Research Paper Volume 15, Issue 9 pp 3549—3571
Exosomal miR-663b from “M1” macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through inhibiting the AMPK/Sirt1 axis
- 1 Department of Respiratory Medicine, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750000, Ningxia, China
- 2 Department of Respiratory Medicine, Third Clinical Medical College, Ningxia Medical University, Yinchuan 750000, Ningxia, China
- 3 College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750000, Ningxia, China
- 4 General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
Received: January 16, 2023 Accepted: April 17, 2023 Published: May 4, 2023
https://doi.org/10.18632/aging.204690How to Cite
Copyright: © 2023 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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.