Fibroblast Growth Factor 23 Stimulates Cardiac Fibroblast Activity through Phospholipase C-Mediated Calcium Signaling.

Int J Mol Sci

Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.

Published: December 2021

AI Article Synopsis

  • FGF-23 contributes to cardiac issues by promoting hypertrophy and calcium dysregulation in heart cells, potentially leading to arrhythmia and heart failure.
  • The study focused on FGF-23's impact on cardiac fibroblast activity, finding that higher doses (25 ng/mL) significantly increased the proliferation and migration of human atrial fibroblasts.
  • Key findings include increased calcium entry and elevated expression of specific calcium channels in FGF-23-treated cells, underscoring the role of FGF-23 signaling through FGF receptor 1, which can be inhibited to reduce its effects.

Article Abstract

Fibroblast growth factor (FGF)-23 induces hypertrophy and calcium (Ca) dysregulation in cardiomyocytes, leading to cardiac arrhythmia and heart failure. However, knowledge regarding the effects of FGF-23 on cardiac fibrogenesis remains limited. This study investigated whether FGF-23 modulates cardiac fibroblast activity and explored its underlying mechanisms. We performed MTS analysis, 5-ethynyl-2'-deoxyuridine assay, and wound-healing assay in cultured human atrial fibroblasts without and with FGF-23 (1, 5 and 25 ng/mL for 48 h) to analyze cell proliferation and migration. We found that FGF-23 (25 ng/mL, but not 1 or 5 ng/mL) increased proliferative and migratory abilities of human atrial fibroblasts. Compared to control cells, FGF-23 (25 ng/mL)-treated fibroblasts had a significantly higher Ca entry and intracellular inositol 1,4,5-trisphosphate (IP) level (assessed by fura-2 ratiometric Ca imaging and enzyme-linked immunosorbent assay). Western blot analysis showed that FGF-23 (25 ng/mL)-treated cardiac fibroblasts had higher expression levels of calcium release-activated calcium channel protein 1 (Orai1) and transient receptor potential canonical (TRPC) 1 channel, but similar expression levels of α-smooth muscle actin, collagen type IA1, collagen type Ⅲ, stromal interaction molecule 1, TRPC 3, TRPC6 and phosphorylated-calcium/calmodulin-dependent protein kinase II when compared with control fibroblasts. In the presence of ethylene glycol tetra-acetic acid (a free Ca chelator, 1 mM) or U73122 (an inhibitor of phospholipase C, 1 μM), control and FGF-23-treated fibroblasts exhibited similar proliferative and migratory abilities. Moreover, polymerase chain reaction analysis revealed that atrial fibroblasts abundantly expressed FGF receptor 1 but lacked expressions of FGF receptors 2-4. FGF-23 significantly increased the phosphorylation of FGF receptor 1. Treatment with PD166866 (an antagonist of FGF receptor 1, 1 μM) attenuated the effects of FGF-23 on cardiac fibroblast activity. In conclusion, FGF-23 may activate FGF receptor 1 and subsequently phospholipase C/IP signaling pathway, leading to an upregulation of Orai1 and/or TRPC1-mediated Ca entry and thus enhancing human atrial fibroblast activity.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745152PMC
http://dx.doi.org/10.3390/ijms23010166DOI Listing

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