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| Status |
Public on Jul 16, 2024 |
| Title |
BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 accumula_x0002_tion. 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 fer_x0002_roptosis. 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 ef_x0002_fects of BRD4770 may reveal a potential therapeutic approach for targeting SMC ferroptosis in AD.
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| Overall design |
Human aortic smooth muscle cells (SMCs) were subjected to various interventions to induce ferroptosis and examine the protective effects of BRD4770, an inhibitor of histone methyltransferases. The experimental groups included: DMSO control group, Imidazole ketone erastin group, Imidazole ketone erastin + BRD4770 group, Cystine deprivation group,Cystine deprivation + BRD4770 group. RNA sequencing (RNA-seq) was performed on these groups to analyze gene expression changes.
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| Contributor(s) |
Chen Y, Jiang D, Wei X, Yi X |
| Citation missing |
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| BioProject |
PRJNA1129314 |
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| Submission date |
Jul 11, 2024 |
| Last update date |
Jul 16, 2024 |
| Contact name |
yue chen |
| Organization name |
Huazhong University of Science and Technology
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| Department |
Tongji Hospital
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| Lab |
Division of Cardiothoracic and Vascular Surgery
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| Street address |
no.1095 Jiefang Avenue
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| City |
Wuhan |
| State/province |
Hubei Province |
| ZIP/Postal code |
430030 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (15)
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE272018_gene_fpkm.xls.gz |
3.6 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
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