Atorvastatin treatment ameliorates cardiac function and remodeling induced by isoproterenol attack through mitigation of ferroptosis
Atorvastatin treatment ameliorates cardiac function and remodeling induced by isoproterenol attack through mitigation of ferroptosis
复制标题
阿托伐他汀治疗通过减轻铁死亡来改善异丙肾上腺素攻击引起的心脏功能和重塑
DOI：
10.1016/j.bbrc.2021.08.017
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发表时间：
2021-08-23
影响因子：
3.1
通讯作者：
Wang, Daxin
中科院分区：
文献类型：
--
作者：
Ning, Dong;Yang, Xinquan;Wang, Daxin
铁凋亡已被确定为在受损心脏中的重要作用。同时，他汀类药物治疗已被报道在不同条件下对心力衰竭（HF）的治疗有益。然而，他汀类药物治疗对心力衰竭患者铁凋亡调节的有益作用已被揭示。本研究的目的是探讨阿托伐他汀对异丙肾上腺素（ISO）诱导的心力衰竭中铁凋亡相关信号通路的保护作用。我们发现，ATV和ferostatin-1（Fer-1，作为阳性对照）显着改善ISO降低的细胞活力和细胞存活，通过减少氧化应激和Fe 2+依赖性脂质过氧化作用在H9 C2细胞。此外，ISO触发了显著的铁蛋白吞噬，伴随着在受损细胞中上调LC 3BII、NCOA 4和Beclin 1的蛋白水平以及下调P62和FTH 1的蛋白水平，然而，这被ATV施用显著阻断，并且这些结果与3-甲基腺嘌呤（3-MA）处理后获得的结果平行。同样，本研究中使用C57 BL/6 J小鼠，并给予5 mg/kg/天ISO 2周以模拟心脏损伤。20 mg/kg/d ATV治疗2周，同时显著改善ISO发作引起的心功能不全和重构。ATV通过抑制铁凋亡相关信号通路的激活而发挥明显的保护作用，表现为降低PTGS 2（铁凋亡的标志物）的mRNA水平、丙二醛含量和NOX 4的蛋白水平，增加谷胱甘肽（GSH）含量、GSH/GSSG比值和GPX 4和SLC 7A 11的蛋白水平。此外，ISO在衰竭的心脏中明显地引发FTH 1的降解。然而，ATV显着防止这些变化在受损的心脏。总体而言，这些结果表明，阿托伐他汀通过抑制铁蛋白吞噬介导的铁细胞凋亡来抑制铁细胞凋亡，并对ISO损伤后小鼠衰竭的心肌具有保护作用，这可能是预防ISO相关心肌病的潜在治疗策略。(C)2021爱思唯尔公司All rights reserved.
Ferroptosis has been identified as an important role in damaged heart. Meanwhile, statin therapy has been reported to be beneficial for the treatment of heart failure(HF) under different conditions. However, the beneficial effects of statin treatment on regulation of ferroptosis in failing heart is unveiled. The aim of this study is to explore the protective efficacy of atorvastatin against the ferroptosis related signaling pathway in isoproterenol(ISO)-induced HF. We found that ATV and ferrostatin-1(Fer-1,as a positive control) significantly improved ISO-decreased cell viability and cell survival by reducing oxidative stress and Fe2+-dependent lipid peroxidation in H9C2 cells. Additionally, ISO triggered marked ferritinophagy accompanied by up-regulating protein levels of LC3BII,NCOA4 and Beclin1 and down-regulating protein levels of P62 and FTH1 in damaged cells, which nevertheless was significantly blocked by administration of ATV and these results were in parallel with the results obtained after 3-methyadenine(3-MA) treatment. Consistently, C57BL/6J mice were used in used in this study and administered 5 mg/kg/day ISO for 2 weeks to simulate cardiac injury. 20 mg/kg/day ATV treatment for 2 weeks simultaneously markedly improved cardiac dysfunction and remodeling induced by ISO attack. ATV showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2(a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione(GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. Moreover, ISO evidently triggered degradation of FTH1 in failing heart. However, ATV significantly prevented these changes in damaged heart. Overall, these results reveal atorvastatin suppresses ferroptosis and exhibits protective effect on failing myocardium of mice after ISO insult though inhibiting ferritinophagy-mediated ferroptosis, which might be a potential therapeutic strategy in the prevention of ISO-associated cardiomyopathy. (C) 2021 Elsevier Inc. All rights reserved.