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

Abstract

Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown whether 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 coreceptor ␣-klotho was expressed at very low levels. We tested an animal model of chronic kidney disease (Col4a3 Ϫ/Ϫ mice) that has elevated serum FGF23. We found elevations in common hypertrophy gene markers in Col4a3 Ϫ/Ϫ hearts compared with wild type but did not observe changes in wall thickness or cell size by week 10. However, the Col4a3 Ϫ/Ϫ hearts did show reduced fractional shortening (Ϫ17%) and ejection fraction (Ϫ11%). Acute exposure of primary cardiomyocytes to FGF23 resulted in elevated intracellular Ca 2ϩ ([Ca 2ϩ ]i; F/Fo ϩ 86%) which was blocked by verapamil pretreatment. FGF23 also increased ventricular muscle strip contractility (67%), which was inhibited by FGF receptor antagonism. We hypothesize that although FGF23 can acutely increase [Ca 2ϩ ]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 Ca 2ϩ regulation and contractile function during chronic kidney disease. fibroblast growth factor 23; pathological cardiac hypertrophy; chronic kidney disease; Col4a3; cardiac function; ␣-klotho FIBROBLAST GROWTH FACTOR 23 (FGF23) is a hormone released primarily by osteocytes (2, 4, 14, 38) that functions to regulate phosphate and vitamin D homeostasis through direct actions on the kidney and parathyroid (2). Although an endocrine axis has been established between bone and kidney, a new paradigm is emerging in which FGF23 could be important in establishing an endocrine axis between bone and heart. Circulating levels of FGF23 are markedly elevated 100-to 1,000-fold in patients with chronic kidney disease (CKD) (24, 31) and are independently associated with cardiovascular morbidity and mortality (8,22,26,34,35,48,52). Specifically, an association between left ventricular (LV) hypertrophy and serum FGF23 levels has been established in CKD patients (20,36,52).Nevertheless, despite strong associations between FGF23 and adverse outcomes, it remains relatively unknown whether FGF23 is simply a marker of cardiac disease risk or a direct mediator of cardiac pathology and cardiac performance. Only one study to date has analyzed the direct effects of FGF23 on the heart both in vitro and in vivo (13). This important work by Faul et al. (13) shows that FGF23 can directly induce hypertrophy in isolated neonatal cardiomyocytes as well as with intramyocardial FGF23 injections. These authors also demonstrated that a FGF receptor (FGF...

Pathogenesis of Arrhythmias in a Model of CKD

“…44 In cultured cardiomyocytes, FGF23 can induce a rise in intracellular calcium that can be prevented by pretreatment with verapamil. 45 Both PTH and FGF23 progressively rise with loss of kidney function in humans with CKD 46 and this animal model, perhaps explaining the increased calcium influx, and might further alter normal calcium recycling within the cytoplasm. This result, together with a downregulation of SERCA2a, may lead to a concomitant increase in arrhythmias.…”

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

“…Hence, of great relevance to these epidemiologic observations were the landmark findings of Faul et al (7), showing that FGF23 can directly induce hypertrophic gene programs in the cardiomyocyte, leading to LVH at the elevated levels seen in some advanced CKD patients. Independent investigators have subsequently corroborated these finding, showing the hypertrophic effect of FGF23 on cultured cardiomyocytes, and suggested that FGF23 might also have additional effects on myocardial contractility (68). Notably, in the study by Faul et al (7), these effects were apparently transduced by the FGF receptor independent of a-klotho, which, according to the current paradigm, is an obligate coreceptor for physiologic FGF23 signaling in the kidney tubules and parathyroid glands (69).…”

FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability

“…Recently, Faul et al (16) and our research group (67) have shown that high concentrations of FGF23 have direct actions on the heart that alter contractile performance and induce cardiac hypertrophy. These data strongly suggest that FGF23 has the potential to directly initiate some of the pathological cardiovascular changes observed during CKD.…”