Current and Future Strategies for the Diagnosis and Treatment of Cardiac Fibrosis

Roché, Pauline; Czubryt, Michael P.

doi:10.1007/978-3-319-17437-2_11

Cardiac Fibrosis and Heart Failure: Cause or Effect? 2015

DOI: 10.1007/978-3-319-17437-2_11

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Current and Future Strategies for the Diagnosis and Treatment of Cardiac Fibrosis

Pauline Roché

Michael P. Czubryt

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Cited by 2 publications

References 276 publications

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Regulation of fibronectin gene expression in cardiac fibroblasts by scleraxis

et al. 2016

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The glycoprotein fibronectin is a key component of the extracellular matrix. By interacting with numerous matrix and cell surface proteins, fibronectin plays important roles in cell adhesion, migration and intracellular signaling. Up-regulation of fibronectin occurs in tissue fibrosis, and previous studies have identified the pro-fibrotic factor TGFβ as an inducer of fibronectin expression, although the mechanism responsible remains unknown. We have previously shown that a key downstream effector of TGFβ signaling in cardiac fibroblasts is the transcription factor scleraxis, which in turn regulates the expression of a wide variety of extracellular matrix genes. We noted that fibronectin expression tracked closely with scleraxis expression, but it was unclear whether scleraxis directly regulated the fibronectin gene. Here, we report that scleraxis acts via two E-box binding sites in the proximal human fibronectin promoter to govern fibronectin expression, with the second E-box being both sufficient and necessary for scleraxis-mediated fibronectin expression to occur. A combination of electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that scleraxis interacted to a greater degree with the second E-box. Over-expression or knockdown of scleraxis resulted in increased or decreased fibronectin expression, respectively, and scleraxis null mice presented with dramatically decreased immunolabeling for fibronectin in cardiac tissue sections compared to wild-type controls. Furthermore, scleraxis was required for TGFβ-induced fibronectin expression: TGFβ lost its ability to induce fibronectin expression following scleraxis knockdown. Together, these results demonstrate a novel and required role for scleraxis in the regulation of cardiac fibroblast fibronectin gene expression basally or in response to TGFβ.

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Regulation of fibronectin gene expression in cardiac fibroblasts by scleraxis

et al. 2016

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What’s in a name? On fibroblast phenotype and nomenclature

Nagalingam

Al‐Hattab

Czubryt

2019

Can. J. Physiol. Pharmacol.

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Fibroblasts have long been recognized as important stromal cells, playing key roles in synthesizing and maintaining the extracellular matrix, but historically were treated as a relatively uniform cell type. Studies in recent years have revealed a surprising level of heterogeneity of fibroblasts across tissues, and even within organs such as the skin and heart. This heterogeneity may have functional consequences, including during stress and disease. While the field has moved forward quickly to begin to address the scientific import of this heterogeneity, the descriptive language used for these cells has not kept pace, particularly when considering the phenotype changes that occur as fibroblasts convert to myofibroblasts in response to injury. We discuss here the nature and sources of the heterogeneity of fibroblasts, and review how our understanding of the complexity of the fibroblast to myofibroblast phenotype conversion has changed with increasing scrutiny. We propose that the time is opportune to reevaluate how we name and describe these cells, particularly as they transition to myofibroblasts through discrete stages. A standardized nomenclature is essential to address the confusion that currently exists in the literature as to the usage of terms like myofibroblast and the description of fibroblast phenotype changes in disease.

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Current and Future Strategies for the Diagnosis and Treatment of Cardiac Fibrosis

Cited by 2 publications

References 276 publications

Regulation of fibronectin gene expression in cardiac fibroblasts by scleraxis

Regulation of fibronectin gene expression in cardiac fibroblasts by scleraxis

What’s in a name? On fibroblast phenotype and nomenclature

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