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FGF23/FGFR4-mediated left ventricular hypertrophy is reversible.
Sci Rep. 2017 05 16; 7(1):1993.SR

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- and age-related LVH.

Authors+Show Affiliations

Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. Division of Nephrology, Department of Medicine, Duke University Medical Center, Duke University, Durham, North Carolina, USA.Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA.Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA. Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA. Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA.Division of Nephrology, Department of Medicine, Duke University Medical Center, Duke University, Durham, North Carolina, USA.European Institute for Molecular Imaging, University of Münster, Münster, Germany.Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.Department of Internal Medicine D, University Hospital Münster, Münster, Germany.Department of Internal Medicine D, University Hospital Münster, Münster, Germany.Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. cfaul@uabmc.edu. Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA. cfaul@uabmc.edu. Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA. cfaul@uabmc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28512310

Citation

Grabner, Alexander, et al. "FGF23/FGFR4-mediated Left Ventricular Hypertrophy Is Reversible." Scientific Reports, vol. 7, no. 1, 2017, p. 1993.
Grabner A, Schramm K, Silswal N, et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Rep. 2017;7(1):1993.
Grabner, A., Schramm, K., Silswal, N., Hendrix, M., Yanucil, C., Czaya, B., Singh, S., Wolf, M., Hermann, S., Stypmann, J., Di Marco, G. S., 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
Grabner A, et al. FGF23/FGFR4-mediated Left Ventricular Hypertrophy Is Reversible. Sci Rep. 2017 05 16;7(1):1993. PubMed PMID: 28512310.
* Article titles in AMA citation format should be in sentence-case
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 - Di Marco,Giovana Seno, AU - Brand,Marcus, AU - Wacker,Michael J, AU - Faul,Christian, Y1 - 2017/05/16/ PY - 2017/03/01/received PY - 2017/04/12/accepted PY - 2017/5/18/entrez PY - 2017/5/18/pubmed PY - 2018/12/19/medline SP - 1993 EP - 1993 JF - Scientific reports JO - Sci Rep VL - 7 IS - 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- and age-related LVH. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/28512310/FGF23/FGFR4_mediated_left_ventricular_hypertrophy_is_reversible_ L2 - https://doi.org/10.1038/s41598-017-02068-6 DB - PRIME DP - Unbound Medicine ER -