Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease.
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SUBMITTER: Courbebaisse M
PROVIDER: S-EPMC5286949 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rationale & objectiveAn elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals.Study designProspective cohort study.Setting & participantsParticipants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789).ExposureBaseline carboxy-terminal FGF-23 (cFGF-23) level.OutcomesAll-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years.Analytical approachWe assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort.ResultsAddition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome.LimitationsPower to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds.ConclusionsAmong individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.
| S-EPMC6875624 | biostudies-literature
Project description:ObjectivesFibroblast Growth Factor 23 (FGF23) is well documented as a crucial player in the systemic regulation of phosphate homeostasis. Moreover, loss-of-function experiments have revealed that FGF23 also has a phosphate-independent and local impact on skeletogenesis. Here, we used ATDC5 cell line to investigate the expression of FGF23 and the role it may play locally during the differentiation of these cells.MethodsATDC5 cells were differentiated in the presence of insulin, and treated with recombinant FGF23 (rFGF23), inorganic phosphate (Pi) and/or PD173074, an inhibitor of FGF receptors (FGFRs). The mRNA expressions of FGF23, FGFRs and markers of hypertophy, Col X and MMP13, were determined by qPCR analysis and FGF23 production was assessed by ELISA. FGFR activation was determined by immunoprecipitation and immunoblotting.ResultsFGF23 mRNA expression and production were increased during ATDC5 differentiation. At D28 in particular, rFGF23 stimulation increased hypertrophic markers expression, as Col X and MMP13, and mineralization. A synergic effect of Pi and rFGF23 stimulation was observed on these markers and on the mineralization process. The use of PD173074, a pan-FGFR inhibitor, decreased terminal differentiation of ATDC5 by preventing rFGF23 pro-hypertrophic effects.ConclusionsAltogether, our results provide evidence that FGF23 plays an important role during differentiation of ATDC5 cell line, by promoting both hypertrophy and mineralization.
| S-EPMC5390990 | biostudies-literature
Project description:Fibroblast growth factor (FGF) 23 is elevated in chronic kidney disease (CKD) to maintain phosphate homeostasis. FGF23 is associated with left ventricular hypertrophy (LVH) in CKD and induces LVH via klotho-independent FGFR4-mediated activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling in animal models, displaying systemic alterations possibly contributing to heart injury. Whether elevated FGF23 per se causes LVH in healthy animals is unknown. By generating a mouse model with high intra-cardiac Fgf23 synthesis using an adeno-associated virus (AAV) expressing murine Fgf23 (AAV-Fgf23) under the control of the cardiac troponin T promoter, we investigated how cardiac Fgf23 affects cardiac remodeling and function in C57BL/6 wild-type mice. We report that AAV-Fgf23 mice showed increased cardiac-specific Fgf23 mRNA expression and synthesis of full-length intact Fgf23 (iFgf23) protein. Circulating total and iFgf23 levels were significantly elevated in AAV-Fgf23 mice compared to controls with no difference in bone Fgf23 expression, suggesting a cardiac origin. Serum of AAV-Fgf23 mice stimulated hypertrophic growth of neonatal rat ventricular myocytes (NRVM) and induced pro-hypertrophic NFAT target genes in klotho-free culture conditions in vitro. Further analysis revealed that renal Fgfr1/klotho/extracellular signal-regulated kinases 1/2 signaling was activated in AAV-Fgf23 mice, resulting in downregulation of sodium-phosphate cotransporter NaPi2a and NaPi2c and suppression of Cyp27b1, further supporting the bioactivity of cardiac-derived iFgf23. Of interest, no LVH, LV fibrosis, or impaired cardiac function was observed in klotho sufficient AAV-Fgf23 mice. Verified in NRVM, we show that co-stimulation with soluble klotho prevented Fgf23-induced cellular hypertrophy, supporting the hypothesis that high cardiac Fgf23 does not act cardiotoxic in the presence of its physiological cofactor klotho. In conclusion, chronic exposure to elevated cardiac iFgf23 does not induce LVH in healthy mice, suggesting that Fgf23 excess per se does not tackle the heart.
| S-EPMC8581397 | biostudies-literature
Project description: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.C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ?65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (? = 6.71 [95% CI 4.35-9.01] g per doubling of FGF23). 32% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM ? = 9.71 [95% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (? = 3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97-1.48]).In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
| S-EPMC3840534 | biostudies-literature
Project description:Enhanced fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney and heart disease. Experimentally, FGF23 directly induces cardiac hypertrophy and vice versa cardiac hypertrophy stimulates FGF23. Besides the bone, FGF23 is expressed by cardiac myocytes, whereas its synthesis in other cardiac cell types and its paracrine role in the heart in health and disease is unknown. By co-immunofluorescence staining of heart tissue of wild-type mice, we show that Fgf23 is expressed by cardiac myocytes, fibroblasts and endothelial cells. Cardiac Fgf23 mRNA and protein level increases from neonatal to six months of age, whereas no age-related changes in bone Fgf23 mRNA expression were noted. Cardiac myocyte-specific disruption of Fgf23 using Cre-LoxP system (Fgf23fl/fl/cre+) caused enhanced mortality, but no differences in cardiac function or structure. Although pressure overload-induced cardiac hypertrophy induced by transverse aortic constriction (TAC) resulted in a slightly worse phenotype with a more severe reduced ejection fraction, higher end-systolic volume and more enlarged systolic LV diameter in Fgf23fl/fl/cre+ mice compared to controls, this was not translated to any worse cellular hypertrophy, fibrosis or chamber remodeling. TAC induced Fgf23 mRNA expression in whole cardiac tissue in both genotypes. Interestingly, co-immunofluorescence staining revealed enhanced Fgf23 synthesis in cardiac fibroblasts and endothelial cells but not in cardiac myocytes. RNA sequencing of isolated adult cardiac myocytes, cardiac fibroblasts and endothelial cells confirmed significantly higher Fgf23 transcription in cardiac fibroblasts and endothelial cells after TAC. Our data indicate that Fgf23 is physiologically expressed in various cardiac cell types and that cardiac fibroblasts and endothelial cells might be an important source of FGF23 in pathological conditions. In addition, investigations in Fgf23fl/fl/cre+ mice suggest that cardiac myocyte-derived FGF23 is needed to maintain cardiac function during pressure overload.
| S-EPMC8804498 | biostudies-literature
Project description:Development of rational therapeutic treatments of Alzheimer disease (AD) requires the elucidation of the etiopathogenic mechanisms of neurofibrillary degeneration and β-amyloidosis, the two hallmarks of this disease. Here we show, employing an adeno-associated virus serotype 1 (AAV1)-induced expression of the C-terminal fragment (I(2CTF)) of I(2)(PP2A), also called SET, in rat brain, decrease in protein phosphatase 2A (PP2A) activity, abnormal hyperphosphorylation of tau, and neurodegeneration; littermates treated identically but with vector only, i.e., AAV1-enhanced green fluorescent protein (GFP), served as a control. Furthermore, there was an increase in the level of activated glycogen synthase kinase-3β and enhanced expression of intraneuronal Aβ in AAV1-I(2CTF) animals. Morris water maze behavioral test revealed that infection with AAV1-I(2CTF) induced spatial reference memory and memory consolidation deficits and a decrease in the brain level of pSer133-CREB. These findings suggest a novel etiopathogenic mechanism of AD, which is initiated by the cleavage of I(2)(PP2A), producing I(2CTF), and describe a novel disease-relevant nontransgenic animal model of AD.
| S-EPMC3229424 | biostudies-literature
Project description:Background Higher fibroblast growth factor-23 ( FGF -23) levels are associated with incident heart failure ( HF ) in MESA (the Multiethnic Study of Atherosclerosis). FGF -23 is also associated with left ventricular hypertrophy. Whether the FGF -23 association with HF is similar for heart failure with reduced ejection fraction ( HF r EF ) and heart failure with preserved ejection fraction ( HF p EF ) is not well established. Methods and Results We studied 6542 participants (mean age 62±10 years, 53% women, mean estimated glomerular filtration rate of 81±18 mL/min per 73 m2) from MESA who were free of cardiovascular disease at baseline (2000-2002). HF events were ascertained by an adjudication committee for a median follow-up of 12.1 years. We classified HF events as HF r EF (ejection fraction [ EF ] <50%) or HF p EF [ EF ] ≥50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios and 95% confidence intervals for the association between baseline serum FGF -23 and incident HF r EF and HF p EF . A total of 134 events were classified as HF p EF , 151 HF r EF , and 49 unknown EF . Following imputation, 149 were classified as HF p EF , 176 HF r EF , and 291 participants had HF (34 participants had HF p EF then HF r EF ). In the fully adjusted model, higher FGF -23 levels were associated with incident HF p EF but not with HF r EF (hazard ratio 1.29, 95% confidence interval, 1.08-1.54) versus (hazard ratio 1.04, 95% confidence interval, 0.84-1.29) for each 20 pg/mL higher serum FGF -23 concentration. Conclusions FGF -23 association with HF is driven by the association with HF p EF but not with HF r EF in a population-based cohort. Further studies are needed to determine the pathological mechanisms mediating this association.
| S-EPMC6222949 | biostudies-literature
Project description:BackgroundHeart failure with preserved ejection fraction (HFpEF) is characterized by left ventricular hypertrophy and decreased exercise capacity. Fibroblast growth factor 23 (FGF23), a hormone involved in phosphate, vitamin D, and iron homeostasis, is linked to left ventricular hypertrophy and HF. We measured c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels and examined their associations with exercise capacity in patients with HFpEF.Methods and resultsUsing multivariable linear regression and linear mixed models, we studied the associations of cFGF23 and iFGF23 with baseline and mean weekly change over 24 weeks in peak oxygen consumption and 6-minute walk distance in individuals enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial. Our study population included 172 individuals with available plasma for cFGF23 and iFGF23 measurements. Median (25th-75th percentile) baseline cFGF23 and iFGF23 levels were 208.7 RU/mL (132.1-379.5 RU/mL) and 90.3 pg/mL (68.6-128.5 pg/mL), respectively. After adjustment for cardiovascular disease and hematologic and kidney parameters, higher cFGF23 was independently associated with a lower peak oxygen consumption at baseline. Higher iFGF23 was independently associated with shorter 6-minute walk distance at baseline. No significant associations were appreciated with the longitudinal outcomes.ConclusionsIn patients with HFpEF, higher FGF23 levels are independently associated with decreased exercise capacity at baseline.
| S-EPMC7914143 | biostudies-literature
Project description:BackgroundElevated fibroblast growth factor 23 (FGF23) levels have been associated with mortality in adults with heart failure (HF), but data on FGF23 levels in paediatric HF are limited. In this prospective cohort study, we aimed to assess the prognostic value of FGF23 in children with chronic HF.MethodsWe prospectively enrolled 40 children with chronic HF and 20 matched healthy controls. In each patient, a complete diagnostic workup was performed, including transthoracic echocardiography to evaluate cardiac systolic and diastolic functions. Serum FGF23, renal function tests, parathyroid hormone, serum calcium and phosphate were measured in patients and controls. N-terminal probrain natriuretic peptide (NT-proBNP) was measured in patients. The severity of symptoms was assessed using the modified Ross HF classification for children. Patients were followed for 1 year, and clinical worsening events such as death and HF hospitalisation were recorded.ResultsPatients with HF had significantly higher FGF23 levels compared with controls (355.68±97.27 pg/mL and 60.20±11.04 pg/mL, respectively; p<0.001). Three patients died and 11 were admitted with HF. In comparison with patients without clinical worsening events, these 14 patients exhibited significantly higher FGF23 levels (320.04±89.56 pg/mL and 421.86±75.50 pg/mL, respectively; p<0.001). FGF23 was positively correlated with NT-proBNP and left ventricular end-diastolic diameter and negatively correlated with ejection fraction and fractional shortening. The ability of FGF23 to predict clinical worsening events in patients was analysed using a receiver operating characteristic curve. The optimal cut-off point was 375 pg/mL, with 85.71% sensitivity, 84.62% specificity, positive predictive value of 75.0, negative predictive value of 91.7 and area under the curve (AUC) of 0.878. Multivariable regression analysis revealed that FGF23 is the only independent predictor of clinical worsening events in children with chronic HF.ConclusionFGF23 levels were elevated in children with chronic HF and increased significantly as Ross score class increased. FGF23 levels increased in patients who experienced clinical worsening events.
| S-EPMC9972412 | biostudies-literature
Project description:This review examines the role of fibroblast growth factor-23 (FGF-23) in mineral metabolism, innate immunity and adverse cardiovascular outcomes.FGF-23, produced by osteocytes in bone, activates FGFR/?-Klotho (?-Kl) complexes in the kidney. The resulting bone-kidney axis coordinates renal phosphate reabsorption with bone mineralization, and creates a counter-regulatory feedback loop to prevent vitamin D toxicity. FGF-23 acts to counter-regulate the effects of vitamin D on innate immunity and cardiovascular responses. FGF-23 is ectopically expressed along with ?-Kl in activated macrophages, creating a proinflammatory paracrine signaling pathway that counters the antiinflammatory actions of vitamin D. FGF-23 also inhibits angiotensin-converting enzyme 2 expression and increases sodium reabsorption in the kidney, leading to hypertension and left ventricular hypertrophy. Finally, FGF-23 is purported to cause adverse cardiac and impair neutrophil responses through activation of FGFRs in the absence of ?-Kl. Although secreted forms of ?-Kl have FGF-23 independent effects, the possibility of ?-Kl independent effects of FGF-23 is controversial and requires additional experimental validation.FGF-23 participates in a bone-kidney axis regulating mineral homeostasis, proinflammatory paracrine macrophage signaling pathways, and in a bone-cardio-renal axis regulating hemodynamics that counteract the effects of vitamin D.
| S-EPMC5051268 | biostudies-literature