Download Chelsea Shapland - UMKC School of Medicine

Fibroblast growth factor 23 (FGF23) increases cardiac contractility and induces cardiac
mechanical alternans which are eliminated by FGFR4 antibody treatment and a PLC inhibitor.
1Chelsea
Shapland, 2Alexander Grabner, 2Christian Faul, 1Michael Wacker
1UMKC School of Medicine, 2University of Miami Miller School of Medicine
INTRODUCTION
• FGF23 is a hormone released from osteocytes to maintain
phosphate homeostasis. Serum levels increase up to 1000 fold
during chronic kidney disease (1).
• Our lab has previously shown that FGF23 increases intracellular
calcium in cardiac myocytes as well as increases contraction in
ventricular muscle strips (1).
• FGFR1-4 are expressed in the heart, but it is unknown which
receptor and pathway mediates these effects on contractility.
• Recently, it has been shown that FGF23-induced pathological
hypertrophy was mediated by FGFR4 (2) and inhibited by a
phospholipase C (PLC) inhibitor (3).
RESULTS
A
B
SUMMARY
Our working model is that stimulation of FGFR4 by FGF23 may lead to activation
of PLC, which activates of voltage-gated calcium channels (VGCC) to increase
intracellular calcium (1), and stimulates SERCA to increase SR calcium stores (3).
This increase in Ca+2 causes the inotropic effects and leakage of sarcoplasmic
reticulum (SR) calcium caused by calcium overload may promote the
mechanical alternans (arrhythmias) we observed.
HYPOTHESIS
• We hypothesize that pretreatment with FGFR4 blocking antibody
(U3 Pharma/Daiichi-Sankyo) as well as a PLC inhibitor (U73122)
will eliminate changes in cardiac contractility and mechanical
alternans caused by FGF23.
C
D
CONCLUSION/SIGNIFICANCE
•
METHODS
• Adult CD1 male mouse hearts were tested by cannulating the
aortas of isolated hearts and the coronary vasculature was
reverse perfused using a modified Langendorff-perfusion
system.
• Hearts were suspended in an oxygenated organ bath and paced
at 1.5 Hz with bipolar electrodes.
• FGF23 was given at 9000 pg/mL, FGFR4 antibody at 1 µM, and
U73122 at 5 µM.
• Contraction waveforms were analyzed using Powerlab hardware
and LabChart data acquisition software (ADInstruments)
•
•
Panel A: Modified Langendorff-perfusion system with aortic cannulation in an oxygenated organ
bath between stimulating electrodes. Hearts were paced at 1.5 Hz. Panel B: Average increase in
contractility caused by perfusion with FGF23. This was eliminated with pretreatment with the
FGFR4 antibody and U73122. (n=3-5, P<0.05). Panel C: Representative mechanical alternans after
treatment with FGF23. Panel D: Summary data of the average maximum number of alternans/min
caused by FGF23 which were eliminated by pretreatment with FGFR4 antibody and U73122. (n=35; P<0.05)
CREDITS/REFERENCES
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* denotes statistical significance from vehicle
FGF23 works through FGFR4 to alter contractility via the PLC
pathway. These results have implications for the ability of FGF23 to
induce arrhythmias in addition to other cardiac effects.
The cellular mechanisms responsible for the cardiac contractility and
cardiac alternans may be linked through the activation of calcium
pathways via PLC.
Cardiac FGFR4 and the PLC pathway are important targets for
preventing the pathological effects of FGF23 on the heart during
conditions like chronic kidney disease.
•
This project was supported by American Heart Association Grant (11SDG5330016) to MW and UMKC Sarah
Morrison Award to CS .
1. Touchberry et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to
cardiac hypertrophyJP Endo 2013.
2. Grabner et al. Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular
Hypertrophy. Cell Metab 2015.
3. Faul et al. FGF23 induced left ventricular hypertrophy. J.Clin. Invest. 2011