Circ_0079480 通过促进 miR-338-3p 来激活 THBS1/TGF-β1/Smad3 信号通路，从而促进心房颤动中心房成纤维细胞的增殖、迁移和纤维化。
Circ_0079480 facilitates proliferation, migration and fibrosis of atrial fibroblasts in atrial fibrillation by sponing miR-338-3p to activate the THBS1/TGF-β1/Smad3 signaling.
机构信息
Department of General Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of General Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
出版信息
Int J Cardiol. 2024 Dec 1;416:132486. doi: 10.1016/j.ijcard.2024.132486. Epub 2024 Aug 24.
BACKGROUND
Atrial fibrosis is associated with the pathogenesis of atrial fibrillation (AF). This study aims to discuss the function of circ_0079480 in atrial fibrosis and its underlying mechanism.
METHODS
In vitro and in vivo models of atrial fibrosis were established by using angiotensin II (Ang II) to treat human atrial fibroblasts (HAFs) and C57/B6J mice. qRT-PCR and western blot were used to examine the mRNA and protein expression levels. CCK-8, EdU, cell strach, and transwell assays were performed to determine the proliferation and migration of HAFs. Dual-luciferase reporter and RIP/RNA pull-down assays were explored to identify the interaction of miR-338-3p and circ_0079480/THBS1. HE and Masson's trichrome staining experiments were performed to analyze the histopathological change in mice atrial tissues.
RESULTS
Circ_0079480 expression was increased in AF patients' atrial tissues and Ang II-treated HAFs. Silencing circ_0079480 inhibited cell proliferation and migration and reduced fibrosis-associated gene expression in Ang II-treated HAFs. Circ_0079480 could target miR-338-3p to repress its expression. MiR-338-3p inhibitor blocked the inhibitory effects of circ_0079480 knockdown on HAFs proliferation, migration, and fibrosis. Thrombospondin-1 (THBS1) was confirmed as a downstream target of miR-338-3p, and circ_0079480 could sponge miR-338-3p to upregulate THBS1 expression. Moreover, silencing THBS1 suppressed Ang II-induced proliferation, migration, and fibrosis in HAFs. More importantly, depletion of circ_0079480 inactivated the THBS1/TGF-β1/Smad3 signaling by upregulating miR-338-3p. Mice experiments also confirmed the suppression of circ_0079480 knockdown on atrial fibrosis.
CONCLUSION
Circ_0079480 acts as a sponge of miR-338-3p to upregulate THBS1 expression and activate the TGF-β1/Smad3 signaling, finally promoting Ang II-induced atrial fibrosis.
背景
心房纤维化与心房颤动（AF）的发病机制有关。本研究旨在探讨 circ_0079480 在心房纤维化中的作用及其潜在机制。
方法
使用血管紧张素 II（Ang II）处理人心房成纤维细胞（HAFs）和 C57/B6J 小鼠建立心房纤维化的体外和体内模型。qRT-PCR 和 Western blot 用于检测 mRNA 和蛋白表达水平。CCK-8、EdU、细胞划痕和 Transwell 测定用于测定 HAFs 的增殖和迁移。双荧光素酶报告和 RIP/RNA 下拉测定用于鉴定 miR-338-3p 和 circ_0079480/THBS1 的相互作用。HE 和 Masson 三色染色实验用于分析小鼠心房组织的组织病理学变化。
结果
AF 患者心房组织和 Ang II 处理的 HAFs 中 circ_0079480 的表达增加。沉默 circ_0079480 抑制 Ang II 处理的 HAFs 中的细胞增殖和迁移，并降低纤维化相关基因的表达。Circ_0079480 可以靶向 miR-338-3p 以抑制其表达。miR-338-3p 抑制剂阻断了 circ_0079480 敲低对 HAFs 增殖、迁移和纤维化的抑制作用。血小板反应蛋白 1（THBS1）被确认为 miR-338-3p 的下游靶标，circ_0079480 可以海绵 miR-338-3p 以上调 THBS1 表达。此外，沉默 THBS1 抑制了 Ang II 诱导的 HAFs 增殖、迁移和纤维化。更重要的是，沉默 circ_0079480 通过上调 miR-338-3p 使 THBS1/TGF-β1/Smad3 信号失活。小鼠实验也证实了 circ_0079480 敲低对心房纤维化的抑制作用。
结论
Circ_0079480 作为 miR-338-3p 的海绵上调 THBS1 表达并激活 TGF-β1/Smad3 信号，最终促进 Ang II 诱导的心房纤维化。
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