway

2016 ◽  
Vol 94 (9) ◽  
pp. 987-995 ◽  
Author(s):  
Ying-Hua He ◽  
Zeng Li ◽  
Ming-Ming Ni ◽  
Xing-Yan Zhang ◽  
Ming-Fang Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Type I ◽  
African Countries ◽  
Shh Pathway ◽  
Tgf Β1

Liver fibrosis is a worldwide problem with a significant morbidity and mortality. Cryptolepis sanguinolenta (family Periplocaceae) is widely used in West African countries for the treatment of malaria, as well as for some other diseases. However, the role of C. sanguinolenta in hepatic fibrosis is still unknown. It has been reported that Methyl-CpG binding protein 2 (MeCP2) had a high expression in liver fibrosis and played a central role in its pathobiology. Interestingly, we found that a cryptolepine derivative (HZ-6h) could inhibit liver fibrosis by reducing MeCP2 expression, as evidenced by the dramatic downregulation of α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) in protein levels in vitro. Meanwhile, we also found that HZ-6h could reduce the cell viability and promote apoptosis of hepatic stellate cells (HSCs) treated with transforming growth factor beta 1(TGF-β1). Then, we investigated the potential molecular mechanisms and found that HZ-6h blocked Shh signaling in HSC-T6 cells, resulting in the decreased protein expression of Patched-1 (PTCH-1), Sonic hedgehog (Shh), and glioma-associated oncogene homolog 1 (GLI1). In short, these results indicate that HZ-6h inhibits liver fibrosis by downregulating MeCP2 through the Shh pathway in TGF-β1-induced HSC-T6 cells.

scholarly journals Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Hui Dai ◽  
Liang Chen ◽  
Dongyue Gao ◽  
Aihua Fei
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Cardiomyocyte Apoptosis ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Type I ◽  
Alpha Smooth Muscle Actin

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-β1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.

scholarly journals Haploinsufficient Rock1+/− and Rock2+/− Mice Are Not Protected from Cardiac Inflammation and Postinflammatory Fibrosis in Experimental Autoimmune Myocarditis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 700
Author(s):  
Karolina Tkacz ◽  
Filip Rolski ◽  
Marcin Czepiel ◽  
Edyta Działo ◽  
Maciej Siedlar ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Type I ◽  
Wild Type ◽  
Autoimmune Myocarditis ◽  
Inflammatory Monocytes ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Progressive cardiac fibrosis is a common cause of heart failure. Rho-associated, coiled-coil-containing protein kinases (ROCKs) have been shown to enhance fibrotic processes in the heart and in other organs. In this study, using wild-type, Rock1+/− and Rock2+/− haploinsufficient mice and mouse model of experimental autoimmune myocarditis (EAM) we addressed the role of ROCK1 and ROCK2 in development of myocarditis and postinflammatory fibrosis. We found that myocarditis severity was comparable in wild-type, Rock1+/− and Rock2+/− mice at day 21 of EAM. During the acute stage of the disease, hearts of Rock1+/− mice showed unaffected numbers of CD11b+CD36+ macrophages, CD11b+CD36–Ly6GhiLy6chi neutrophils, CD11b+CD36–Ly6G–Ly6chi inflammatory monocytes, CD11b+CD36–Ly6G–Ly6c– monocytes, CD11b+SiglecF+ eosinophils, CD11b+CD11c+ inflammatory dendritic cells and type I collagen-producing fibroblasts. Isolated Rock1+/− cardiac fibroblasts treated with transforming growth factor-beta (TGF-β) showed attenuated Smad2 and extracellular signal-regulated kinase (Erk) phosphorylations that were associated with impaired upregulation of smooth muscle actin alpha (αSMA) protein. In contrast to cardiac fibroblasts, expanded Rock1+/− heart inflammatory myeloid cells showed unaffected Smad2 activation but enhanced Erk phosphorylation following TGF-β treatment. Rock1+/− inflammatory cells responded to TGF-β by a reduced transcriptional profibrotic response and failed to upregulate αSMA and fibronectin at the protein levels. Unexpectedly, in the EAM model wild-type, Rock1+/− and Rock2+/− mice developed a similar extent of cardiac fibrosis at day 40. In addition, hearts of the wild-type and Rock1+/− mice showed comparable levels of cardiac vimentin, periostin and αSMA. In conclusion, despite the fact that ROCK1 regulates TGF-β-dependent profibrotic response, neither ROCK1 nor ROCK2 is critically involved in the development of postinflammatory fibrosis in the EAM model.

scholarly journals Eruberin A, a Natural Flavanol Glycoside, Exerts Anti-Fibrotic Action on Pancreatic Stellate Cells

2015 ◽  
Vol 36 (6) ◽  
pp. 2433-2446 ◽  
Author(s):  
Siu Wai Tsang ◽  
Hong-Jie Zhang ◽  
Ye-Gao Chen ◽  
Kathy Ka-Wai Auyeung ◽  
Zhao-Xiang Bian
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Type I ◽  
Alpha Smooth Muscle Actin ◽  
Expression Levels

Background: Eruberin A (2, 3-dehydroflavonoid), a flavanol glycoside isolated from Pronephrium penangianum, has been used as a blood-nourishing folk medicine for centuries; however, it indeed possesses a variety of other health-promoting benefits including anti-fibrotic bioactivity. Activation of pancreatic stellate cells (PSCs) is the key initiating step in pancreatic fibrosis, which is a characteristic feature associated with chronic pancreatitis and pancreatic adenocarcinoma. Methods: The anti-fibrotic effect of eruberin A and the underlying mechanisms of its anti-fibrotic action in LTC-14 cells, which retained essential characteristics and morphological features of primary PSCs, were examined by means of real-time polymerase chain reactions, Western blotting and immunostaining. Results: The application of eruberin A (20 µg/ml) effectively inhibited the expression levels of fibrotic mediators namely alpha-smooth muscle actin, fibronectin and type I-collagen, so as the sonic hedgehog signaling pathway components post transforming growth factor-beta (5 ng/ml) stimulation. Eruberin A treatment also led to a notable decrease in the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT). Conclusion: Our results demonstrated that eruberin A significantly suppressed the expression levels of fibrotic mediators in PSCs, and we suggest that its anti-fibrotic mechanism was associated with an attenuation of the PI3K/AKT/NF-κB signaling pathway.

scholarly journals Modulation of EndMT by Hydrogen Sulfide in the Prevention of Cardiovascular Fibrosis

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 910
Author(s):  
Lara Testai ◽  
Vincenzo Brancaleone ◽  
Lorenzo Flori ◽  
Rosangela Montanaro ◽  
Vincenzo Calderone
Keyword(s):  
Hydrogen Sulfide ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Type I ◽  
Vascular Endothelial ◽  
Independent Manner ◽  
Mesenchymal Transition ◽  
Adult Age ◽  
Cardiovascular Fibrosis

Endothelial mesenchymal transition (EndMT) has been described as a fundamental process during embryogenesis; however, it can occur also in adult age, underlying pathological events, including fibrosis. Indeed, during EndMT, the endothelial cells lose their specific markers, such as vascular endothelial cadherin (VE-cadherin), and acquire a mesenchymal phenotype, expressing specific products, such as α-smooth muscle actin (α-SMA) and type I collagen; moreover, the integrity of the endothelium is disrupted, and cells show a migratory, invasive and proliferative phenotype. Several stimuli can trigger this transition, but transforming growth factor (TGF-β1) is considered the most relevant. EndMT can proceed in a canonical smad-dependent or non-canonical smad-independent manner and ultimately regulate gene expression of pro-fibrotic machinery. These events lead to endothelial dysfunction and atherosclerosis at the vascular level as well as myocardial hypertrophy and fibrosis. Indeed, EndMT is the mechanism which promotes the progression of cardiovascular disorders following hypertension, diabetes, heart failure and also ageing. In this scenario, hydrogen sulfide (H2S) has been widely described for its preventive properties, but its role in EndMT is poorly investigated. This review is focused on the evaluation of the putative role of H2S in the EndMT process.

scholarly journals Targeting lncRNA H19/miR-29b/COL1A1 Axis Impedes Myofibroblast Activities of Precancerous Oral Submucous Fibrosis

2021 ◽  
Vol 22 (4) ◽  
pp. 2216
Author(s):  
Cheng-Chia Yu ◽  
Yi-Wen Liao ◽  
Pei-Ling Hsieh ◽  
Yu-Chao Chang
Keyword(s):  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Oral Submucous Fibrosis ◽  
Ectopic Expression ◽  
Collagen Gel ◽  
Type I ◽  
Migration Ability ◽  
Potentially Malignant ◽  
Submucous Fibrosis

Oral submucous fibrosis (OSF) is known as a potentially malignant disorder, which may result from chemical irritation due to areca nuts (such as arecoline). Emerging evidence suggests that fibrogenesis and carcinogenesis are regulated by the interaction of long noncoding RNAs (lncRNAs) and microRNAs. Among these regulators, profibrotic lncRNA H19 has been found to be overexpressed in several fibrosis diseases. Here, we examined the expression of H19 in OSF specimens and its functional role in fibrotic buccal mucosal fibroblasts (fBMFs). Our results indicate that the aberrantly overexpressed H19 contributed to higher myofibroblast activities, such as collagen gel contractility and migration ability. We also demonstrated that H19 interacted with miR-29b, which suppressed the direct binding of miR-29b to the 3′-untranslated region of type I collagen (COL1A1). We showed that ectopic expression of miR-29b ameliorated various myofibroblast phenotypes and the expression of α-smooth muscle actin (α-SMA), COL1A1, and fibronectin (FN1) in fBMFs. In OSF tissues, we found that the expression of miR-29b was downregulated and there was a negative correlation between miR-29b and these fibrosis markers. Lastly, we demonstrate that arecoline stimulated the upregulation of H19 through the transforming growth factor (TGF)-β pathway. Altogether, this study suggests that increased TGF-β secretion following areca nut chewing may induce the upregulation of H19, which serves as a natural sponge for miR-29b and impedes its antifibrotic effects.

scholarly journals mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nozomi Igarashi ◽  
Megumi Honjo ◽  
Makoto Aihara
Keyword(s):  
Trabecular Meshwork ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mtor Inhibitors ◽  
In Vivo Model ◽  
Type I ◽  
Fibrotic Response ◽  
Alpha Smooth Muscle Actin

AbstractWe examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.

Abstract 292: TRPA1 Promoting Myofibroblast Differentiation Mediate Pressure Overload-Induced Cardiac Fibrosis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Shuang Li ◽  
Dong Han ◽  
Dachun Yang
Keyword(s):  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Gene Transfection ◽  
Pressure Overload

Background: Hypertensive ventricular remodeling is a common cause of heart failure. Activation and accumulation of cardiac fibroblasts is the key contributors to this progression. Our previous studies indicate that transient receptor potential ankyrin 1 (TRPA1), a Ca 2+ channel necessary and sufficient, play a prominent role in ventricular remodeling. However, the molecular mechanisms regulating remain poorly understood. Methods: We used TRPA1 agonists cinnamaldehyde (CA) pretreatment and TRPA1 knockout mice to understand the role of TRPA1 in ventricular remodeling of hypertensive heart. We also examine the mechanisms through gene transfection and in vitro experiments. Results: TRPA1 overexpression fully activated myofibroblast transformation, while fibroblasts lacking TRPA1 were refractory to transforming growth factor β (TGF-β) -induced transdifferentiation. TRPA1 knockout mice showed hypertensive ventricular remodeling reversal following pressure overload. We found that the TGF-β induced TRPA1 expression through calcineurin-NFAT-Dyrk1A signaling pathway via the TRPA1 promoter. Once induced, TRPA1 activates the Ca 2+ -responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPA1-dependent transdifferentiation. Conclusion: Our study provides the first evidence that TRPA1 regulation in cardiac fibroblasts transformation in response to hypertensive stimulation. The results suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-β, Calcineurin, NFAT and Dyrk1A. Furthermore, these data indicate that negative modulation of cardiac fibroblast TRPA1 may represent a therapeutic strategy against hypertensive cardiac remodeling.

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