FGF23/FGFR4-mediated left ventricular hypertrophy is reversible

Alexander Grabner, Karla Schramm, Neerupma Silswal, Matt Hendrix, Christopher Yanucil, Brian Czaya, Saurav Singh, Myles Wolf, Sven Hermann, Jörg Stypmann, Giovana Seno DI Marco, Marcus Brand, Michael J. Wacker, Christian Faul

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35 Scopus citations

Abstract

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that directly targets cardiac myocytes via FGF receptor (FGFR) 4 thereby inducing hypertrophic myocyte growth and the development of left ventricular hypertrophy (LVH) in rodents. Serum FGF23 levels are highly elevated in patients with chronic kidney disease (CKD), and it is likely that FGF23 directly contributes to the high rates of LVH and cardiac death in CKD. It is currently unknown if the cardiac effects of FGF23 are solely pathological, or if they potentially can be reversed. Here, we report that FGF23-induced cardiac hypertrophy is reversible in vitro and in vivo upon removal of the hypertrophic stimulus. Specific blockade of FGFR4 attenuates established LVH in the 5/6 nephrectomy rat model of CKD. Since CKD mimics a form of accelerated cardiovascular aging, we also studied age-related cardiac remodeling. We show that aging mice lacking FGFR4 are protected from LVH. Finally, FGF23 increases cardiac contractility via FGFR4, while known effects of FGF23 on aortic relaxation do not require FGFR4. Taken together, our data highlight a role of FGF23/FGFR4 signaling in the regulation of cardiac remodeling and function, and indicate that pharmacological interference with cardiac FGF23/FGFR4 signaling might protect from CKD- A nd age-related LVH.

Original languageEnglish (US)
Article number1993
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

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    Grabner, A., Schramm, K., Silswal, N., Hendrix, M., Yanucil, C., Czaya, B., Singh, S., Wolf, M., Hermann, S., Stypmann, J., Marco, G. S. DI., Brand, M., Wacker, M. J., & Faul, C. (2017). FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Scientific reports, 7(1), [1993]. https://doi.org/10.1038/s41598-017-02068-6