BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection
BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection
复制标题
BRD4770 作为一种新型铁死亡抑制剂来预防主动脉夹层
DOI：
10.1016/j.phrs.2022.106122
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发表时间：
2022-02-11
影响因子：
9.3
通讯作者：
Jiang, Ding-Sheng
中科院分区：
文献类型：
--
作者：
Chen, Yue;Yi, Xin;Jiang, Ding-Sheng
平滑肌细胞（SMC）丢失是主动脉夹层（AD）发病机制中的特征性特征，而铁凋亡（ferroptosis）是一种由脂质过氧化积累驱动的新型铁依赖性调节性细胞死亡。然而，靶向铁凋亡是否是SMC损失和AD治疗的有效方法仍不清楚。在此，我们发现，铁水平，铁凋亡相关分子TFR，HOMX 1，铁蛋白和脂质过氧化产物4-羟基壬烯醛在AD的主动脉中增加。然后，我们筛选了几种组蛋白甲基转移酶抑制剂，发现BRD 4770对胱氨酸剥夺、咪唑酮erastin或RSL 3诱导的SMC铁凋亡具有保护作用。BRD 4770通过抑制组蛋白H3在赖氨酸9处的单甲基化、二甲基化和三甲基化（H3 K9 me 1/2/3）而重新激活经典的铁凋亡途径，即系统Xc-GPX 4、FSP 1CoQ 10和GCH 1-BH 4途径，这些途径被铁凋亡诱导剂抑制。RNA测序分析表明，铁凋亡与炎症反应之间存在正反馈调节，BRD 4770可逆转炎症激活对铁凋亡的影响。更重要的是，在13-氨基丙腈单富马酸盐诱导的小鼠AD模型中，BRD 4770治疗通过抑制炎症反应、脂质过氧化和铁凋亡减弱了主动脉扩张并降低了发病率和死亡率。总之，我们的研究结果表明，铁凋亡是一种新的和关键的病理机制，参与SMC损失和AD的发展。BRD 4770是一种新型的铁凋亡抑制剂，在最佳浓度下具有与Ferrostatin-1相当的保护作用。对BRD 4770的抗铁凋亡作用的理解可能揭示了一种靶向AD中SMC铁凋亡的潜在治疗方法。
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, FSP1CoQ10 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 13-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.