Unveiling the role of Jagged2 in hypoxic pulmonary arterial hypertension: A NOX2‐mediated pathway

TL;DR

This study reveals that Jagged2 promotes hypoxic pulmonary arterial hypertension by activating a pathway involving NOX2 and reactive oxygen species, suggesting a new therapeutic target.

Contribution

The study identifies a novel role for Jagged2 in PAH through NOX2/ROS signaling, offering a new therapeutic target.

Findings

Jagged2 is upregulated in hypoxia and promotes vascular remodeling via NOX2/ROS signaling.

Inhibiting Jagged2 reduces hemodynamic changes and vascular inflammation in PAH rat models.

The Jagged2/NOX2 axis is a critical driver of PAH pathology.

Abstract

Hypoxic pulmonary arterial hypertension (PAH) is a severe cardiovascular condition involving vascular remodeling and inflammation. Jagged2 (Jag2) has been implicated in various pathologies but its role in PAH remains unclear. We integrated bioinformatics analysis of transcriptomic data with in vitro and in vivo experiments to investigate Jag2's function in hypoxic PAH. We focused on primary rat pulmonary artery smooth muscle cells (PASMCs) for cellular responses and a rat model for hemodynamic changes. Jag2 was upregulated under hypoxic conditions, promoting PASMC proliferation and migration and inhibiting apoptosis through NADPH oxidase 2 (NOX2)/reactive oxygen species (ROS) signaling. Inhibition of Jag2 ameliorated hemodynamic changes and vascular remodeling in the PAH rat model. Jag2 activation of NOX2/ROS signaling is a critical driver of vascular inflammation and remodeling in hypoxic PAH, suggesting the Jag2/NOX2 axis as a therapeutic target.

Molecular Mechanism of Jag2 Activation of the NOX2/ROS Pathway in Hypoxic PAH Pathology. This study provides important insights into the mechanism of Jag2 in PAH, particularly its critical role in vascular inflammation and remodeling through the NOX2/ROS pathway. This discovery offers a new direction for PAH pathology research and establishes a theoretical basis for developing Jag2‐targeted therapies. Inhibiting Jag2 may effectively mitigate PAH progression and improve patient outcomes. However, the main limitation of this study lies in the experimental models and cell lines used. The results are primarily based on rat models and in vitro cell experiments, which may differ from human physiological and pathological conditions. Although our data strongly support the role of the Jag2/NOX2/ROS pathway in PAH, further studies are needed to validate its generality and specific mechanisms across different PAH subtypes. Future research should focus on clinical validation, evaluating the safety and efficacy of Jag2 inhibitors in PAH patients and exploring other molecular mechanisms that may contribute to PAH pathology for a comprehensive understanding and treatment of PAH.

Figures