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Published on: March 23, 2015
Calcitriol downregulates fibroblast growth factor receptor 1 through histone deacetylase activation in HL-1 atrial
Ting-Wei Lee1,2, Ting-I Lee2,3, Yung-Kuo Lin4,5
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei, 11031, Taiwan.
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.
Insights
Calcitriol reduces fibroblast growth factor receptor 1 (FGFR1) expression in cardiac cells. This action mitigates the harmful effects of fibroblast growth factor 2 (FGF-2) signaling, offering potential therapeutic benefits for cardiovascular diseases.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Signaling
Background:
- Fibroblast growth factor (FGF)-2 contributes to cardiovascular disease (CVD) pathophysiology by inducing cardiac hypertrophy via FGF receptor 1 (FGFR1) activation.
- Calcitriol is being investigated as a potential therapeutic agent for CVDs.
Purpose of the Study:
- To investigate if calcitriol regulates FGFR1 expression to modulate FGF-2 signaling in cardiac myocytes.
- To explore the underlying regulatory mechanisms of calcitriol's action on FGFR1.
Main Methods:
- Utilized Western blot, PCR, siRNA, and chromatin immunoprecipitation (ChIP) assays.
- Evaluated expressions of FGFR1-4, p-ERK, β-MHC, p-PLCγ, NFAT, and HDACs in HL-1 cells.
- Assessed effects of calcitriol, FGF-2, and SAHA (HDAC inhibitor) on cellular signaling pathways.
Main Results:
- Calcitriol significantly reduced FGFR1 expression in HL-1 cells, while FGFR2-4 remained unchanged.
- FGF-2-induced cardiac hypertrophy markers (p-ERK, β-MHC) were lower in calcitriol-treated cells.
- Calcitriol increased nuclear HDAC activity, leading to decreased histone H4 acetylation and increased HDAC3 at the FGFR1 promoter, thus downregulating FGFR1.
Conclusions:
- Calcitriol diminishes FGFR1 expression by activating histone deacetylases (HDACs).
- This mechanism ameliorates the detrimental effects of FGF-2 on cardiac myocytes, suggesting a novel therapeutic strategy for CVDs.
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