Micafungin protects mouse heart against doxorubicin-induced oxidative injury via suppressing MALT1-dependent k48-linked ubiquitination of Nrf2.

Autor: Lu LQ; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China., Li MR; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China., Huang LL; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China., Che YX; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China., Qi YN; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China., Luo XJ; Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China., Peng J; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China. Electronic address: Junpeng@csu.edu.cn.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Sep 01; Vol. 400, pp. 111179. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1016/j.cbi.2024.111179
Abstrakt: Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 μM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 μM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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