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Sleep and Breathing

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12.09.2023 | Sleep Breathing Physiology and Disorders • Original Article

Intermittent hypoxia induces myofibroblast differentiation and extracellular matrix production of MRC5s via HIF-1α-TGF-β/Smad pathway

verfasst von: Maoli Liang, Liang Si, Zhi Yu, Hui Ding, Le Wang, Xing Chen, Baoyuan Chen, Jing Zhang, Jie Cao

Erschienen in: Sleep and Breathing | Ausgabe 1/2024

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Abstract

Purpose

To investigate whether or not intermittent hypoxia (IH), the main characteristic of obstructive sleep apnea (OSA) may affect the myofibroblast differentiation and extracellular matrix (ECM) production of lung fibroblast through the HIF-1α-TGF-β/Smad pathway and assess the interventional role of a HIF-1α inhibitor, 2-methoxyestradiol (2-ME2).

Method

The human lung fibroblast MRC5 cells were exposed to normoxia or IH conditions, and the expression of myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and ECM protein collagen I were evaluated. To clarify the underlying mechanism, the expression level of HIF-1α, TGF-β, and p-Smads/Smads were measured and the effects of inhibiting HIF-1α with 2-ME2 on the α-SMA expression level and ECM production through the TGF-β/Smad pathway were assessed. Si HIF-1α was applied to genetically inhibit HIF-1α in MRC5 cells, and the related proteins were assessed.

Results

IH increased the protein and mRNA expression of Collagen I and α-SMA of MRC5 cells in a time-dependent manner. IH activated the protein and mRNA level of HIF-1α and TGF-β and increased the phosphorylation of Smad2/Smad3 of MRC5 cells in a time-dependent manner. 2-ME2 inhibited the activation of HIF-1α induced by IH and decreased overexpression of TGF-β, p-Smad2/Smad2, and p-Smad3/Smad3, which in turn partially reversed the upregulation of α-SMA and Collagen I induced by IH in MRC5 cells. When HIF-1α was successfully silenced by si-HIF-1α, upregulation of TGF-β induced by intermittent hypoxia was partially decreased.

Conclusions

This study showed that IH contributes to myofibroblast differentiation and excessive ECM production of MRC5 cells through activation of the HIF-1α-TGF-β/Smad pathway. 2-ME2 partially attenuated myofibroblast differentiation induced by IH by inhibiting the HIF-1α-TGF-β/Smad pathway.

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Titel: Intermittent hypoxia induces myofibroblast differentiation and extracellular matrix production of MRC5s via HIF-1α-TGF-β/Smad pathway
verfasst von: Maoli Liang
Liang Si
Zhi Yu
Hui Ding
Le Wang
Xing Chen
Baoyuan Chen
Jing Zhang
Jie Cao
Publikationsdatum: 12.09.2023
Verlag: Springer International Publishing
Erschienen in: Sleep and Breathing / Ausgabe 1/2024
Print ISSN: 1520-9512
Elektronische ISSN: 1522-1709
DOI: https://doi.org/10.1007/s11325-023-02889-y

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Intermittent hypoxia induces myofibroblast differentiation and extracellular matrix production of MRC5s via HIF-1α-TGF-β/Smad pathway