Fibroblast growth factor 13 deficiency attenuates doxorubicin-induced cardiotoxicity by regulating Parkin-mediated myocardial injury

Abstract

The clinical use of doxorubicin (DOX) as a chemotherapeutic agent is limited by its cardiotoxic effects. Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, has been increasingly recognized as an important regulator of cardiovascular disease. However, its role in doxorubicin-induced cardiotoxicity remains unknown. Therefore, the objective of this study is to investigate the role and mechanism of FGF13 in doxorubicin-induced cardiac injury. C57BL/6 mice are used to establish Dox-induced cardiotoxicity models. The results reveal that mouse weight, cardiomyocyte cross-sectional area, ejection fraction and fractional shortening are decreased in the DOX group. In contrast, Fgf13 deficiency mitigates doxorubicin-mediated cardiotoxicity, as indicated by increased mouse weight, cardiomyocyte cross-sectional area, ejection fraction and fractional shortening. Mechanistically, the protein expressions of bax and cleaved caspase 3 are elevated in the DOX-treated group, along with decreased JC-1 fluorescence intensity and bcl-2 expression, whereas Fgf13 knockout prevents these alterations. In addition, Parkin, but not p53, interacts with FGF13 and is upregulated in response to Fgf13 deficiency in a mouse model of doxorubicin-induced cardiotoxicity. Overall, Fgf13 knockout attenuates doxorubicin-induced cardiomyocyte apoptosis and mitochondrial damage through the modulation of Parkin, indicating that FGF13 may serve as a promising therapeutic target for DOX-induced cardiotoxicity.

1. Introduction

Doxorubicin (DOX), an anthracycline-class drug, is widely used as a chemotherapeutic agent in various malignancies [1]. However, its dose-dependent cardiotoxicity leads to irreversible myocardial degeneration, significantly restricting its clinical application [2,3]. Moreover, DOX-induced cardiotoxicity can manifest both acutely and years after anthracycline treatment, leading to left ventricular dilation and systolic dysfunction, cardiomyocyte apoptosis, and myocardial damage and atrophy [2,4]. Optimizing the options for chemotherapy while avoiding cardiac complications remains a key priority in clinical care. Therefore, further efforts to understand the underlying mechanisms involved in this condition are essential for the development of new therapies.

Fibroblast growth factor (FGF) homologous factors (FHFs) are encoded by four genes within the FGF superfamily (FGF11-14). As part of the FGF superfamily, FHFs do not function as growth factors and are incapable of activating FGF receptors [5]. FGF13, the most abundantly expressed FHF in the murine heart [6], directly binds to microtubules, participates in regulating calcium signaling in heart failure [7, 8], and modulates ROCK signaling in cardiac fibrosis [9]. Moreover, Fgf13 deficiency enhances caveolae-mediated cardioprotection [10] and inhibits NF-κB activation during cardiac pressure overload [11]. These studies suggest that FGF13 is a potentially significant regulator of heart disease. However, its effect on DOX-induced injury remains unexplored.

Parkin, a RING-between-RING E3 ubiquitin ligase, participates in various complex cellular processes, including mitophagy, apoptosis, immune signaling, and differentiation [12,13]. Moreover, the FGF13-sensitive alteration of Parkin safeguards mitochondrial homeostasis in the endothelium in type 2 diabetic nephropathy through the promotion of mitophagy and the inhibition of apoptosis [14]. Although insights into the molecular mechanism involved in DOX-induced cardiotoxicity are increasing, it remains unclear whether Fgf13 deficiency mitigates this toxicity through the regulation of Parkin.