BRD4 blockage alleviates pathological cardiac hypertrophy through the suppression of fibrosis and inflammation via reducing ROS generation

Zhu, Wen; Wu, Ruodai; Lv, Yun-gang; Liu, Yumeng; Huang, Hua; Xu, Junqiang

doi:10.1016/j.biopha.2019.109368

Cited by 63 publications

(38 citation statements)

References 43 publications

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“…Following trauma, the release of large amounts of reactive oxygen species (ROS) will disrupt the redox balance in cells and cause oxidative death in spinal cord neurons. Interestingly, Brd4 expression has been reported to be markedly increased in cardiomyocytes subjected to oxidative stress, indicating that oxidative stress induced by Brd4 is involved in cardiac hypertrophy ( Zhu et al, 2020 ). In addition, recent studies have proven that inhibition of Brd4 by JQ1 or Brd4 knockdown significantly enhances the plasma levels of antioxidant enzymes and reduces lipid peroxidation, suggesting that JQ1 exerts a protective effect in augmenting antioxidant levels and protecting against oxidative stress ( Michaeloudes et al, 2014 ; Chatterjee and Bohmann, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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“…Nevertheless, persistent inflammatory response contributes greatly to myocardial remodeling and ultimately heart failure. 157 BET-mediated transcription of proinflammatory and pro-fibrogenic genes are involved in various cardiovascular diseases, such as cardiac hypertrophy, 158 pulmonary arterial hypertension, 62,159,160 and myocardial infarction. 66 The upregulation of BRD4 in cardiomyocytes may induce cardiac hypertrophy by increasing the expression of pro-fibrotic genes and activating RELA-driven inflammation.…”

Section: Bets In Diseasesmentioning

confidence: 99%

The BET family in immunity and disease

Wang

Tang

et al. 2021

Sig Transduct Target Ther

180

146

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Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.

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“…BRD4 inhibitors block airway inflammation caused by the virus (37). BRD4 blockers reduce pathological cardiac hypertrophy by reducing ROS production and inhibiting fibrosis and inflammation (38). BRD4 inhibitors also have a protective effect against vincristine induced peripheral neuropathy by reducing inflammation (39).…”

Section: Discussionmentioning

confidence: 99%

Hepatic BRD4 Is Upregulated in Liver Fibrosis of Various Etiologies and Positively Correlated to Fibrotic Severity

Cheng

Peng

et al. 2021

Front. Med.

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Bromodomain-containing protein 4 (BRD4) has been implicated to play a regulatory role in fibrogenic gene expression in animal models of liver fibrosis. The potential role of BRD4 in liver fibrosis in humans remains unclear. We sought to investigate the expression and cellular localization of BRD4 in fibrotic liver tissues. Human liver tissues were collected from healthy individuals and patients with liver fibrosis of various etiologies. RNA-seq showed that hepatic BRD4 mRNA was elevated in patients with liver fibrosis compared with that in healthy controls. Subsequent multiple manipulations such as western blotting, real-time quantitative polymerase chain reaction, and dual immunofluorescence analysis confirmed the abnormal elevation of the BRD4 expression in liver fibrosis of various etiologies compared to healthy controls. BRD4 expression was positively correlated with the severity of liver fibrosis, and also correlated with the serum levels of aspartate aminotransferase and total bilirubin. Moreover, the expression of C-X-C motif chemokine ligand 6 (CXCL6), a factor interplayed with BRD4, was increased in hepatic tissues of the patients with liver fibrosis. Its expression level was positively correlated with BRD4 level. BRD4 is up-regulated in liver fibrosis, regardless of etiology, and its increased expression is positively correlated with higher degrees of liver fibrosis. Our data indicate that BRD4 play a critical role in the progress of liver fibrosis, and it holds promise as a potential target for intervention of liver fibrosis.

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BRD4 blockage alleviates pathological cardiac hypertrophy through the suppression of fibrosis and inflammation via reducing ROS generation

Cited by 63 publications

References 43 publications

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

The BET family in immunity and disease

Hepatic BRD4 Is Upregulated in Liver Fibrosis of Various Etiologies and Positively Correlated to Fibrotic Severity

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