Chapter 10 - FGF23 and heart and vascular disease

Abstract

Fibroblast growth factor 23 (FGF23) is secreted by osteocytes to maintain serum phosphate within the normal range. Endocrine effects of bone-derived FGF23 on the cardiovascular system were not considered possible for a long time, because its physiological coreceptor α-Klotho is not or only to a small extent expressed in heart tissue of humans and rodents. However, enhanced circulating FGF23 levels were associated with the progression of left ventricular hypertrophy (LVH) and all-cause and cardiovascular mortality in patients with chronic kidney disease. Experimental studies demonstrated that FGF23 directly induces hypertrophic growth of cardiac myocytes via FGFR4-dependent activation of PLCγ/calcineurin/NFAT signaling independent of α-Klotho. Further studies suggest an upregulation of intracardiac FGF23 in certain clinical settings, which may also promote pathological cardiac remodeling and heart failure independent of preserved or reduced renal function through autocrine or paracrine mechanisms. Thereby, FGF23 is expressed in cardiac myocytes, cardiac fibroblasts, vascular smooth muscle and endothelial cells, and in inflammatory macrophages, thereby promoting LVH, LV fibrosis, and endothelial dysfunction. However, it seems that the context, level, and duration of FGF23 synthesis are key factors for its cardiotoxicity. To date, it is not clear whether high circulating and/or cardiac FGF23 levels per se lead to a pathological cardiac phenotype. Likewise, multiple studies in humans, animals, and cell culture models raise the suggestion that FGF23 is not only a bad player causing adverse outcomes but may also act beneficial, depending on the concentration, duration of exposure or disease versus health status. Here, we summarize recent clinical and experimental data regarding pathological and physiological mechanisms of FGF23's action on the heart and vascular system and discuss novel target strategies for the generation of drugs tackling FGF23-mediated cardiovascular diseases.