Key result
LncRNA-IH overexpression markedly exacerbates post-MI cardiac dysfunction and fibrosis by activating the TGF-β1/ZEB1 pathway.
Why the study?
Mechanisms driving post-MI cardiac fibrosis remain incompletely understood, and the role of LncRNA-IH in this process and its underlying mechanisms needed to be determined.
Does LncRNA-IH overexpression promote post-myocardial infarction cardiac fibrosis and dysfunction in a mouse model?
Does LncRNA-IH overexpression promote post-myocardial infarction cardiac fibrosis and dysfunction in a mouse model?
LncRNA-IH promotes post-MI cardiac fibrosis and dysfunction by activating the TGF-β1/ZEB1 pathway, identifying it as a potential therapeutic target for mitigating post-MI remodeling.
Hypothesis-generating for LncRNA-IH inhibition in post-MI remodeling; leaves open translation beyond mouse models.
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.
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Hu et al. (2026) studied this question. Cardiac-specific overexpression of LncRNA-IH markedly exacerbated post-myocardial infarction cardiac dysfunction and fibrosis by activating the TGF-β1/ZEB1 pathway.
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