Long noncoding RNA SOX2OT is associated with myocardial fibrosis (MF) in heart failure (HF). This article aims to investigate the role of SOX2OT in MF. We constructed HF mouse models by subcutaneous injection of isoprenaline (ISO). Cardiac fibroblasts (CFs) were treated with ISO to induce MF.Hematoxylin‐eosin, Masson, and Sirius‐red staining were used to identify myocardial injury and collagen deposition in heart tissues. The relationship among SOX2OT, miR‐138‐5p, TGF‐β1, and Smad3 were evaluated by chromatin immunoprecipitation and luciferase reporter assay. The gene and protein expression were verified by quantitative real‐time PCR and western blot. We found that SOX2OT was up‐regulated in HF mice and ISO‐induced CFs. SOX2OT knockdown reduced myocardial injury and collagen deposition in HF mice. The expression of collagen I, α‐SMA, TGF‐β1, and p‐Smad3 were inhibited by SOX2OT down‐regulation in HF mice and ISO‐induced CFs. Furthermore, TGF‐β1 was a target gene of miR‐138‐5p and indirectly regulated by SOX2OT. SOX2OT promoted MF in HF by activating TGF‐β1/Smad3, and then Smad3 interacted with the SOX2OT promoter and formed a positive feedback loop. In conclusion, our work verifies that SOX2OT/Smad3 feedback loop promotes MF in HF. Thus, SOX2OT is potentially a novel therapeutic target for MF in HF.

中文翻译：

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LncRNA SOX2OT/Smad3反馈回路促进心力衰竭心肌纤维化

长链非编码 RNA SOX2OT 与心力衰竭 (HF) 中的心肌纤维化 (MF) 相关。本文旨在研究 SOX2OT 在 MF 中的作用。我们通过皮下注射异丙肾上腺素 (ISO) 构建了 HF 小鼠模型。用 ISO 处理心脏成纤维细胞 (CFs) 以诱导 MF。苏木精-伊红、马森和天狼星红染色用于鉴定心肌损伤和心脏组织中的胶原沉积。通过染色质免疫沉淀和荧光素酶报告基因检测评估 SOX2OT、miR-138-5p、TGF-β1 和 Smad3 之间的关系。通过实时定量 PCR 和蛋白质印迹验证基因和蛋白质的表达。我们发现 SOX2OT 在 HF 小鼠和 ISO 诱导的 CF 中上调。SOX2OT 敲低减少了 HF 小鼠的心肌损伤和胶原蛋白沉积。胶原蛋白 I、α-SMA、TGF-β1、在 HF 小鼠和 ISO 诱导的 CF 中，SOX2OT 下调抑制了 p-Smad3 和 p-Smad3。此外，TGF-β1 是 miR-138-5p 的靶基因，受 SOX2OT 间接调控。SOX2OT通过激活TGF-β1/Smad3促进HF中的MF，然后Smad3与SOX2OT启动子相互作用并形成正反馈回路。总之，我们的工作验证了 SOX2OT/Smad3 反馈回路在 HF 中促进了 MF。因此，SOX2OT 可能是 HF 中 MF 的新治疗靶点。