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<p>Cardiac fibrosis following myocardial infarction (MI) is a critical determinant of progressive cardiac dysfunction, yet the underlying mechanisms driving this pathological process remain incompletely understood. Elucidating these regulatory pathways holds profound implications for improving post-MI prognosis.</p><p>Our prior work demonstrated that chronic intermittent hypoxia (CIH) exacerbates cardiac fibrosis while modulating the expression of long non-coding RNA (lncRNA) nonnmmut065573 (tentatively designated LncRNA-IH) in cardiac tissues. Herein, we sought to determine the role of LncRNA-IH in post-MI cardiac fibrosis and its underlying mechanisms. Using a C57BL/6 mouse model of MI, we established a mouse model with cardiac-specific overexpression of LncRNA-IH to evaluate post-MI cardiac fibrosis. In vitro, primary cardiac fibroblasts (MCF) and the PA12 cell line were subjected to LncRNA-IH overexpression or siRNA-mediated knockdown, and cell proliferation and migration were assessed. Transcriptomic profiling was performed to characterize LncRNA-IH-induced changes in cardiac gene expression and signaling pathways, aiming to elucidate the molecular mechanisms involved.</p><p>Results showed that CIH significantly exacerbated post-MI cardiac fibrosis, and LncRNA-IH was predominantly localized to cardiac fibroblasts. Cardiac-specific overexpression of LncRNA-IH in MI mice markedly exacerbated post-MI cardiac dysfunction and fibrosis. In vitro, LncRNA-IH overexpression significantly enhanced the proliferation and migration capacities of primary cardiac fibroblasts and PA12 cells, whereas these effects were abrogated by LncRNA-IH knockdown. Transcriptomic analysis revealed that LncRNA-IH elicited significant alterations in cardiac gene expression profiles, specifically activating the TGF-β1 signaling pathway and upregulating the expression of its downstream target, ZEB1.</p><p>Collectively, our findings indicate that LncRNA-IH promotes cardiac fibroblast proliferation and migration, thereby exacerbating post-MI cardiac remodeling, at least in part through activation of the TGF-β1 signaling pathway. This study identifies LncRNA-IH as a potential therapeutic target for mitigating post-MI cardiac fibrosis and preserving cardiac function.</p>

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LncRNA nonnmmut065573 promotes post-myocardial infarction cardiac fibrosis and activates the TGF-β1/ZEB1 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Chaowei Hu,
  • Lijie Han,
  • Zhiyong Du,
  • Huahui Yu,
  • Yunhui Du,
  • Linyi Li,
  • Haili Sun,
  • Yu Wang,
  • Xiaoqian Gao,
  • Xuechun Sun,
  • Zihan Zhang,
  • Lanqing Liu,
  • Yanjing Zhang,
  • Yanwen Qin

摘要

Cardiac fibrosis following myocardial infarction (MI) is a critical determinant of progressive cardiac dysfunction, yet the underlying mechanisms driving this pathological process remain incompletely understood. Elucidating these regulatory pathways holds profound implications for improving post-MI prognosis.

Our prior work demonstrated that chronic intermittent hypoxia (CIH) exacerbates cardiac fibrosis while modulating the expression of long non-coding RNA (lncRNA) nonnmmut065573 (tentatively designated LncRNA-IH) in cardiac tissues. Herein, we sought to determine the role of LncRNA-IH in post-MI cardiac fibrosis and its underlying mechanisms. Using a C57BL/6 mouse model of MI, we established a mouse model with cardiac-specific overexpression of LncRNA-IH to evaluate post-MI cardiac fibrosis. In vitro, primary cardiac fibroblasts (MCF) and the PA12 cell line were subjected to LncRNA-IH overexpression or siRNA-mediated knockdown, and cell proliferation and migration were assessed. Transcriptomic profiling was performed to characterize LncRNA-IH-induced changes in cardiac gene expression and signaling pathways, aiming to elucidate the molecular mechanisms involved.

Results showed that CIH significantly exacerbated post-MI cardiac fibrosis, and LncRNA-IH was predominantly localized to cardiac fibroblasts. Cardiac-specific overexpression of LncRNA-IH in MI mice markedly exacerbated post-MI cardiac dysfunction and fibrosis. In vitro, LncRNA-IH overexpression significantly enhanced the proliferation and migration capacities of primary cardiac fibroblasts and PA12 cells, whereas these effects were abrogated by LncRNA-IH knockdown. Transcriptomic analysis revealed that LncRNA-IH elicited significant alterations in cardiac gene expression profiles, specifically activating the TGF-β1 signaling pathway and upregulating the expression of its downstream target, ZEB1.

Collectively, our findings indicate that LncRNA-IH promotes cardiac fibroblast proliferation and migration, thereby exacerbating post-MI cardiac remodeling, at least in part through activation of the TGF-β1 signaling pathway. This study identifies LncRNA-IH as a potential therapeutic target for mitigating post-MI cardiac fibrosis and preserving cardiac function.