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

Biomed Pharmacother. 2020 Jan:121:109368. doi: 10.1016/j.biopha.2019.109368. Epub 2019 Nov 25.

Abstract

Hypertension is an essential regulator of cardiac injury and remodeling. However, the pathogenesis that contributes to cardiac hypertrophy remains to be fully explored. BRD4, as a bromodomain and extra-terminal (BET) family member, plays an important role in critical biological processes. In the study, our results showed that BRD4 expression was up-regulated in human and mouse hypertrophied hearts, and importantly these effects were modulated by reactive oxygen species (ROS) generation. In angiotensin II (Ang II)-treated cardiomyocytes, BRD4 decrease markedly blunted the prohypertrophic effect, which was further promoted by the combinational treatment of ROS scavenger (N-acetyl-cysteine, NAC). In addition, NAC pre-treatment markedly elevated the anti-fibrotic role of BRD4 suppression in Ang II-incubated cardiomyocytes by repressing transforming growth factor β1 (TGF-β1)/SMADs signaling pathway. NAC combined with BRD4 reduction further alleviated inflammation and oxidative stress in Ang II-exposed cardiomyocytes, which was partly through inhibiting nuclear factor-κB (NF-κB) signaling and improving nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathway, respectively. Furthermore, the in vivo results confirmed the protective effects of BRD4 suppression on mice against aortic banding (AB)-induced cardiac hypertrophy, as evidenced by the reduced cross sectional area and fibrotic area using H&E and Masson trichrome staining. What's more, the degree of cardiac hypertrophy (ANP and BNP), the expression of pro-fibrotic genes (TGF-β1, Collagen I, Collagen III and CTGF), the levels of inflammation and oxidative stress were all significantly attenuated by the blockage of BRD4 in AB-operated mice. Taken together, repressing BRD4 expression was found to confer a protective effect against experimental cardiac hypertrophy in mice, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.

Keywords: BRD4; Cardiac hypertrophy; Fibrosis; Inflammation; Reactive oxygen species (ROS).

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Cardiomegaly / drug therapy
  • Cardiomegaly / metabolism*
  • Cell Line
  • Fibrosis / drug therapy
  • Fibrosis / metabolism*
  • Heart / drug effects
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • NF-kappa B / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Oxidative Stress / drug effects
  • Protective Agents / pharmacology*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects
  • Transcription Factors / antagonists & inhibitors*
  • Transforming Growth Factor beta1 / metabolism
  • Up-Regulation / drug effects

Substances

  • Brd4 protein, mouse
  • NF-kappa B
  • Nuclear Proteins
  • Protective Agents
  • Reactive Oxygen Species
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Angiotensin II
  • Heme Oxygenase-1