Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability

Abstract

Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, boasts significant potential for therapeutic intervention in cardiovascular dysfunctions. However, its impact on regulating fibrosis remains unexplored. This study aims to elucidate the role and mechanism of FGF13 on cardiac fibrosis. Here, we show that following transverse aortic constriction (TAC) surgery, interstitial fibrosis and collagen content increase in mice, along with reduced ejection fraction and fractional shortening, augmented heart mass. However, following Fgf13 deletion, interstitial fibrosis is decreased, ejection fraction and fractional shortening are increased, and heart mass is decreased, compared with those in the TAC group. Mechanistically, incubation of cardiac fibroblasts with transforming growth factor β (TGFβ) increases the expressions of types I and III collagen proteins, as well as α-smooth muscle actin (α-SMA) proteins, and enhances fibroblast proliferation and migration. In the absence of Fgf13, the expressions of these proteins are decreased, and fibroblast proliferation and migration are suppressed, compared with those in the TGFβ-stimulated group. Overexpression of FGF13, but not FGF13 mutants defective in microtubule binding and stabilization, rescues the decrease in collagen and α-SMA protein and weakens the proliferation and migration function of the Fgf13 knockdown group. Furthermore, Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. Collectively, cardiac Fgf13 knockdown protects the heart from fibrosis in response to haemodynamic stress by modulating microtubule stabilization and ROCK signaling pathway.

1. Introduction

Cardiac fibrosis serves as an integral component of cardiac remodeling, leading to diastolic dysfunction, arrhythmia, and heart failure [1]. It is a devastating condition typified by collagen accumulation in the extracellular matrix [2]. In the course of cardiac fibrosis pathology, cardiac fibroblasts first become activated and subsequently differentiate into myofibroblasts by signaling pathways such as transforming growth factor β (TGFβ) signaling [3], thus results in increased α-smooth muscle actin (α-SMA) expression. Subsequently, myofibroblasts which act as the main mediators of pathological remodeling, migrate to the injured site and produce a large amount of collagen, thereby leading to the pathological process of cardiac structural alterations [4–6]. Therefore, it is of great clinical significance to find effective methods to delay cardiac fibrosis.

Fibroblast growth factor (FGF) 13 is a member of the factor homologous factors (FHFs) family. The four FHFs, a subpopulation of the FGF family, have gained increased interest for their ability to regulate pressure overload heart disease. FGFs interact with the extracellular domains of FGF cell surface receptors (FGFRs) to trigger receptor activation and biological responses. FGF homologous factors (FHF1–FHF4, also referred to as FGF11–FGF14) exhibit substantial sequence homology with FGFs but fail to activate all seven known FGFRs and cannot be secreted [7,8]. FGF13 is the predominant FHF in adult mouse ventricular myocytes. It aids in regulating arrhythmias by controlling the current density of Na+ channels [9] and Ca2+-induced Ca2+ release [10]. Moreover, Fgf13 knockdown enhances caveolae-mediated cardioprotection during cardiac pressure overload [11]. Additionally, as a microtubule stabilizer, FGF13 regulates neuronal polarization and migration [12], manages inflammatory pain [13], and enhances the resistance of cancer cells to platinum drugs [14]. Although FGF13 is a potentially significant regulator of heart disease, its function in CFs remains unexplored.