Abstract

Bromodomain containing protein 4 (BRD4) belongs to the bromodomain and external domain family of proteins. It is crucial for the transcriptional regulation of various immune responses and cell survival processes. This study elucidated the role of (BRD4) in the inflammatory pathway associated with cardiovascular disease, particularly in the formation of abdominal aortic aneurysms (AAAs). BRD4 expression was increased in primary human aortic smooth muscle cells (HuAoSMCs) upon treatment with pro-inflammatory stimuli, demonstrating its involvement in the inflammatory responses of primary HuAoSMCs. Knockdown of BRD4 led to a significant decrease in the levels of MCP-1, a chemokine linked to AAA development, indicating a direct regulatory connection. Two BET inhibitors, JQ1 and ARV-825, inhibited the induction of MCP-1 by TNF-α at both transcriptional and translational levels while ARV-825 was more effective. Furthermore, immunofluorescent assays revealed that ARV-825 reduced NF-κB activation more potently than that of JQ1. In vivo Ang II treated ApoE-/- mice models showed induced AAA formation, however, treatment with ARV-825 led to a marked decrease in both the incidence of AAA and vessel size compared to vehicle control, suggesting its viability as a future therapeutic option. The findings from this study suggest that targeting BRD4 might serve as a promising therapeutic option in the treatment or prevention of AAAs.

Date of publication

2025

Document Type

Thesis

Language

english

Persistent identifier

http://hdl.handle.net/10950/4864

Committee members

Xia Guo, PhD, Mitsuo Ikebe, PhD, Guoqing Qian, PhD, Pierre Neuenschwander, PhD, Shih-Feng Chou, PhD

Degree

Master of Science in Biotechnology

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