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Exosomal miR-663b from "M1" macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through
Honghong Ma1,2, Yang Yu3, Lirong Mo1,2
1Department of Respiratory Medicine, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750000, Ningxia, China.
Background:
Inflammatory mediators from macrophages are proven to be involved in pulmonary vascular remodeling in pulmonary hypertension (PH). Here, this study intends to explore the mechanism of "M1" macrophage-derived exosomal miR-663b in pulmonary artery smooth muscle cells (PASMCs) dysfunctions and pulmonary hypertension.
Methods:
Hypoxia-treated PASMCs were utilized for constructing an in-vitro pulmonary hypertension model. THP-1 cells were treated with PMA (320 nM) and LPS (10 μg/mL) + IFN-γ (20 ng/ml) for eliciting macrophage "M1" polarization. Exosomes derived from "M1" macrophages were isolated and added into PASMCs. The proliferation, inflammation, oxidative stress, and migration of PASMCs were evaluated. RT-PCR or Western blot examined the levels of miR-663b and the AMPK/Sirt1 pathway. Dual luciferase activity assay and RNA pull-down assay were carried out for confirming the targeted association between miR-663b and AMPK. An in-vivo PH model was built. Macrophage-derived exosomes with miR-663b inhibition were used for treating the rats, and alterations of pulmonary histopathology were monitored.
Results:
miR-663b was obviously up-regulated in hypoxia-elicited PASMCs and M1 macrophages. miR-663b overexpression boosted hypoxia-induced proliferation, inflammation, oxidative stress, and migration in PASMCs, whereas miR-663b low expression resulted in the opposite situation. AMPK was identified as a target of miR-663b, and miR-663b overexpression curbed the AMPK/Sirt1 pathway. AMPK activation ameliorated the damaging impact of miR-663b overexpression and "M1" macrophage exosomes on PASMCs. In vivo, "M1" macrophage exosomes with miR-663b low expression alleviated pulmonary vascular remodeling in pulmonary hypertension rats.
Conclusion:
Exosomal miR-663b from "M1" macrophage facilitates PASMC dysfunctions and PH development by dampening the AMPK/Sirt1 axis.
Insights
Exosomal miR-663b from M1 macrophages drives pulmonary hypertension by impairing the AMPK/Sirt1 pathway in pulmonary artery smooth muscle cells. Inhibiting this microRNA alleviates disease progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Pathophysiology
Background:
- Macrophages, particularly M1-polarized macrophages, release inflammatory mediators implicated in pulmonary vascular remodeling.
- Pulmonary hypertension (PH) involves complex cellular and molecular mechanisms, including macrophage-derived factors.
Purpose of the Study:
- To investigate the role of exosomal miR-663b from M1 macrophages in pulmonary artery smooth muscle cell (PASMC) dysfunction.
- To elucidate the mechanism by which exosomal miR-663b contributes to the development of pulmonary hypertension.
Main Methods:
- Established in vitro and in vivo models of pulmonary hypertension using hypoxia-treated PASMCs and rats.
- Isolated exosomes from M1-polarized macrophages and applied them to PASMCs.
- Assessed PASMC proliferation, inflammation, oxidative stress, and migration.
- Quantified miR-663b and AMPK/Sirt1 pathway components via RT-PCR and Western blot.
- Confirmed the direct interaction between miR-663b and AMPK using dual luciferase and RNA pull-down assays.
Main Results:
- miR-663b was upregulated in hypoxia-induced PASMCs and M1 macrophages.
- Overexpression of miR-663b exacerbated hypoxia-induced PASMC dysfunction, while its inhibition reversed these effects.
- miR-663b directly targeted and inhibited the AMPK/Sirt1 pathway.
- AMPK activation mitigated the detrimental effects of miR-663b and M1 macrophage exosomes on PASMCs.
- In vivo, M1 macrophage-derived exosomes with reduced miR-663b expression ameliorated pulmonary vascular remodeling in PH rats.
Conclusions:
- Exosomal miR-663b secreted by M1 macrophages promotes PASMC dysfunction and pulmonary hypertension.
- This process occurs via the suppression of the AMPK/Sirt1 signaling pathway.
- Targeting exosomal miR-663b presents a potential therapeutic strategy for pulmonary hypertension.
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