Abstract 15231: Oncostatin M Receptor Deletion Decreases FGF23 After Transaortic Constriction in Mice and Receptor Activation Correlates With Increased FGF23 in Patients With Aortic Stenosis

Objectives: Fibroblast growth factor 23 (FGF23) is becoming increasingly recognized as biomarker for heart failure (HF). We have previously shown that oncostatin M (OSM) is the strongest cytokine which induces FGF23 secretion from cultured cardiomyocytes. Although the bone is regarded as the source of FGF23, we have also demonstrated that cardiomyocytes of patients with end-stage HF strongly express FGF23. In this study we tested the hypothesis that the hypertrophied, non-failing heart is a source of circulating FGF23 via OSM receptor (Oβ) activation. Methods: Transaortic constriction (TAC) was performed in WT and Oβ knock-out mice (OβKO). Sham operated mice served as control. We have analysed myocardial biopsies and serum from patients with aortic stenosis (AS) with preserved ejection fraction. Patients with kidney disease were excluded from the study. Serum from healthy volunteers served as a control. Proteome and transcriptome profiling of serum and tissue samples in mice and AS patients were performed by mass spectrometry, multiplex assays, RT-PCR, ELISA, confocal microscopy (CM) and Western blots (WB). Results: Four weeks after TAC, WT mice animals showed significant increases in circulating FGF23 in comparison to sham-operated mice (583±117 (n=10) vs 218±36 pg/mL (n=10); p<0.05). Furthermore, CM, WB and RT-PCR analysis consistently revealed up-regulation of FGF23 expression and increased Oβ mRNA levels (100±10% (n=8) vs 284±26% (n=8); p<0.01) in cardiomyocytes. Conversely, TAC-OβKO showed reduction of circulating FGF23 to Sham levels (215±39 pg/mL (n=11); p<0.02) and significantly decreased myocardial FGF23 expression as compared to TAC in WT mice. Similarly, AS patients showed a 2.7-fold higher expression of Oβ in comparison to control tissue (269±77 (n=8) vs 100±28% (n=4); p<0.05). FGF23 serum levels were elevated 4-fold in comparison to serum from volunteers (85±47 (n=19) vs 23±2 (n=16) RU/mL; p<0.01). Conclusions: Our data demonstrate that Oβ activation is responsible for the cardiac release of FGF23 into the circulation in TAC animals. Activation of Oβ and increased levels of FGF23 in patients with AS indicates that FGF23 is a potential biomarker in AS patients with compensated hypertrophy before the onset of HF.