scholarly journals Regulators of cardiac fibroblast cell state

2020 ◽  
Vol 91-92 ◽  
pp. 117-135 ◽  
Author(s):  
Ross Bretherton ◽  
Darrian Bugg ◽  
Emily Olszewski ◽  
Jennifer Davis
Keyword(s):  
Fibroblast Cell ◽  
Cardiac Fibroblast ◽  
Cell State

scholarly journals Repurposing mesalazine against cardiac fibrosis in vitro

2020 ◽  
Author(s):  
Maximilian Hoffmann ◽  
Theresa A. Kant ◽  
Ramona Emig ◽  
Johanna S. E. Rausch ◽  
Manja Newe ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Drug Repurposing ◽  
Fibroblast Cell ◽  
Cardiac Fibroblast ◽  
Cell Stiffness ◽  
Fibroblast Proliferation ◽  
Time Saving ◽  
Solvent Control ◽  
Vitro Model

Abstract Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ induces fibroblast activation and differentiation into myofibroblasts that secrete excessive extracellular matrix proteins leading to stiffening of the heart, concomitant cardiac dysfunction, and arrhythmias. However, effective pharmacotherapy for preventing or reversing cardiac fibrosis is presently unavailable. Therefore, drug repurposing could be a cost- and time-saving approach to discover antifibrotic interventions. The aim of this study was to investigate the antifibrotic potential of mesalazine in a cardiac fibroblast stress model. TGFβ was used to induce a profibrotic phenotype in a human cardiac fibroblast cell line. After induction, cells were treated with mesalazine or solvent control. Fibroblast proliferation, key fibrosis protein expression, extracellular collagen deposition, and mechanical properties were subsequently determined. In response to TGFβ treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary αSMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGFβ led to increased cell stiffness and adhesion, which were reversed by mesalazine treatment. Collagen 1 expression and deposition—key drivers of fibrosis—were significantly increased upon TGFβ stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NFκB translocation, were identified as potential modes of action. The current study provides experimental pre-clinical evidence for antifibrotic effects of mesalazine in an in vitro model of cardiac fibrosis. Furthermore, it sheds light on possible mechanisms of action and suggests further investigation in experimental and clinical settings.

scholarly journals Platelet-derived growth factor receptor-α is essential for cardiac fibroblast survival

2019 ◽  
Vol 317 (2) ◽  
pp. H330-H344 ◽  
Author(s):  
Malina J. Ivey ◽  
Jill T. Kuwabara ◽  
Kara L. Riggsbee ◽  
Michelle D. Tallquist
Keyword(s):  
Growth Factor ◽  
Cardiac Fibroblasts ◽  
Growth Factor Receptor ◽  
Fibroblast Cell ◽  
Cardiac Fibroblast ◽  
Platelet Derived Growth Factor ◽  
Activating Transcription Factor 3 ◽  
Rapid Reduction ◽  
Functional Changes

Platelet-derived growth factor receptor α (PDGFRα), a receptor tyrosine kinase required for cardiac fibroblast development, is uniquely expressed by fibroblasts in the adult heart. Despite the consensus that PDGFRα is expressed in adult cardiac fibroblasts, we know little about its function when these cells are at rest. Here, we demonstrate that loss of PDGFRα in cardiac fibroblasts resulted in a rapid reduction of resident fibroblasts. Furthermore, we observe that phosphatidylinositol 3-kinase signaling was required for PDGFRα-dependent fibroblast maintenance. Interestingly, this reduced number of fibroblasts was maintained long-term, suggesting that there is no homeostatic mechanism to monitor fibroblast numbers and restore hearts to wild-type levels. Although we did not observe any systolic functional changes in hearts with depleted fibroblasts, the basement membrane and microvasculature of these hearts were perturbed. Through in vitro analyses, we showed that PDGFRα signaling inhibition resulted in an increase in fibroblast cell death, and PDGFRα stimulation led to increased levels of the cell survival factor activating transcription factor 3. Our data reveal a unique role for PDGFRα signaling in fibroblast maintenance and illustrate that a 50% loss in cardiac fibroblasts does not result in lethality. NEW & NOTEWORTHY Platelet-derived growth factor receptor α (PDGFRα) is required in developing cardiac fibroblasts, but a functional role in adult, quiescent fibroblasts has not been identified. Here, we demonstrate that PDGFRα signaling is essential for cardiac fibroblast maintenance and that there are no homeostatic mechanisms to regulate fibroblast numbers in the heart. PDGFR signaling is generally considered mitogenic in fibroblasts, but these data suggest that this receptor may direct different cellular processes depending on the cell’s maturation and activation status.

HDAC6 Promotes Cardiac Fibrosis Progression through Suppressing RASSF1A Expression

Cardiology ◽  
2015 ◽  
Vol 133 (1) ◽  
pp. 18-26 ◽  
Author(s):  
Hui Tao ◽  
Jing-Jing Yang ◽  
Wei Hu ◽  
Kai-Hu Shi ◽  
Jun Li
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Fibroblast Cell ◽  
Cardiac Fibroblast ◽  
Matrix Proteins ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Fibrosis Progression ◽  
Hdac6 Inhibitor ◽  
Si Rna

Objectives: Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation and proliferation events. However, the precise mechanisms of how HDAC is associated with cardiac fibrosis progression have not yet been elucidated. Methods: Fifty adult male Sprague-Dawley (SD) rats were randomly divided into two groups. Cardiac fibrosis was produced by common isoprenaline and cardiac fibroblasts were harvested from SD neonate rats and cultured. The expression of HDAC6, RASSF1A, α-SMA and collagen I were measured by Western blotting and qRT-PCR. Small interfering (si)RNA of HDAC6 affects the proliferation of cardiac fibroblasts and the regulation of RASSF1A/ERK1/2 signaling pathways. Results: In this study, we found that mRNA and protein levels of HDAC6 were upregulated in cardiac fibrosis tissues and activated cardiac fibroblast cells. Inhibition of HDAC6 by siRNA or the inhibitor tubacin attenuated the TGF-β1-induced myofibroblast markers. In contrast, HDAC6 knockdown using siRNA inhibited cardiac fibroblast cell proliferation. Furthermore, we demonstrated that knockdown of HDAC6 elevated RASSF1A expression in activated cardiac fibroblasts, and treatment of cardiac fibroblasts with the HDAC6 inhibitor tubacin also elevated RASSF1A expression. Conclusions: The results of this study suggest that a previously unknown mechanism of HDAC6 inactivation of RASSF1A controls cardiac fibroblast proliferation and fibrosis.

scholarly journals Loss of Function in Dopamine D3 Receptor Attenuates Left Ventricular Cardiac Fibroblast Migration and Proliferation in vitro

2021 ◽  
Vol 8 ◽  
Author(s):  
Andrew Kisling ◽  
Shannon Byrne ◽  
Rohan U. Parekh ◽  
Deepthy Melit-Thomas ◽  
Lisandra E. de Castro Brás ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Cardiac Fibroblasts ◽  
Fibroblast Cell ◽  
Left Ventricular ◽  
Cardiac Fibroblast ◽  
Loss Of Function ◽  
Fibroblast Migration ◽  
And Migration ◽  
Proliferation And Migration

Evidence suggests the existence of an intracardiac dopaminergic system that plays a pivotal role in regulating cardiac function and fibrosis through G-protein coupled receptors, particularly mediated by dopamine receptor 3 (D3R). However, the expression of dopamine receptors in cardiac tissue and their role in cardiac fibroblast function is unclear. In this brief report, first we determined expression of D1R and D3R both in left ventricle (LV) tissue and fibroblasts. Then, we explored the role of D3R in the proliferation and migration of fibroblast cell cultures using both genetic and pharmaceutical approaches; specifically, we compared cardiac fibroblasts isolated from LV of wild type (WT) and D3R knockout (D3KO) mice in response to D3R-specific pharmacological agents. Finally, we determined if loss of D3R function could significantly alter LV fibroblast expression of collagen types I (Col1a1) and III (Col3a1). Cardiac fibroblast proliferation was attenuated in D3KO cells, mimicking the behavior of WT cardiac fibroblasts treated with D3R antagonist. In response to scratch injury, WT cardiac fibroblasts treated with the D3R agonist, pramipexole, displayed enhanced migration compared to control WT and D3KO cells. Loss of function in D3R resulted in attenuation of both proliferation and migration in response to scratch injury, and significantly increased the expression of Col3a1 in LV fibroblasts. These findings suggest that D3R may mediate cardiac fibroblast function during the wound healing response. To our knowledge this is the first report of D3R's expression and functional significance directly in mouse cardiac fibroblasts.

scholarly journals Cell-state specific aggresome formation in fibroblasts is driven by stress-activated MAPK signaling

2021 ◽  
Author(s):  
Christopher S. Morrow ◽  
Zachary P. Arndt ◽  
Bo Peng ◽  
Eden Y. Zewdie ◽  
Bérénice A. Benayoun ◽  
...  
Keyword(s):  
Proteasome Inhibition ◽  
Fibroblast Cell ◽  
Mapk Signaling ◽  
Dermal Fibroblasts ◽  
Specific Response ◽  
Cell State ◽  
Distinct Cell ◽  
Aggresome Formation ◽  
Immortalized Cell ◽  
Universal Protein

The aggresome is a protein turnover system in which proteins are trafficked along microtubules to the centrosome for degradation. Despite extensive focus on aggresomes in immortalized cell lines, it remains unclear if the aggresome is conserved in all primary cells and all cell-states. Here we examined the aggresome in primary adult mouse dermal fibroblasts in four distinct cell-states. We found that in response to proteasome inhibition, quiescent and immortalized fibroblasts formed aggresomes whereas proliferating and senescent fibroblasts did not. Transcriptomic analysis of the fibroblast cell-state-specific response to proteasome inhibition revealed that stress-activated MAPK signaling was associated with aggresome formation. Supporting a functional role for stress-activated MAPK signaling in aggresome formation, inhibition of TAK1 and p38α/β MAPKs suppressed aggresome formation. Together, our data suggest that the aggresome is a non-universal protein degradation system that forms through stress-activated MAPK signaling which can be used cell-state specifically.

scholarly journals Overexpression of 12-Lipoxygenase Causes Cardiac Fibroblast Cell Growth

2001 ◽  
Vol 88 (1) ◽  
pp. 70-76 ◽  
Author(s):  
Yeshao Wen ◽  
Jiali Gu ◽  
Yaxia Liu ◽  
Ping H. Wang ◽  
Yanyu Sun ◽  
...  
Keyword(s):  
Cell Growth ◽  
Fibroblast Cell ◽  
Cardiac Fibroblast ◽  
12 Lipoxygenase

THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure

2005 ◽  
Vol 45 (1) ◽  
pp. 657-687 ◽  
Author(s):  
R. Dale Brown ◽  
S. Kelly Ambler ◽  
M. Darren Mitchell ◽  
Carlin S. Long
Keyword(s):  
Therapeutic Target ◽  
Cell Biology ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Fibroblast Cell ◽  
Cardiac Fibroblast ◽  
Myocardial Remodeling ◽  
Candidate Drug ◽  
Metalloproteinase Inhibitors ◽  
Future Challenges

Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.

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