TY - JOUR
T1 - FGF23/FGFR4-mediated left ventricular hypertrophy is reversible
AU - Grabner, Alexander
AU - Schramm, Karla
AU - Silswal, Neerupma
AU - Hendrix, Matt
AU - Yanucil, Christopher
AU - Czaya, Brian
AU - Singh, Saurav
AU - Wolf, Myles
AU - Hermann, Sven
AU - Stypmann, Jörg
AU - Marco, Giovana Seno DI
AU - Brand, Marcus
AU - Wacker, Michael J.
AU - Faul, Christian
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019438573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019438573&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-02068-6
DO - 10.1038/s41598-017-02068-6
M3 - Article
C2 - 28512310
AN - SCOPUS:85019438573
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1993
ER -