Abstract
Enhanced fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney and heart disease. Experimentally, FGF23 directly induces cardiac hypertrophy and vice versa cardiac hypertrophy stimulates FGF23. Besides the bone, FGF23 is expressed by cardiac myocytes, whereas its synthesis in other cardiac cell types and its paracrine role in the heart in health and disease is unknown. By co-immunofluorescence staining of heart tissue of wild-type mice, we show that Fgf23 is expressed by cardiac myocytes, fibroblasts and endothelial cells. Cardiac Fgf23 mRNA and protein level increases from neonatal to six months of age, whereas no age-related changes in bone Fgf23 mRNA expression were noted. Cardiac myocyte-specific disruption of Fgf23 using Cre-LoxP system (Fgf23fl/fl/cre+) caused enhanced mortality, but no differences in cardiac function or structure. Although pressure overload-induced cardiac hypertrophy induced by transverse aortic constriction (TAC) resulted in a slightly worse phenotype with a more severe reduced ejection fraction, higher end-systolic volume and more enlarged systolic LV diameter in Fgf23fl/fl/cre+ mice compared to controls, this was not translated to any worse cellular hypertrophy, fibrosis or chamber remodeling. TAC induced Fgf23 mRNA expression in whole cardiac tissue in both genotypes. Interestingly, co-immunofluorescence staining revealed enhanced Fgf23 synthesis in cardiac fibroblasts and endothelial cells but not in cardiac myocytes. RNA sequencing of isolated adult cardiac myocytes, cardiac fibroblasts and endothelial cells confirmed significantly higher Fgf23 transcription in cardiac fibroblasts and endothelial cells after TAC. Our data indicate that Fgf23 is physiologically expressed in various cardiac cell types and that cardiac fibroblasts and endothelial cells might be an important source of FGF23 in pathological conditions. In addition, investigations in Fgf23fl/fl/cre+ mice suggest that cardiac myocyte-derived FGF23 is needed to maintain cardiac function during pressure overload.
Highlights
Chronic kidney disease (CKD) is a worldwide health problem, and CKD patients suffer from an excessive high risk for cardiovascular disease (CVD) (Sarnak et al, 2003; Eckardt et al, 2013)
Fgf23 was clearly expressed in all regions of endocardium and endothelium (Figure 1A), while it appeared to be only minimal in the tunica media of the depicted vessels, which is predominantly composed of vascular smooth muscle cells (Figure 1A)
Enhanced fibroblast growth factor 23 (FGF23) levels are associated with the development of left ventricular hypertrophy (LVH) in patients with CKD (Kovesdy and Quarles, 2016) and it has been shown that FGF23 directly induces cardiac hypertrophy in vitro and in vivo (Faul et al, 2011)
Summary
Chronic kidney disease (CKD) is a worldwide health problem, and CKD patients suffer from an excessive high risk for cardiovascular disease (CVD) (Sarnak et al, 2003; Eckardt et al, 2013). Increased circulating FGF23 in CKD is linked to LVH development and mortality (Faul et al, 2011). In vitro and in vivo data show that FGF23 induces LVH by directly targeting the heart via binding and phosphorylating the intracellular receptor kinase domain of FGFR4 leading to the activation of the prohypertrophic calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway in a klotho-independent manner (Faul et al, 2011; Grabner et al, 2015). FGF23 promotes myocardial fibrosis via activation of β-Catenin (Hao et al, 2016), activates the intra-cardiac reninangiotensin-aldosterone system (RAAS), which in turn promotes LVH and cardiac fibrosis (Böckmann et al, 2019), and it is associated with endothelial dysfunction in CKD patients (Yilmaz et al, 2010), and in human coronary artery endothelial cells in vitro (Richter et al, 2016)
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