Leucine zipper protein 1 prevents doxorubicin-induced cardiotoxicity in mice.

Di Fan, Zhili Jin, Jianlei Cao, Yi Li, Tao He, Wei Zhang, Li Peng, Huixia Liu, Xiaoyan Wu, Ming Chen, Yongzhen Fan, Bo He, Wenxi Yu, Hairong Wang, Xiaorong Hu, Zhibing Lu

Redox biology 2023 Aug

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Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1 (LUZP1) plays critical roles in cardiovascular development, and this study is designed for determining its function and mechanism in DOX-induced cardiotoxicity. Cardiac-specific Luzp1 knockout (cKO) and transgenic (cTG) mice received a single or repeated DOX injections to establish acute and chronic cardiotoxicity. Biomarkers of inflammation, oxidative damage and cell apoptosis were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Meanwhile, primary cardiomyocytes were applied to confirm the beneficial effects of LUZP1 in depth. LUZP1 was upregulated in DOX-injured hearts and cardiomyocytes. Cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated DOX-associated inflammation, oxidative damage, cell apoptosis and acute cardiac injury. Mechanistic studies revealed that LUZP1 ameliorated DOX-induced cardiotoxicity through activating 5'-AMP-activated protein kinase (AMPK) pathway, and AMPK deficiency abolished the cardioprotection of LUZP1. Further findings suggested that LUZP1 interacted with protein phosphatase 1 to activate AMPK pathway. Moreover, we determined that cardiac-specific LUZP1 overexpression could also attenuate DOX-associated chronic cardiac injury in mice. LUZP1 attenuates DOX-induced inflammation, oxidative damage, cell apoptosis and ventricular impairment through regulating AMPK pathway, and gene therapy targeting LUZP1 may provide novel therapeutic approached to treat DOX-induced cardiotoxicity. Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Di Fan, Zhili Jin, Jianlei Cao, Yi Li, Tao He, Wei Zhang, Li Peng, Huixia Liu, Xiaoyan Wu, Ming Chen, Yongzhen Fan, Bo He, Wenxi Yu, Hairong Wang, Xiaorong Hu, Zhibing Lu. Leucine zipper protein 1 prevents doxorubicin-induced cardiotoxicity in mice. Redox biology. 2023 Aug;64:102780