BET Bromodomain Proteins Mediate Downstream Signaling Events following Growth Factor Stimulation in Human Lung Fibroblasts and Are Involved in Bleomycin-Induced Pulmonary Fibrosis

Tang, Xiaoyan; Peng, Ruoqi; Ren, Yonglin; Apparsundaram, Subramanium; Deguzman, Jeremy; Bauer, Carla M. T.; Hoffman, Ann F.; Hamilton, Shannon; Liang, Zhenmin; Zeng, Hang; Fuentes, María E.; DeMartino, Julie A.; Kitson, Christopher; Stevenson, Christopher S.; Budd, David C.

doi:10.1124/mol.112.081661

Cited by 66 publications

(75 citation statements)

References 46 publications

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“…JQ1 was found to blunt PDGF- and TGF-β-stimulated IL-6 secretion, collagen and α-SMA expression, and proliferation and contraction of cultured lung fibroblasts [96]. Inhibition of fibrotic gene expression was also observed upon genetic knockdown of either BRD2 or BRD4, confirming that the effect of JQ1 was due to BET protein inhibition as opposed to an off-target action.…”

Section: Acetyl-lysine Readers and Fibrosismentioning

confidence: 99%

Epigenetic regulation of cardiac fibrosis

Stratton

McKinsey

2016

Journal of Molecular and Cellular Cardiology

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Fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In the heart, fibrosis may be reparative, replacing areas of myocyte loss with a structural scar following infarction, or reactive, which is triggered in the absence of cell death and involves interstitial ECM deposition in response to long-lasting stress. Interstitial fibrosis can increase the passive stiffness of the myocardium, resulting in impaired relaxation and diastolic dysfunction. Additionally, fibrosis can lead to disruption of electrical conduction in the heart, causing arrhythmias, and can limit myocyte oxygen availability and thus exacerbate myocardial ischemia. Here, we review recent studies that have illustrated key roles for epigenetic events in the control of pro-fibrotic gene expression, and highlight the potential of small molecules that target epigenetic regulators as a means of treating fibrotic cardiac diseases.

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Section: Acetyl-lysine Readers and Fibrosismentioning

confidence: 99%

Epigenetic regulation of cardiac fibrosis

Stratton

McKinsey

2016

Journal of Molecular and Cellular Cardiology

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“…For example, compound 7 suppresses bleomycin-induced lung fibrosis in mice, indicating that BRD4 inhibitors may hold great promise for the treatment of rapidly progressing idiopathic pulmonary fibrosis. 82,83 …”

Section: Brd4 As a Novel Therapeutic Target: Structures And Diseasmentioning

confidence: 99%

Drug Discovery Targeting Bromodomain-Containing Protein 4

et al. 2017

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BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.

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“…Brd4 expression levels correlate with ECM gene expression and Brd4 is involved in gene regulation through RNA processing and chromatin modifications. Brd4 was recently identified as a critical regulator of lung and liver fibrosis [243,244] and blocking Brd4 not only prevents but also reverses fibrosis and myofibroblast differentiation of hepatic stellate cells [244]. Interestingly, Brd4 inhibition also reduces myocardial damage following infarction [245] suggesting a role for Brd4 in the heart.…”

Section: Nuclear Mechanosensing: Long-distance Communicationmentioning

confidence: 99%

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Herum

Lunde

McCulloch

et al. 2017

JCM

140

123

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Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

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BET Bromodomain Proteins Mediate Downstream Signaling Events following Growth Factor Stimulation in Human Lung Fibroblasts and Are Involved in Bleomycin-Induced Pulmonary Fibrosis

Cited by 66 publications

References 46 publications

Epigenetic regulation of cardiac fibrosis

Epigenetic regulation of cardiac fibrosis

Drug Discovery Targeting Bromodomain-Containing Protein 4

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

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