2. Academic Validation
  3. FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis

FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis

  • Acta Pharmacol Sin. 2023 May 24. doi: 10.1038/s41401-023-01101-x.
De-Pu Zhou 1 2,  Lian-Cheng Deng 1,  Xiao Feng 2,  Hui-Jing Xu 2,  Ye Tian 2,  Wei-Wei Yang 2,  Ping-Ping Zeng 2,  Li-Hui Zou 2,  Xi-Hua Yan 2,  Xia-Yan Zhu 1,  Dan-Hua Shu 1,  Qiang Guo 2,  Xiao-Ying Huang 1,  Saverio Bellusci 3,  Zhenkun Lou 4,  Xiao-Kun Li 5,  Jin-San Zhang 6 7
Affiliations

Affiliations

  • 1 Medical Research Center and the Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 2 International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
  • 3 Cardio-Pulmonary Institute and Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, 35392, Germany.
  • 4 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.
  • 5 International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000, China. Xiaokunli@wmu.edu.cn.
  • 6 Medical Research Center and the Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. Zhang_jinsan@wmu.edu.cn.
  • 7 International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000, China. Zhang_jinsan@wmu.edu.cn.
PMID: 37225844 DOI: 10.1038/s41401-023-01101-x
Abstract

Doxorubicin is a common chemotherapeutic agent in clinic, but myocardial toxicity limits its use. Fibroblast Growth Factor (FGF) 10, a multifunctional paracrine growth factor, plays diverse roles in embryonic and postnatal heart development as well as in cardiac regeneration and repair. In this study we investigated the role of FGF10 as a potential modulator of doxorubicin-induced cardiac cytotoxicity and the underlying molecular mechanisms. Fgf10+/- mice and an inducible dominant negative FGFR2b transgenic mouse model (Rosa26rtTA; tet(O)sFgfr2b) were used to determine the effect of Fgf10 hypomorph or blocking of endogenous FGFR2b ligands activity on doxorubicin-induced myocardial injury. Acute myocardial injury was induced by a single injection of doxorubicin (25 mg/kg, i.p.). Then cardiac function was evaluated using echocardiography, and DNA damage, oxidative stress and Apoptosis in cardiac tissue were assessed. We showed that doxorubicin treatment markedly decreased the expression of FGFR2b ligands including FGF10 in cardiac tissue of wild type mice, whereas Fgf10+/- mice exhibited a greater degree of oxidative stress, DNA damage and Apoptosis as compared with the Fgf10+/+ control. Pre-treatment with recombinant FGF10 protein significantly attenuated doxorubicin-induced oxidative stress, DNA damage and Apoptosis both in doxorubicin-treated mice and in doxorubicin-treated HL-1 cells and NRCMs. We demonstrated that FGF10 protected against doxorubicin-induced myocardial toxicity via activation of FGFR2/Pleckstrin homology-like domain family A member 1 (PHLDA1)/Akt axis. Overall, our results unveil a potent protective effect of FGF10 against doxorubicin-induced myocardial injury and identify FGFR2b/PHLDA1/Akt axis as a potential therapeutic target for patients receiving doxorubicin treatment.

Keywords

DNA damage; FGF10; FGFR2b; PHLDA1; doxorubicin cardiotoxicity; oxidative stress.

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