Fibrosis growth factor 23 is a promoting factor for cardiac fibrosis in the presence of transforming growth factor-β1

Abstract

Myocardial fibrosis is often associated with cardiac hypertrophy; indeed, fibrosis is one of the most critical factors affecting prognosis. We aimed to identify the molecules involved in promoting fibrosis under hypertrophic stimuli. We previously established a rat model of cardiac hypertrophy by pulmonary artery banding, in which approximately half of the animals developed fibrosis in the right ventricle. Here, we first comprehensively analyzed mRNA expression in the right ventricle with or without fibrosis in pulmonary artery banding model rats by DNA microarray analysis (GSE141650 at NCBI GEO). The expression levels of 19 genes were up-regulated more than 1.5-fold in fibrotic hearts compared with non-fibrotic hearts. Among them, fibrosis growth factor (FGF) 23 showed one of the biggest increases in expression. Real-time PCR analysis also revealed that, among the FGF receptor (FGFR) family, FGFR1 was highly expressed in fibrotic hearts. We then found that FGF23 was expressed predominantly in cardiomyocytes, while FGFR1 was predominantly expressed in fibroblasts in the rat ventricle. Next, we added FGF23 and transforming growth factor (TGF)-β1 (10-50 ng/mL of each) to isolated fibroblasts from normal adult rat ventricles and cultured them for three days. While FGF23 itself did not directly affect the expression levels of any fibrosis-related mRNAs, FGF23 enhanced the effect of TGF-β1 on increasing the expression levels of α-smooth muscle actin (α-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-β1 and FGF23 was attenuated by the inhibition of FGFR1 or the knockdown of FGFR1 in fibroblasts. Thus, FGF23 synergistically promoted the activation of fibroblasts with TGF-β1, transforming fibroblasts into myofibroblasts via FGFR1. Thus, we identified FGF23 as a paracrine factor secreted from cardiomyocytes to promote cardiac fibrosis under conditions in which TGF-β1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.

Role of fibroblast growth factor signalling in hepatic fibrosis

“…Studies in other organs indicate profibrogenic effects of FGF23. FGF23 has been shown to promote cardiac 129,130 and renal fibrosis. 131 In summary, both FGF19 and FGF21 have been shown to have beneficial effects on hepatic fibrosis, especially in metabolic associated liver disease, and are already investigated in clinical trials in patients with NAFLD.…”

The Multifunctional Contribution of FGF Signaling to Cardiac Development, Homeostasis, Disease and Repair

“…In an animal model of experimental hypertrophy that triggers myocardial fibrosis, Fgf23 and Fgfr1 are highly expressed. Indeed, FGF23 originating from cardiomyocytes elicits a boosting effect on fibrosis in a paracrine manner through FGFR1 on cardiac fibroblasts ( Kuga et al, 2020 ). In another hypertrophic and fibrotic model triggered by Ang II, the observed adverse structural and functional cardiac events are attributed to FGF23 activating the TGFβ1-miR-132 axis ( Ding et al, 2019 ).…”

FGF23, A Novel Muscle Biomarker Detected in The Early Stages of ALS

“…This may relate to a higher specificity of the antibody used in our studies. Interestingly, in cardiac tissue, FGF23 has been shown to promote activation of fibroblasts and fibrosis in the presence of TGF-β1, a cytokine that is elevated in ALS muscle and increases with disease progression 13,28 . Fibrosis is abundant in ALS muscle tissue with evidence linking it to TGF-β1 signaling 29,30 .…”