Inhibition of BRD4 Attenuates Inflammation and Oxidative Stress in Retina

Joseph W Eichenbaum

Research Article

Inhibition of BRD4 Attenuates Inflammation and Oxidative Stress in Retina

Chih-Hung Chen^1,2, SiDe Li^1,2, Elena Rusinova¹, Guangtao Zhang¹, Ming-Ming Zhou¹, Martin J Walsh^1,2,3 and Joseph W Eichenbaum⁴*

¹Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, USA

²Departments of Pediatrics, Icahn School of Medicine at Mount Sinai, USA

³Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA

⁴Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, USA

Corresponding Author

Received Date: July 04, 2022; Published Date: July 29, 2022

Abstract

Aim: To determine how oxidative stress in the zebrafish retina alters the expression of genes linked with stress pathways and how different inhibitors compare in their effectiveness in suppressing damage linked with specific cellular processes.
Methods: To explore these issues, we applied a higher level of Rose Bengal and cold white light, HRBCWL, to the zebrafish eye, to mimic the onset of macula degeneration (AMD). Then, either intravitreally injected BET bromodomain inhibitor, (BRDi), MS255, or VEGF inhibitor, (VEGFi), Ranibizumab, approved for clinically treating AMD, were used, and compared for their respective retinal histologic and transcriptional outcomes.
Key Findings: Examination, after HRBCWL treatment, revealed greater retinal layer height elevation after VEGFi than BRDi and the transcript patterns of the two treatments were strikingly different. After the BRDi there was loss of a core inflammatory gene signature and a moderate decrease in Nrf2 and Keap1, (oxidative stress gene) expression. However, VEGFi treatment did not affect Nrf2 or Keap1 but showed reduction of mitochondrial genes Noxa1 and Ucp3 activity. BRDi suppressed the expression of Sod2 and Sirt2. VEGFi had no effect on their expression. Sirt1 expression showed elevation after HRBCWL followed by BRDi, but mild reduction after VEGFi. MULAN, a key mitochondrial protein involved with NFκΒ signaling, was also reduced after BRDI.
Significance: This study illustrated the first potential and differentiating role for BRDI in mitigating oxidative stress/retinal degeneration transcription factors (Nrf2 and Mul1b) and that the BRDi’s genomic signature is distinct from VEGFi. This could imply that management of AMD could be varied in targeting different transcripts and signaling pathways either individually or in combination as a therapeutic approach for AMD.

Keywords: Bromodomain inhibitor; VEGF inhibitor; Retinal degeneration; Transcription; Oxidative stress; Autophagy; Nrf2; Mul1b; Mitochondria

Article Details

Citation

Chih-Hung Chen, SiDe Li, Elena Rusinova, Guangtao Zhang, Joseph W Eichenbaum, Martin J. Walsh and Ming-Ming Zhou.Inhibition of BRD4 Attenuates Inflammation and Oxidative Stress in Retina. W J Opthalmol & Vision Res. 4(2): 2022. WJOVR.MS.ID.000584. DOI: 10.33552/WJOVR.2022.04.000584.

Keywords

Bromodomain inhibitor, VEGF inhibitor, Retinal degeneration, Transcription, Oxidative stress, Autophagy, Nrf2, Mul1b, Mitochondria, Apoptotsis, Excalibur Pathology Inc, Norman, Oklahoma, Utraviolet light