BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection. (March 2022)

• Record Type: Journal Article
• Authors: Chen, Yue; Yi, Xin; Huo, Bo; He, Yi; Guo, Xian; Zhang, Zihao; Zhong, Xiaoxuan; Feng, Xin; Fang, Ze-Min; Zhu, Xue-Hai; Wei, Xiang; Jiang, Ding-Sheng
• Is Part Of: Pharmacological research. Volume 177(2022)
• Publication Date: 2022-03
• Subjects: SMC Smooth muscle cell -- AD Aortic dissection -- TFR Transferrin receptor -- HMOX1 heme oxygenase 1 -- 4-HNE 4-hydroxynonenal -- CD Cystine deprivation -- IKE Imidazole ketone erastin -- H3K9me1 Mono-methylated histone H3 at lysine 9 -- GPX4 Glutathione peroxidase 4 -- FSP1 Ferroptosis suppressor protein 1 -- CoQ10 Coenzyme Q10 -- GCH1 GTP cyclohydrolase-1 -- BH4 Tetrahydrobiopterin -- Atg5 Autophagy related 5 -- RCD Regulated cell death -- L-OOH Lipid hydroperoxides -- TAAD Stanford type A aortic dissection -- GSH Glutathione -- BAPN β-aminopropionitrile -- HASMCs Human aortic smooth muscle cells -- MDA Malondialdehyde -- LDH Lactate dehydrogenase -- Fer-1 Ferrostatin-1 -- ROS Reactive oxygen species -- SLC7A11 Solute carrier family 7 member 11 -- SLC3A2 Solute carrier family 3 member 2 -- GO Gene ontology -- KEGG Kyoto encyclopedia of genes and genomes -- GSEA Gene set enrichment analysis -- α-SMA α-Smooth muscle actin -- TNF Tumor necrosis factor -- CXCL1 C-X-C motif chemokine ligand 1 -- CSF2 Colony stimulating factor 2 -- LPS Lipopolysaccharide -- MPO Myeloperoxidase; Aortic dissection -- Ferroptosis -- BRD4770 -- Histone methylation -- Inflammation -- Smooth muscle cell; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106122
• Languages: English
• ISSNs: 1043-6618

Abstract

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. Graphical Abstract: ga1 Highlights: Ferroptosis is a novel and critical pathological mechanism involved in SMC loss and AD development. BRD4770 is a novel inhibitor of ferroptosis and protects against SMC ferroptosis via maintaining redox homeostasis. BRD4770 relieves BAPN-induced AD by inhibiting ferroptosis and inflammatory cell infiltration.