2. Academic Validation
  3. BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection

BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection

  • Pharmacol Res. 2022 Mar;177:106122. doi: 10.1016/j.phrs.2022.106122.
Yue Chen 1,  Xin Yi 2,  Bo Huo 1,  Yi He 1,  Xian Guo 1,  Zihao Zhang 1,  Xiaoxuan Zhong 1,  Xin Feng 1,  Ze-Min Fang 1,  Xue-Hai Zhu 3,  Xiang Wei 4,  Ding-Sheng Jiang 5
Affiliations

Affiliations

  • 1 Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 3 Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
  • 4 Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.. Electronic address: xiangwei@tjh.tjmu.edu.cn.
  • 5 Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.. Electronic address: jds@hust.edu.cn.
PMID: 35149187 DOI: 10.1016/j.phrs.2022.106122
Abstract

Smooth muscle cell (SMC) loss is the characteristic feature in the pathogenesis of aortic dissection (AD), and Ferroptosis is a novel iron-dependent regulated cell death driven by the excessive lipid peroxidation accumulation. However, whether targeting Ferroptosis is an effective approach for SMC loss and AD treatment remains unclear. Here, we found that the iron level, ferroptosis-related molecules TFR, HOMX1, ferritin and the lipid peroxidation product 4-hydroxynonenal were increased in the aorta of AD. Then, we screened several inhibitors of histone methyltransferases and found that BRD4770 had a protective effect on cystine deprivation-, imidazole ketone erastin- or RSL3-induced Ferroptosis of SMCs. The classic Ferroptosis pathways, System Xc--GPX4, FSP1-CoQ10 and GCH1-BH4 pathways which were inhibited by Ferroptosis inducers, were re-activated by BRD4770 via inhibiting mono-, di- and tri- methylated histone H3 at lysine 9 (H3K9me1/2/3). RNA-sequencing analysis revealed that there was a positive feedback regulation between Ferroptosis and inflammatory response, and BRD4770 can reverse the effects of inflammation activation on Ferroptosis. More importantly, treatment with BRD4770 attenuated aortic dilation and decreased morbidity and mortality in a β-Aminopropionitrile monofumarate-induced mouse AD model via inhibiting the inflammatory response, lipid peroxidation and Ferroptosis. Taken together, our findings demonstrate that Ferroptosis is a novel and critical pathological mechanism that is involved in SMC loss and AD development. BRD4770 is a novel Ferroptosis inhibitor and has equivalent protective effect to Ferrostatin-1 at the optimal concentration. Translating insights into the anti-ferroptosis effects of BRD4770 may reveal a potential therapeutic approach for targeting SMC Ferroptosis in AD.

Keywords

Aortic dissection; BRD4770; Ferroptosis; Histone methylation; Inflammation; Smooth muscle cell.

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