FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy

1University of Missouri-Kansas City School of Medicine.
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 02/2013; 304(8). DOI: 10.1152/ajpendo.00596.2012
Source: PubMed


Fibroblast growth factor 23 (FGF23) is a hormone primarily released by osteocytes that regulates phosphate and vitamin D metabolism. Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown if FGF23 can directly alter cardiac function. We found that FGF23 significantly increased cardiomyocyte cell size in vitro, the expression of gene markers of cardiac hypertrophy, and total protein content of cardiac muscle. In addition, FGFR1 and FGFR3 mRNA were the most abundantly expressed FGF receptors in cardiomyocytes and the co-receptor α-Klotho was expressed at very low levels. We tested an animal model of chronic kidney disease (Col4a3(-/-) mice) which has elevated serum FGF23. We found elevations in common hypertrophy gene markers in Col4a3(-/-) hearts compared to wild type, but did not observe changes in wall thickness or cell size by week 10. However, the Col4a3(-/-) hearts did show reduced fractional shortening (-17%) and ejection fraction (-11%). Acute exposure of primary cardiomyocytes to FGF23 resulted in elevated intracellular Ca(2+) ([Ca2+]i) (F/Fo +86%) which was blocked by verapamil pretreatment. FGF23 also increased ventricular muscle strip cardiac contractility (67%) which was inhibited by FGF receptor antagonism. We hypothesize that while FGF23 can acutely increase [Ca(2+)]i , chronically this may lead to decreases in contractile function or stimulate cardiac hypertrophy as observed with other stress hormones. In conclusion, FGF23 is a novel bone-heart endocrine factor and may be an important mediator of cardiac Ca2+ regulation and contractile function during chronic kidney disease.

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    • "FGF23 activated calcineurin/NFAT signaling in cultured cardiomyocytes. These findings indicate that FGF23 promotes cardiac hypertrophy by activating calcineurin/NFAT signaling in an endocrine manner (Table 1) (Faul et al., 2011; Faul, 2012; Touchberry et al., 2013). However, the mechanism of αKlotho-independent FGF23 signaling remains unclear. "
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