Apelin-13 attenuates hyperoxia-induced pulmonary arterial smooth muscle cell dysfunction via BMPR2/IL-6 modulation in pulmonary arterial hypertension
Year: 2026
Type: article
Abstract: Background: 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. Methods: 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). Results: 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. Conclusions: 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.
Source: Translational Pediatrics
Authors: Feifei Pan, Dong Huang, Lianqing Mo
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223682550