AUTHOR=Zhang Haiyan , Wang Zheng , Liu Zhengxia , Du Kang , Lu Xiang 

TITLE=Protective Effects of Dexazoxane on Rat Ferroptosis in Doxorubicin-Induced Cardiomyopathy Through Regulating HMGB1

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.685434

DOI=10.3389/fcvm.2021.685434

ISSN=2297-055X

ABSTRACT=Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). However, the mechanism of DXZ in ferroptosis and cardiomyopathy remains unclear. The research therefore explored the role and mechanism of DXZ in DOX-induced ferroptosis and cardiomyopathy in rats. Kaplan–Meier survival analysis was performed in rats treated by DOX in combination with ferroptosis inhibitor (FER-1) or other cell death-associated inhibitors. The ferroptosis, cardiotoxicity and expression of high mobility group box 1 (HMGB1) in rats treated by DOX in combination with FER-1 or with DXZ were determined by hematoxylin eosin (H&E) staining, Echo-cardiographic analysis and quantitative real-time PCR (qRT-PCR). The ferroptosis in DOX-treated rats received HMGB1  knockdown or overexpression was further detected using molecular experiments. Finally, the viability, the level of MDA and the expressions of ferroptosis-related markers (PTGS2, GPX4 and FTH1) of rat cardiomyocytes H9c2 exposed to DOX combined with FER-1, zVAD (an apoptosis inhibitor), DXZ or not were detected by performing molecular experiments. FER-1 increased the survival of the rats induced by DOX. The DOX-induced ferroptosis and cardiotoxicity could be reversed by FER-1 or DXZ. HMGB1 was induced by DOX but was inhibited by DXZ or FER-1. Overexpression of HMGB1 promoted the ferroptosis and cardiotoxicity induced by DOX in the rats, while silencing of HMGB1 showed opposite effects. The data indicated that DOX suppressed the viability and increased the MDA level in H9c2 cells in a dose-dependent manner. Moreover, DOX-induced increase of PTGS2 and decrease of GPX4 and FTH1 in H9c2 cells was reversed by DXZ or FER-1. Therefore, DXZ has protective effects on the ferroptosis and cardiomyopathy in rats through regulating HMGB1.