FGF23/FGFR4-mediated left ventricular hypertrophy is reversible.

Published on May 16, 2017in Scientific Reports4.38
· DOI :10.1038/S41598-017-02068-6
Alexander Grabner16
Estimated H-index: 16
(UM: University of Miami),
Karla Schramm5
Estimated H-index: 5
(UM: University of Miami)
+ 11 AuthorsChristian Faul40
Estimated H-index: 40
(UAB: University of Alabama at Birmingham)
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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.
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References31
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#8Wang-jun Liao (Southern Medical University)H-Index: 16
// Huixin Hao 1,* , Xixian Li 1,* , Qingman Li 1,* , Hairuo Lin 1 , Zhenhuan Chen 1 , Jiahe Xie 1 , Wanling Xuan 1 , Wangjun Liao 2 , Jianping Bin 1 , Xiaobo Huang 1 , Masafumi Kitakaze 1,3 and Yulin Liao 1 1 State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China 3 Cardiovascular Division of the Department of Medicine, Nation...
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#1Alexander Grabner (UM: University of Miami)H-Index: 16
#2Ansel P. Amaral (UM: University of Miami)H-Index: 7
Last. Christian Faul (UM: University of Miami)H-Index: 40
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Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that...
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#2Stefan ReuterH-Index: 29
Last. Marcus Brand (WWU: University of Münster)H-Index: 17
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Background. Activation of fibroblast growth factor receptor (FGFR)-dependent signalling by FGF23 may contribute to the complex pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). Pan FGFR blockade by PD173074 prevented development of LVH in the 5/6 nephrectomy rat model of CKD, but its ability to treat and reverse established LVH is unknown. Methods. CKD was induced in rats by 5/6 nephrectomy. Two weeks later, rats began treatment with vehicle (0.9% NaCl) or PD173...
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#1Neerupma Silswal (UMKC: University of Missouri–Kansas City)H-Index: 9
#2Chad D. Touchberry (UMKC: University of Missouri–Kansas City)H-Index: 12
Last. Michael J. Wacker (UMKC: University of Missouri–Kansas City)H-Index: 22
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Fibroblast growth factor 23 (FGF23) is secreted primarily by osteocytes and regulates phosphate and vitamin D metabolism. Elevated levels of FGF23 are clinically associated with endothelial dysfunc...
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#1Jyothsna Gattineni (UTSW: University of Texas Southwestern Medical Center)H-Index: 16
#2Priyatharshini Alphonse (UTSW: University of Texas Southwestern Medical Center)H-Index: 1
Last. Michel BaumH-Index: 55
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Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D3 [1,25(OH)2 Vitamin D3]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1–4 with “b” and “c” isofor...
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#1Sarah N. Cilvik (WashU: Washington University in St. Louis)H-Index: 2
#2Joy I. Wang (WashU: Washington University in St. Louis)H-Index: 2
Last. David M. Ornitz (WashU: Washington University in St. Louis)H-Index: 109
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Fibroblast growth factors (FGFs) and their receptors are highly conserved signaling molecules that have been implicated in postnatal cardiac remodeling. However, it is not known whether cardiomyocyte-expressed FGF receptors are necessary or sufficient for ventricular remodeling in the adult heart. To determine whether cardiomyocytes were competent to respond to an activated FGF receptor, and to determine if this signal would result in the development of hypertrophy, we engineered a doxycycline (...
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#1Anna Jovanovich (University of Colorado Denver)H-Index: 13
#2Joachim H. Ix (UCSD: University of California, San Diego)H-Index: 83
Last. Michel Chonchol (University of Colorado Denver)H-Index: 76
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Objectives In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.
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#1Gina M. YanochkoH-Index: 5
#2Allison VitskyH-Index: 8
Last. Eileen R. BlasiH-Index: 8
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mg/ kg) or once daily for 6 days with a small molecule MEK inhibitor (3 mg/kg). Serum phosphorous and FGF23 levels increased in all rats during the course of the study. Histologically, rats dosed with either drug exhibited multifocal, multiorgan soft tissue mineralization. Expression levels of the sodium phosphate transporter Npt2a and the vitamin D–metabolizing enzymes Cyp24a1 and Cyp27b1 were modulated in kidneys of animals dosed with the pan-FGFR inhibitor. Both inhibitors decreased ERK phosp...
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#7Adeera Levin (UBC: University of British Columbia)H-Index: 29
In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinar...
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#1Chad D. Touchberry (UMKC: University of Missouri–Kansas City)H-Index: 12
#2Troy M. Green (UMKC: University of Missouri–Kansas City)H-Index: 2
Last. Michael J. Wacker (UMKC: University of Missouri–Kansas City)H-Index: 22
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Fibroblast growth factor 23 (FGF23) is a hormone released primarily by osteocytes that regulates phosphate and vitamin D metabolism. Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown whether FGF23 can directly alter cardiac function. We found that FGF23 significantly increased cardiomyocyte cell size in vitro, the expression of gene markers of cardiac hypertrophy, and total protein...
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Cited By58
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#1Z. Dai (UA: University of Arizona)
Last. M. Zhu (Children's Memorial Hospital)
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Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological proce...
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#1Ludmila Milovanova (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 1
#2M V Taranova (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 5
Last. Mikhail Ratanov (MSMU: I.M. Sechenov First Moscow State Medical University)
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BACKGROUND In chronic kidney disease (CKD) cardiovascular remodeling (CVR) is very frequent compared with general population and, as suppose, may be associated with «new» renal risk factors. The aim of study was to estimate association of new serum biomarkers (FGF-23, Klotho) and traditional biomarker of cardiac damage-serum Troponin I (sTr-I) with signs of CVR. METHODS One hundred thirty CKD G1-5D patients without cardiovascular disease (CVD) clinical manifestation were included. We measured se...
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#1Helen Alderson (Salford Royal NHS Foundation Trust)H-Index: 8
#2Rajkumar Chinnadurai (Salford Royal NHS Foundation Trust)H-Index: 5
Last. Philip A. Kalra (Salford Royal NHS Foundation Trust)H-Index: 54
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BACKGROUND Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes. METHODS We m...
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#1L Yu Milovanova (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 3
#2V. D. Beketov (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 2
Last. A. I. Pasechnik (MSMU: I.M. Sechenov First Moscow State Medical University)
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#1Christopher Yanucil (UM: University of Miami)H-Index: 8
#2Dominik Kentrup (UAB: University of Alabama at Birmingham)H-Index: 16
Last. Kylie Heitman (UAB: University of Alabama at Birmingham)H-Index: 1
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Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2...
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AIMS Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF. METHODS AND RESULTS A case-cohort design with 1.8 -1.9 years follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The ...
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#1Andrea Grund (MHH: Hannover Medical School)H-Index: 6
#2Manish D. Sinha ('KCL': King's College London)H-Index: 25
Last. Maren Leifheit-Nestler (MHH: Hannover Medical School)H-Index: 14
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Cardiovascular diseases (CVD) are a hallmark in paediatric patients with chronic kidney disease (CKD) contributing to an enhanced risk of all-cause and CV morbidity and mortality in these patients. The bone-derived phosphaturic hormone fibroblast growth factor (FGF) 23 progressively rises with declining kidney function to maintain phosphate homeostasis. Up to 1000-fold increase in patients with kidney failure, FGF23 is associated with the development of left ventricular hypertrophy (LVH) and the...
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#4J. S.H. Lee (NU: Northwestern University)H-Index: 207
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