Apelin-13 attenuates hyperoxia-induced pulmonary arterial smooth muscle cell dysfunction via BMPR2/IL-6 modulation in pulmonary arterial hypertension.
- 1Department of Pediatric Intensive Care Medicine, Shanghai Children's Medical Center Guizhou Hospital, Shanghai Jiao Tong University School of Medicine, Guiyang, China.
- 2Department of Pediatric Intensive Care Medicine, Guizhou Provincial People's Hospital, Guiyang, China.
Abstract
Pulmonary arterial hypertension (PAH) is mainly driven by the excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Hyperoxic injury exacerbates the dysfunction of PASMCs, but the protective role of the Apelin-APJ system in this context remains unclear. This study aimed to investigate the protective role and underlying mechanism of the Apelin-APJ system in hyperoxia-induced pulmonary artery smooth muscle cell dysfunction and its therapeutic potential in pulmonary arterial hypertension. Immortalized mouse PASMCs were exposed to 85% oxygen for 0-9 hours to establish a temporal profile of hyperoxia-induced injury. Cells were subsequently treated with Apelin-13 in the presence or absence of the APJ antagonist ML221 under 3-hour hyperoxia. Cell viability, proliferation, migration, intracellular reactive oxygen species (ROS) levels, and phenotypic marker expression were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), Transwell/wound healing, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), Western blotting (WB), and enzyme-linked immunosorbent assay (ELISA). Hyperoxia elicited a biphasic response in PASMCs, with maximal proliferation, migration, and ROS generation at 3 hours, followed by functional decline upon prolonged exposure. Notably, endogenous Apelin expression remained unchanged at 3 hours, indicating an insufficient early compensatory response. Exogenous Apelin-13 significantly attenuated hyperoxia-induced PAS and migration, reversed the phenotypic switch from contractile (α-SMA) to synthetic (OPN) state, restored BMPR2 expression, and suppressed IL-6 overproduction at both mRNA and protein levels. Importantly, all protective effects of Apelin-13 were abolished by ML221 cotreatment, confirming APJ receptor dependence. These findings identify the Apelin-BMPR2/IL-6 axis as a critical counter-regulatory mechanism against oxidative stress-induced PASMC dysfunction and pulmonary vascular remodeling, supporting its therapeutic potential in PAH.
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BibTeX
@article{pan2026apelin13,
title = {{Apelin-13 attenuates hyperoxia-induced pulmonary arterial smooth muscle cell dysfunction via BMPR2/IL-6 modulation in pulmonary arterial hypertension.}},
author = {Feifei Pan and Dong Huang and Lianqing Mo},
journal = {Translational pediatrics},
year = {2026},
month = sep,
doi = {10.21037/tp-2026-0643},
url = {https://europepmc.org/article/MED/42996378},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Apelin-13 attenuates hyperoxia-induced pulmonary arterial smooth muscle cell dysfunction via BMPR2/IL-6 modulation in pulmonary arterial hypertension.
AU - Feifei Pan
AU - Dong Huang
AU - Lianqing Mo
PY - 2026
DA - 2026/09/30
JO - Translational pediatrics
DO - 10.21037/tp-2026-0643
UR - https://europepmc.org/article/MED/42996378
AB - Pulmonary arterial hypertension (PAH) is mainly driven by the excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Hyperoxic injury exacerbates the dysfunction of PASMCs, but the protective role of the Apelin-APJ system in this context remains unclear. This study aimed to investigate the protective role and underlying mechanism of the Apelin-APJ system in hyperoxia-induced pulmonary artery smooth muscle cell dysfunction and its therapeutic potential in pulmonary arterial hypertension. Immortalized mouse PASMCs were exposed to 85% oxygen for 0-9 hours to establish a temporal profile of hyperoxia-induced injury. Cells were subsequently treated with Apelin-13 in the presence or absence of the APJ antagonist ML221 under 3-hour hyperoxia. Cell viability, proliferation, migration, intracellular reactive oxygen species (ROS) levels, and phenotypic marker expression were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), Transwell/wound healing, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), Western blotting (WB), and enzyme-linked immunosorbent assay (ELISA). Hyperoxia elicited a biphasic response in PASMCs, with maximal proliferation, migration, and ROS generation at 3 hours, followed by functional decline upon prolonged exposure. Notably, endogenous Apelin expression remained unchanged at 3 hours, indicating an insufficient early compensatory response. Exogenous Apelin-13 significantly attenuated hyperoxia-induced PAS and migration, reversed the phenotypic switch from contractile (α-SMA) to synthetic (OPN) state, restored BMPR2 expression, and suppressed IL-6 overproduction at both mRNA and protein levels. Importantly, all protective effects of Apelin-13 were abolished by ML221 cotreatment, confirming APJ receptor dependence. These findings identify the Apelin-BMPR2/IL-6 axis as a critical counter-regulatory mechanism against oxidative stress-induced PASMC dysfunction and pulmonary vascular remodeling, supporting its therapeutic potential in PAH.
SN - 2224-4336
SN - 2224-4344
ER -