Dexmedetomidine inhibits ferroptosis through the Akt/GSK3β/Nrf2 axis and alleviates adriamycin-induced cardiotoxicity

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-03 DOI:10.1016/j.lfs.2025.123609

Xuefeng Cao , Liang Zhao , Jian Zhou , Shi Ding , Ying Sun , Yang Ma , Zijian Ma , Hancheng Liu , Tianxin Dong , Aijing Luo , Yan Li , Bo Fang

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引用次数: 0

Abstract

The cardiotoxicity of Adriamycin(ADR) limits its clinical application, and its molecular mechanism is not very clear. At present, Dexrazoxane (DXZ) is the only approved drug to prevent ADR-induced cardiotoxicity (DIC), but it also has serious adverse reactions. Therefore, it is a key scientific challenge to find a drug with strong myocardial protection, few adverse reactions and no effect on the anti-tumor effect of ADR. In this study, we established the DIC model in rats. Cardiomyocyte hypertrophy and myocardial fibrosis increased significantly, and MDA and LDH increased significantly in serum. Dexmedetomidine (DEX) is a carbohydrate with multiple biological activities that can significantly improve the above DIC process. Echocardiography confirmed that DEX could reverse the changes of ESV, EDV, EF and FS induced by ADR. In vitro, experiments confirmed that DEX reversed the upregulation of ANP, BNP, MHC and Collagen III protein levels induced by ADR. DEX improves DIC by inhibiting ferroptosis. Erastin, a ferroptosis agonist, confirmed that DEX improved DIC by inhibiting ferroptosis. Mechanically, DEX increases the expression of Nrf2 in the nucleus through the Akt/Gsk3β signalling axis, thereby regulating ferroptosis in cardiomyocytes. In addition, DEX can improve DIC while not affecting the anti-tumor effect of ADR.

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右美托咪定通过Akt/GSK3β/Nrf2轴抑制铁下垂，减轻阿霉素诱导的心脏毒性

阿霉素的心脏毒性限制了其临床应用，其分子机制也不是很清楚。Dexrazoxane （DXZ）是目前唯一被批准用于预防adr诱导的心脏毒性（DIC）的药物，但它也有严重的不良反应。因此，寻找一种心肌保护作用强、不良反应少、不影响ADR抗肿瘤作用的药物是一项关键的科学挑战。本研究建立大鼠DIC模型。心肌细胞肥大、心肌纤维化明显增加，血清MDA、LDH明显升高。右美托咪定（DEX）是一种具有多种生物活性的碳水化合物，可以显著改善上述DIC过程。超声心动图证实，DEX可逆转ADR引起的ESV、EDV、EF和FS的变化。体外实验证实，DEX可逆转ADR诱导的ANP、BNP、MHC和Collagen III蛋白水平上调。DEX通过抑制铁下垂改善DIC。Erastin，一种铁下垂激动剂，证实了DEX通过抑制铁下垂改善DIC。从机械上讲，DEX通过Akt/Gsk3β信号轴增加细胞核中Nrf2的表达，从而调节心肌细胞的铁凋亡。DEX可改善DIC，但不影响ADR的抗肿瘤作用。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.