Calcitriol downregulates fibroblast growth factor receptor 1 through histone deacetylase activation in HL-1 atrial myocytes.
Calcitriol downregulates fibroblast growth factor receptor 1 through histone deacetylase activation in HL-1 atrial myocytes.
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DOI：
10.1186/s12929-018-0443-3
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发表时间：
2018-05-18
影响因子：
11
通讯作者：
Chen YJ
中科院分区：
文献类型：
--
作者：
Lee TW;Lee TI;Lin YK;Kao YH;Chen YJ
成纤维细胞生长因子（FGF）-2在心血管疾病（CVD）的病理生理学中起着至关重要的作用。据报道，FGF-2通过激活FGF受体1（FGFR 1）诱导心脏肥大。多项实验室检查结果表明骨化三醇可能是心血管疾病的潜在治疗方法。在本研究中，我们试图研究骨化三醇是否通过调节心肌细胞中FGFR 1的表达来调节FGF-2信号转导的作用，并探讨其潜在的调节机制。采用Western blot、聚合酶链反应、小分子干扰RNA、荧光活性分析和染色质免疫沉淀（ChIP）分析方法检测FGFR 1、FGFR 2、FGFR 3、FGFR 4、磷酸化细胞外信号调节激酶（p-ERK）、β-肌球蛋白重链（β-MHC）、磷酸化磷脂酶Cγ（p-PLCγ）、活化T细胞核因子（NFAT）、在不存在和存在FGF-2（25 ng/mL）或辛二酰异羟肟酸（SAHA，一种泛HDAC抑制剂，1 μM）的情况下，HL-1心房肌细胞中组蛋白去乙酰化酶（HDAC）的表达和酶活性。我们发现，与对照细胞相比，骨化三醇处理的HL-1细胞具有显著降低的FGFR 1表达。相反，FGFR 2、FGFR 3和FGFR 4的表达在骨化三醇处理的HL-1细胞和对照HL-1细胞之间相似。与对照细胞相比，FGF-2处理的HL-1细胞具有相似的PLCγ磷酸化和核/胞质NFAT表达。FGF-2诱导HL-1细胞p-ERK和β-MHC的表达低于对照组。FGFR 1敲低阻断FGF-2信号传导并逆转骨化三醇的保护作用。与对照细胞相比，骨化三醇处理的HL-1细胞具有更高的核HDAC活性。ChIP分析表明乙酰组蛋白H4显著减少，这与FGFR 1启动子中HDAC 3的增加有关。骨化三醇介导的FGFR 1下调在SAHA存在下减弱。骨化三醇通过HDAC激活减少FGFR 1表达，从而减轻FGF-2对心肌细胞的有害作用。
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. 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). 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. Calcitriol diminished FGFR1 expression through HDAC activation, which ameliorated the harmful effects of FGF-2 on cardiac myocytes.
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影响因子：
3.5
作者：
Lee, Ting-Wei;Kao, Yu-Hsun;Chen, Yi-Jen
通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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