Signaling Mechanisms of Myofibroblastic Activation: Outside-in and Inside-Out

Zent, Joshua; Guo, Lian‐Wang

doi:10.1159/000493217

Cited by 90 publications

(77 citation statements)

References 203 publications

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“…TGF-β1 signaling is crucial for the induction and maintenance of activated fibroblast phenotype through the Smad2/3 pathways 7,28 . In the present study, we found TNAP inhibition significantly suppressed the myofibroblast differentiation and collagen deposition both in post-MI hearts and in TGF-β1-treated CFs evidenced by the reducing expression of α-SMA, vimentin, collagen-related genes, and migration.…”

Section: Discussionmentioning

confidence: 99%

TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways

et al. 2020

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Tissue nonspecific alkaline phosphatase (TNAP) is expressed widely in different tissues, modulating functions of metabolism and inflammation. However, the effect of TNAP on cardiac fibrosis remains controversial and needs to be further studied. The present study aims to investigate the role of TNAP on myocardial infarction (MI)-induced fibrosis and its mechanism. TNAP was upregulated in patients with MI, both in serum and injured hearts, and predicted inhospital mortality. TNAP was also significantly upregulated after MI in rats, mostly in the border zone of the infarcted hearts combined with collagen synthesis. Administration of TNAP inhibitor, tetramisole, markedly improved cardiac function and fibrosis after MI. In the primary cultures of neonatal rat cardiac fibroblasts (CFs), TNAP inhibition significantly attenuated migration, differentiation, and expression of collagen-related genes. The TGF-β1/Smads signaling suppression, and p-AMPK and p53 upregulation were involved in the process. When p53 inhibitor was administered, the antifibrotic effect of TNAP inhibition can be blocked. This study provides a direct evidence that inhibition of TNAP might be a novel regulator in cardiac fibrosis and exert an antifibrotic effect mainly through AMPK-TGF-β1/Smads and p53 signals.

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Section: Discussionmentioning

confidence: 99%

TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways

et al. 2020

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“…It had been demonstrated previously that the ECM is an important regulator of myofibroblast activation [32]. Notably, a fibrotic ECM scaffold was shown to lead to activation of control fibroblasts, while conversely, plating of activated myofibroblasts derived from IPF patients onto an ECM scaffold from control lungs resulted into a quiescent phenotype similar to control fibroblasts, suggesting that ECM is a prominent determinant that dictates fibroblast activation [33].…”

Section: Fig 6 Evaluation Of Epithelial and Mesenchymal Gene Expressmentioning

confidence: 94%

Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models

et al. 2020

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The stress-induced kinase, c-Jun-N-terminal kinase 1 (JNK1) has previously been implicated in the pathogenesis of lung fibrosis. However, the exact cell type(s) wherein JNK1 exerts its pro-fibrotic role(s) remained enigmatic. Herein we demonstrate prominent activation of JNK in bronchial epithelia using the mouse models of bleomycin-or AdTGFβ1induced fibrosis. Furthermore, in lung tissues of patients with idiopathic pulmonary fibrosis (IPF), active JNK was observed in various regions including type I and type II pneumocytes and fibroblasts. No JNK activity was observed in adjacent normal tissue or in normal control tissue. To address the role of epithelial JNK1, we ablated Jnk1 form bronchiolar and alveolar type II epithelial cells using CCSP-directed Cre recombinase-mediated ablation of LoxPflanked Jnk1 alleles. Our results demonstrate that ablation of Jnk1 from airway epithelia resulted in a strong protection from bleomycin-or adenovirus expressing active transforming growth factor beta-1 (AdTGFβ1)-induced fibrosis. Ablation of the Jnk1 allele at a time when collagen increases were already present showed a reversal of existing increases in collagen content. Epithelial Jnk1 ablation resulted in attenuation of mesenchymal genes and proteins in lung tissue and preserved expression of epithelial genes. Collectively, these data suggest that epithelial JNK1 contributes to the pathogenesis of pulmonary fibrosis. Given the presence of active JNK in lungs from patients with IPF, targeting JNK1 in airway epithelia may represent a potential treatment strategy to combat this devastating disease.

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“…Therapeutically, blockade of the renin-angiotensin II (Ang II)-aldosterone system by angiotensin converting enzyme (ACE) inhibitors or angiotensin II-type1 receptor antagonists can slow down fibrosis [1], but it is not yet possible to halt or reverse fibrosis. Cardiac fibrosis is driven by myofibroblasts, which arise mainly from transdifferentiation of resident cardiac fibroblasts after exposure to mediators like Ang II and transforming growth factor-β as well as in response to altered biomechanical properties of their surroundings [2][3][4][5]. Understanding the molecular events underlying fibrosis is essential to identify new therapeutic antifibrotic strategies for the treatment of heart failure.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cardiac fibrosis is a hallmark of heart failure for which there is no effective pharmacological therapy. By genetic modification and in vivo inhibitor approaches it was suggested that the Rho-associated kinases (ROCK1 and ROCK2) are involved in pro-fibrotic signalling in cardiac fibroblasts and that they may serve as targets for anti-fibrotic therapies. We demonstrate that simultaneous inhibition of ROCK1 and ROCK2 strongly interfered with tissue formation and their biomechanical properties in a model of engineered connective tissue (ECT), comprised of cardiac fibroblasts and collagen. These effects were observed with both rat and human ECT. Inhibitors of different chemistries, including the isoquinoline inhibitors Fasudil and H1152P as well as the pyrazol-phenyl inhibitor SR-3677, showed comparable effects. By combined treatment of ECT with TGF-β and H1152P, we could identify ROCK as a mediator of TGF-β-dependent tissue stiffening. Moreover, expression analyses suggested that lysyl oxidase (LOX) is a downstream target of the ROCK-actin-MRTF/SRF pathway and inhibition of this pathway by Latrunculin A and CCG-203971 showed similar anti-fibrotic effects in the ECT model as ROCK inhibitors. In line with the collagen crosslinking function of LOX, its inhibition by βaminopropionitrile resulted in reduced ECT stiffness, but let tissue compaction unaffected. Finally, we show that ROCK inhibition also reduced the compaction and stiffness of engineered heart muscle tissues. Our results indicate that pharmacological inhibition of ROCK has a strong anti-fibrotic potential which is in part due to a decrease in the expression of the collagen crosslinking enzyme lysyl oxidase.

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Signaling Mechanisms of Myofibroblastic Activation: Outside-in and Inside-Out

Cited by 90 publications

References 203 publications

TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways

TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways

Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

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