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Abstract Background Fibroblast growth factor (FGF)-2 plays a crucial role in the pathophysiology of cardiovascular diseases (CVDs). FGF-2 was reported to induce cardiac hypertrophy through activation of FGF receptor 1 (FGFR1). Multiple laboratory findings indicate that calcitriol may be a potential treatment for CVDs. In this study, we attempted to investigate whether calcitriol regulates FGFR1 expression to modulate the effects of FGF-2 signaling in cardiac myocytes and explored the potential regulatory mechanism. Methods Western blot, polymerase chain reaction, small interfering RNA, fluorometric activity assay, and chromatin immunoprecipitation (ChIP) analyses were used to evaluate FGFR1, FGFR2, FGFR3, FGFR4, phosphorylated extracellular signal-regulated kinase (p-ERK), β-myosin heavy chain (β-MHC), phosphorylated phospholipase Cγ (p-PLCγ), nuclear factor of activated T cells (NFAT), and histone deacetylase (HDAC) expressions and enzyme activities in HL-1 atrial myocytes without and with calcitriol (1 and 10 nM) treatment, in the absence and presence of FGF-2 (25 ng/mL) or suberanilohydroxamic acid (SAHA, a pan-HDAC inhibitor, 1 μM). Results We found that calcitriol-treated HL-1 cells had significantly reduced FGFR1 expression compared to control cells. In contrast, expressions of FGFR2, FGFR3, and FGFR4 were similar between calcitriol-treated and control HL-1 cells. FGF-2-treated HL-1 cells had similar PLCγ phosphorylation and nuclear/cytoplasmic NFAT expressions compared to control cells. FGF-2 induced lower expressions of p-ERK and β-MHC in calcitriol-treated HL-1 cells than in control cells. FGFR1-knockdown blocked FGF-2 signaling and reversed the protective effects of calcitriol. Compared to control cells, calcitriol-treated HL-1 cells had higher nuclear HDAC activity. The ChIP analysis demonstrated a significant decrease in acetyl-histone H4, which is associated with an increase in HDAC3 in the FGFR1 promoter. Calcitriol-mediated FGFR1 downregulation was attenuated in the presence of SAHA. Conclusions Calcitriol diminished FGFR1 expression through HDAC activation, which ameliorated the harmful effects of FGF-2 on cardiac myocytes. |
