An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

Abstract

Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

The Complexity of FGF23 Effects on Cardiomyocytes in Normal and Uremic Milieu

“…Activated PLCy results in calcineurin activation and nuclear factor of activated T-cells (NFAT) dephosphorylation, which is then translocated to the nucleus with ensuing transcription of pro-hypertrophic genes (brain natriuretic peptide (BNP), regulator of calcineurin 1 (Rcan1), β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), etc.) [25,[60][61][62][63]. Of note, ANP and BNP are well-defined markers of cardiac hypertrophy [64].…”

“…To return to a previous intracellular Ca 2+ concentration in order to conduct relaxation, cytosolic Ca 2+ is either pumped to the sarcoplasmic reticulum (92% of cytosolic Ca 2+ ) by the action of the SR-Ca 2+ -adenosine triphosphatase 2a (SERCA) or is extruded to the extracellular space by the Na + -Ca 2+ exchanger (NCX) (7% of cytosolic Ca 2+ ) [67]. Calmodulin kinase II (CaMKII) and cAMP-dependent protein kinase (PKA) are involved in the opening of RyRs and they can also phosphorylate phospholamban (PLB), a sarcoplasmic reticulum membrane protein that regulates SERCA activity [63,68]. Depolarization of the cardiomyocyte membrane action potential opens L-type calcium channels at the sarcolemma allowing the Ca 2+ influx into the cytoplasm [66] that activates ryanodine receptors (RyRs), triggering a greater amount of Ca 2+ release from the sarcoplasmic reticulum into the cytoplasm [67].…”

“…To return to a previous intracellular Ca 2+ concentration in order to conduct relaxation, cytosolic Ca 2+ is either pumped to the sarcoplasmic reticulum (92% of cytosolic Ca 2+ ) by the action of the SR-Ca 2+ -adenosine triphosphatase 2a (SERCA) or is extruded to the extracellular space by the Na + -Ca 2+ exchanger (NCX) (7% of cytosolic Ca 2+ ) [67]. Calmodulin kinase II (CaMKII) and cAMP-dependent protein kinase (PKA) are involved in the opening of RyRs and they can also phosphorylate phospholamban (PLB), a sarcoplasmic reticulum membrane protein that regulates SERCA activity [63,68].…”

“…Experimental studies indicated FGF23 is involved in this Ca 2+ handling increasing phosphorylation of regulator proteins, such as CaMKII, inducing cardiomyocytes to develop a cellular phenotype related to contractile dysfunction and predisposition to arrhythmias [63,[69][70][71].…”

Changes in Intestinal Flora Structure and Metabolites Are Associated With Myocardial Fibrosis in Patients With Persistent Atrial Fibrillation

“…They are considered functional factors that directly reflect the degree of fibrosis ( 6 ). In addition, FGF-23 directly participates in the development of myocardial fibrosis by activating fibroblast growth factor receptor (FGFR) ( 7 ). Studies have also shown that FGF-23 induces atrial fibrosis in patients with atrial fibrillation by increasing reactive oxygen species (ROS) production and subsequently activating signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling ( 8 ).…”