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FGF23 induced left ventricular hypertrophy mediated by FGFR4 signaling in the myocardium is attenuated by soluble Klotho in mice.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2019-11-21 , DOI: 10.1016/j.yjmcc.2019.11.149
Xiaobin Han 1 , Chun Cai 1 , Zhousheng Xiao 1 , L Darryl Quarles 1
Affiliation  

There is controversy regarding whether excess FGF23 causes left ventricular hypertrophy (LVH) directly through activation of fibroblast growth factor receptor 4 (FGFR4) in cardiomyocytes or indirectly through reductions in soluble Klotho (sK). We investigated the respective roles of myocardial FGFR4 and sKL in mediating FGF23-induced LVH using mouse genetic and pharmacological approaches. To investigate a direct role of myocardial FGFR4 in mediating the cardiotoxic effects of excess circulating FGF23, we administered rFGF23 to mice with cardiac-specific loss of FGFR4 (FGFR4 heart-cKO). We tested a model of sKL deficiency, hypertension and LVH created by the conditional deletion of FGFR1 in the renal distal tubule (FGFR1DT cKO mice). The cardioprotective effects of sKL in both mouse models was assessed by the systemic administration of recombinant sKL. We confirmed that FGF23 treatment activates PLCγ in the heart and induces LVH in the absence of membrane α-Klotho. Conditional deletion of FGFR4 in the myocardium prevented rFGF23-induced LVH in mice, establishing direct cardiotoxicity of FGF23 through activation of FGFR4. Recombinant sKL administration prevented LVH, but not HTN, in FGFR1DT cKO mice, consistent with direct cardioprotective effects. Co-administration of recombinant sKL with FGF23 in culture inhibited rFGF23-induced p-PLCγ signaling. Thus, FGF23 ability to include LVH represents a balance between FGF23 direct cardiac activation of FGFR4 and the modulating effects of circulating sKL to alter FGF23-dependent myocardial signaling pathways.

中文翻译:


在小鼠中,可溶性 Klotho 可减弱心肌中 FGFR4 信号介导的 FGF23 诱导的左心室肥大。



关于过量的 FGF23 是否直接通过心肌细胞中成纤维细胞生长因子受体 4 (FGFR4) 的激活或通过可溶性 Klotho (sK) 的减少间接导致左心室肥厚 (LVH) 存在争议。我们使用小鼠遗传和药理学方法研究了心肌 FGFR4 和 sKL 在介导 FGF23 诱导的 LVH 中各自的作用。为了研究心肌 FGFR4 在介导过量循环 FGF23 的心脏毒性作用中的直接作用,我们给心脏特异性 FGFR4 缺失(FGFR4 heart-cKO)的小鼠施用 rFGF23。我们测试了通过条件性删除肾远曲小管中 FGFR1 建立的 sKL 缺陷、高血压和 LVH 模型(FGFR1DT cKO 小鼠)。通过全身施用重组 sKL 来评估 sKL 在两种小鼠模型中的心脏保护作用。我们证实,FGF23 治疗可激活心脏中的 PLCγ,并在膜 α-Klotho 缺失的情况下诱导 LVH。心肌中 FGFR4 的条件性缺失可阻止 rFGF23 诱导的小鼠 LVH,通过激活 FGFR4 确定 FGF23 的直接心脏毒性。在 FGFR1DT cKO 小鼠中,重组 sKL 给药可以预防 LVH,但不能预防 HTN,这与直接心脏保护作用一致。重组 sKL 与培养物中的 FGF23 共同施用可抑制 rFGF23 诱导的 p-PLCγ 信号传导。因此,FGF23 包括 LVH 的能力代表了 FGF23 直接心脏激活 FGFR4 与循环 sKL 改变 FGF23 依赖性心肌信号传导途径的调节作用之间的平衡。
更新日期:2019-11-21
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