Guo Lei, Yang Bo, Chen Fa, Yuan Xiaoshuang, Cheng Jinyang, Chen Xiaoxu, Zhou Ying, Yang Xu, Li Yanju, Liu Yang, Tang Dongxin, Wang Feiqing
Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, Guizhou Province, 550001, China.
Department of Hematology Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China.
Biol Trace Elem Res. 2025 Sep 18. doi: 10.1007/s12011-025-04828-2.
Fluoride (F), an environmental contaminant, is known to induce cardiotoxicity, although the precise molecular mechanisms remain unclear. This study aimed to investigate the role of the SIRT1/PI3K/AKT signaling pathway in F-induced cardiotoxicity and explore the potential protective effects of SIRT1 activation. Human AC16 cardiomyocytes and zebrafish embryos were exposed to increasing concentrations of sodium NaF. Cellular assays were used to assess viability, apoptosis, cell cycle distribution, and oxidative stress. Expression levels of oxidative and inflammatory markers, as well as components of the SIRT1/PI3K/AKT pathway, were analyzed by western blotting, immunofluorescence, and real-time PCR. Zebrafish were evaluated for cardiac developmental abnormalities, apoptosis, and oxidative stress. The SIRT1 agonist SRT1720 was used to evaluate the protective effects of SIRT1 activation. Statistical analysis was performed using SPSS 23 Software and GraphPad Prism7 software, with significant differences evaluated by one-way analysis of variance (ANOVA) and Dunnett's test (p < 0.05). NaF exposure significantly inhibited AC16 cell proliferation, induced G1 phase arrest, and increased apoptosis in a dose-dependent manner. Reactive oxygen species levels were elevated, accompanied by downregulation of antioxidant proteins and upregulation of inflammatory cytokines. NaF markedly suppressed SIRT1, PI3K, and AKT expression while activating FOXO1a. Zebrafish embryos exhibited dose-dependent cardiac malformations, increased apoptosis, and elevated oxidative stress markers. Treatment with SRT1720 restored SIRT1/PI3K/AKT pathway activity, enhanced cell proliferation, reduced apoptosis, and alleviated oxidative and inflammatory responses in both cell and zebrafish models. This study demonstrates that F induces cardiotoxicity by disrupting the SIRT1/PI3K/AKT signaling pathway, leading to increased oxidative stress, inflammation, and apoptosis. Activation of SIRT1 by SRT1720 mitigates these effects, highlighting the protective role of this pathway in F-related cardiac injury. These findings provide mechanistic insights and identify potential molecular targets for the prevention and treatment of fluorosis-associated cardiovascular toxicity.
氟化物（F）作为一种环境污染物，已知会诱发心脏毒性，但其确切的分子机制仍不清楚。本研究旨在探讨SIRT1/PI3K/AKT信号通路在氟诱导的心脏毒性中的作用，并探索激活SIRT1的潜在保护作用。将人AC16心肌细胞和斑马鱼胚胎暴露于浓度不断增加的氟化钠（NaF）中。采用细胞实验评估细胞活力、凋亡、细胞周期分布和氧化应激。通过蛋白质免疫印迹、免疫荧光和实时定量PCR分析氧化和炎症标志物以及SIRT1/PI3K/AKT通路成分的表达水平。对斑马鱼的心脏发育异常、凋亡和氧化应激进行评估。使用SIRT1激动剂SRT1720评估激活SIRT1的保护作用。使用SPSS 23软件和GraphPad Prism7软件进行统计分析，通过单因素方差分析（ANOVA）和Dunnett检验评估显著差异（p < 0.05）。暴露于NaF会显著抑制AC16细胞增殖，诱导G1期阻滞，并以剂量依赖的方式增加细胞凋亡。活性氧水平升高，同时抗氧化蛋白下调，炎症细胞因子上调。NaF显著抑制SIRT1、PI3K和AKT的表达，同时激活FOXO1a。斑马鱼胚胎表现出剂量依赖性的心脏畸形、细胞凋亡增加以及氧化应激标志物升高。在细胞和斑马鱼模型中，用SRT1720处理可恢复SIRT1/PI3K/AKT通路活性，增强细胞增殖，减少细胞凋亡，并减轻氧化和炎症反应。本研究表明，氟通过破坏SIRT1/PI3K/AKT信号通路诱导心脏毒性，导致氧化应激、炎症和细胞凋亡增加。SRT1720激活SIRT1可减轻这些影响，突出了该通路在氟相关心脏损伤中的保护作用。这些发现提供了机制性见解，并确定了预防和治疗氟中毒相关心血管毒性的潜在分子靶点。
