scholarly journals Roles of TGF-βSignals in Endothelial-Mesenchymal Transition during Cardiac Fibrosis

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Yasuhiro Yoshimatsu ◽  
Tetsuro Watabe
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Therapeutic Strategies ◽  
Cardiac Diseases ◽  
Mesenchymal Transition ◽  
Multiple Origins ◽  
And Function ◽  
Endothelial Mesenchymal Transition

Most cardiac diseases caused by inflammation are associated with fibrosis in the heart. Fibrosis is characterized by the accumulation of fibroblasts and excess deposition of extracellular matrix (ECM), which results in the distorted organ architecture and function. Recent studies revealed that cardiac fibroblasts are heterogeneous with multiple origins. Endothelial-mesenchymal transition (EndMT) plays important roles in the formation of cardiac fibroblasts during pathological settings. EndMT is regulated by signaling pathways mediated by cytokines including transforming growth factor (TGF)-β. Better understanding of the mechanisms of the formation of cardiac fibroblasts via EndMT may provide an opportunity to develop therapeutic strategies to cure heart diseases.

Abstract P153: Role of Nonreceptor Tyrosine Kinases in Cardiac Fibrosis in a Mouse Model of Pressure Overload Hypertrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Sundaravadivel Balasubramanian ◽  
Harinath Kasiganesan ◽  
Lakeya Quinones ◽  
Yuhua Zhang ◽  
Amy Bradshaw ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Pressure Overload ◽  
In Vivo Studies ◽  
Survival Pathways ◽  
And Function ◽  
Nonreceptor Tyrosine Kinases

During prolonged hypertrophic insult to the myocardium, while the function of cardiomyocytes needs to be protected, the hyperactivation of cardiac fibroblasts has to be curbed to prevent fibrosis. Previously, we showed that integrin-mediated non-receptor tyrosine kinase (NRTK) activation is required for normal functioning of both cardiac fibroblasts and cardiomyocytes. We hypothesized that inhibition of NRTKs in cardiac fibroblasts without affecting cardiomyocytes would be beneficial to the stressed myocardium. Our initial studies using kinase inactive forms of Src, Pyk2 and FAK expressed adenovirally in isolated primary cardiac fibroblasts showed that the pro-fibrotic signaling events as studied by fibronectin and collagen deposition are downregulated. Our in vivo studies in mouse transverse aortic constriction (TAC) model suggest that dasatinib, a multikinase NRTK inhibitor administration via a peritoneally implanted mini-osmotic pump is able to preserve ventricular geometry and function and reduce the accumulation of fibrotic extracellular matrix (ECM) proteins upon 4 wk pressure overload. Data obtained from cell culture experiments with kinase inactive NRTKs and dasatinib suggest that NRTK inhibition is able to reduce the proliferation, migration and mitogenic signaling in cardiac fibroblasts without affecting the cell survival pathways in cardiomyocytes. These data indicate that NRTKs play a significant pro-fibrotic role in cardiac fibroblasts and curbing the activity of NRTKs could be a potential therapeutic approach to treat fibrosis in hypertrophic heart diseases.

scholarly journals Myofibroblasts and Fibrosis

2020 ◽  
Vol 127 (3) ◽  
pp. 427-447
Author(s):  
Andrew A. Gibb ◽  
Michael P. Lazaropoulos ◽  
John W. Elrod
Keyword(s):  
Physiological Response ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Functional Decline ◽  
Transforming Growth Factor Β ◽  
Acute Injury ◽  
Myofibroblast Differentiation ◽  
And Function ◽  
Organ Fibrosis

Cardiac fibrosis is mediated by the activation of resident cardiac fibroblasts, which differentiate into myofibroblasts in response to injury or stress. Although myofibroblast formation is a physiological response to acute injury, such as myocardial infarction, myofibroblast persistence, as occurs in heart failure, contributes to maladaptive remodeling and progressive functional decline. Although traditional pathways of activation, such as TGFβ (transforming growth factor β) and AngII (angiotensin II), have been well characterized, less understood are the alterations in mitochondrial function and cellular metabolism that are necessary to initiate and sustain myofibroblast formation and function. In this review, we highlight recent reports detailing the mitochondrial and metabolic mechanisms that contribute to myofibroblast differentiation, persistence, and function with the hope of identifying novel therapeutic targets to treat, and potentially reverse, tissue organ fibrosis.

scholarly journals Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 865 ◽  
Author(s):  
Tsai ◽  
Lin ◽  
Hang ◽  
Chen
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Umbilical Vein ◽  
Active Form ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Umbilical Vein Endothelial Cells

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes.

scholarly journals P300/CBP-Associated Factor Activates Cardiac Fibroblasts by SMAD2 Acetylation

2021 ◽  
Vol 22 (18) ◽  
pp. 9944
Author(s):  
Yongwoon Lim ◽  
Anna Jeong ◽  
Duk-Hwa Kwon ◽  
Yeong-Un Lee ◽  
Young-Kook Kim ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
High Dose ◽  
Mouse Heart ◽  
Associated Factor ◽  
Tgf Β1

Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-β1 (TGF-β1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-β1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-β1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-β1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation.

scholarly journals The mechanism of TGF-β/miR-155/c-Ski regulates endothelial–mesenchymal transition in human coronary artery endothelial cells

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Juan Wang ◽  
Wen He ◽  
Xiao Xu ◽  
Liping Guo ◽  
Yin Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Human Coronary Artery ◽  
Mesenchymal Transition ◽  
Twist Expression ◽  
Endothelial Mesenchymal Transition

Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial–mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis.

scholarly journals Kanglexin protects against cardiac fibrosis and dysfunction in mice by TGF-β1/ERK1/2 noncanonical pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Xue Liu ◽  
Weina Han ◽  
Na An ◽  
Na Cao ◽  
Tingting Wu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Umbilical Vein ◽  
Mesenchymal Transition ◽  
Antifibrotic Therapy ◽  
Collagen Secretion ◽  
Noncanonical Pathway ◽  
Umbilical Vein Endothelial Cells ◽  
Tgf Β1

Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF β1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-β1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.

scholarly journals Endothelial-Mesenchymal Transition or Functional Tissue Regeneration – Two Outcomes of Heart Remodeling

2021 ◽  
pp. S13-S20
Author(s):  
B. Šalingová ◽  
Z. Červenák ◽  
A. Adamičková ◽  
N. Chomanicová ◽  
S. Valášková ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Current Knowledge ◽  
Cardiac Fibroblasts ◽  
Scar Tissue ◽  
Mesenchymal Transition ◽  
Heart Remodeling ◽  
Circulating Endothelial Progenitor Cells ◽  
Heart Repair ◽  
Endothelial Mesenchymal Transition

Heart remodeling occurs as a compensation mechanism for the massive loss of tissue during initial heart failure and the consequent inflammation process. During heart remodeling fibroblasts differentiate to myofibroblasts activate their secretion functions and produce elevated amounts, of extracellular matrix (ECM) proteins, mostly collagen, that form scar tissue and alter the normal degradation of ECM. Scar formation does replace the damaged tissue structurally; however, it impedes the normal contractive function of cardiomyocytes (CMs) and results in long-lasting effects after heart failure. Besides CMs and cardiac fibroblasts, endothelial cells (ECs) and circulating endothelial progenitor cells (cEPCs) contribute to heart repair. This review summarizes the current knowledge of EC-CM crosstalk in cardiac fibrosis (CF), the role of cEPCs in heart regeneration and the contribution of Endothelial-mesenchymal transition (EndoMT).

Abstract 560: HDAC3 Unconventional Splicing Mediates Endothelial-mesenchymal Transition in Cardiac Fibrosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Ka Hou Lao ◽  
Dario Ummarino ◽  
Ajay Shah ◽  
Lingfang Zeng
Keyword(s):  
Protein Expression ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Pressure Overload ◽  
Immunofluorescent Staining ◽  
Mesenchymal Transition ◽  
Protease Enzyme ◽  
Underlying Mechanisms ◽  
Endothelial Mesenchymal Transition ◽  
Unconventional Splicing

Introduction: Endothelial-mesenchymal transition (EndMT) makes a significant contribution to cardiac fibrosis. Histone deacetylase 3 (HDAC3) is essential in the maintenance of endothelial homeostasis. Our previous study indicates that mouse HDAC3 mRNA can undergo unconventional splicing, and that the HDAC3α spliced isoform promotes the EndMT process in human aortic endothelial cells (HAECs). This work aims to elucidate the role of HDAC3α in mediating EndMT and its part in the underlying mechanisms behind the development of pressure-overload-induced cardiac fibrosis. Methods and Results: Our previous study reveals that HDAC3α promotes EndMT in HAECs via the activation of transforming growth factor-beta 2, possibly through increased protease enzyme activity. HDAC3α was therefore overexpressed in HAECs via adenoviral gene transfer (Ad-HDAC3α). Protease array revealed that cells infected with Ad-HDAC3α have an elevated level of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), and this was further confirmed with increased mRNA and protein expression levels seen in Ad-HDAC3α-infected HAECs using RT-qPCR and Western blotting analysis respectively (both n = 4, P < 0.05). A mouse model of pressure overload-induced cardiac fibrosis was established by transverse aortic constriction (TAC), and cardiac fibrosis was confirmed by increased Col1a1 expression seen using RT-qPCR and picosinus red staining in heart tissue sections from mice 7 d post-TAC. Immunofluorescent staining detected CD31 + /α-SMA + (indicative of EndMT) and HDAC3α + /CD31 + cells in heart tissues from TAC mice but not in those from sham-operated mice. There were significant increases in mRNA expression of HDAC3α and ADAMTS1, together with EndMT transcription factors Snai1, Snai2 and Twist1 in heart tissues from 7 d post-TAC mice compared to those from 7 d post-sham mice (n = 7- 8, P < 0.05). Elevated HDAC3α and ADAMTS1 protein expression were also detected in the TAC heart tissues (n = 5, P < 0.05). Conclusion: These results indicate an association between the HDAC3 splicing isoform HDAC3α, ADAMTS1 and EndMT during TAC-induced cardiac fibrosis. Further investigation of the underlying mechanisms mediated by HDAC3α and ADAMTS1 in cardiac fibrosis is warranted.

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.

Sign in / Sign up

Export Citation Format

Share Document