Direct and indirect effects of fibroblast growth factor 23 on the heart

Abstract

Fibroblast growth factor (FGF)23 is a bone-derived phosphotropic hormone that regulates phosphate and mineral homeostasis. Recent studies have provided evidence that a high plasma concentration of FGF23 is associated with cardiac disease, including left ventricular hypertrophy (LVH), heart failure, atrial fibrillation, and cardiac death. Experimental studies have shown that FGF23 activates fibroblast growth factor receptor 4 (FGFR4)/phospholipase Cγ/calcineurin/nuclear factor of activated T-cells signaling in cardiomyocytes and induces cardiac hypertrophy in rodents. Activation of FGFR4 by FGF23 normally requires the co-receptor α-klotho, and klotho-independent signaling occurs only under conditions characterized by extremely high FGF23 concentrations. Recent studies have demonstrated that FGF23 activates the renin-angiotensin-aldosterone system (RAAS) and induces LVH, at least in part as a result of lower vitamin D activation. Moreover, crosstalk between FGF23 and RAAS results in the induction of cardiac hypertrophy and fibrosis. In this review, we summarize the results of studies regarding the relationships between FGF23 and cardiac events, and describe the potential direct and indirect mechanisms whereby FGF23 induces LVH.

Keywords: FGF23; FGFR4; Heart; Left ventricle hypertrophy; cardiac event.

Figure 1

Direct and indirect mechanisms mediate the effects of fibroblast growth factor (FGF)23 on left ventricular hypertrophy. Hyperphosphatemia induces an increase in circulating FGF23 concentration by increasing its secretion by bone. FGF23 stimulates hypertrophic signaling via fibroblast growth factor receptor (FGFR)4 in cardiomyocytes. FGF23 also suppresses active vitamin D (VitD) synthesis in the kidney, and the activation of VitD is lower in a chronic kidney disease (CKD)-related milieu. Active VitD inhibits renin activity in the kidney and heart and increases serum angiotensin II (Ang II) concentration and its cardiac expression. Ang II binds to angiotensin II receptor type 1 (AT1R) in cardiomyocytes, causing cardiac hypertrophy and fibrosis. Inflammatory cytokines, a uremic milieu, Ang II, and aldosterone induce FGF23 transcription in cardiomyocytes. Circulating FGF23 also causes an increase in local angiotensinogen and Ang II expression in cardiomyocytes, leading to hypertrophy and fibrosis.