Thioredoxin-Interacting Protein-Regulated in Development and DNA Damage-Response 1-Driven Macrophage Senescence...

Pulmonary hypertension (PH) is a life-threatening vascular disorder characterized by pulmonary arterial remodeling and right ventricular failure, posing a significant clinical challenge. Although macrophage dysfunction is implicated in PH pathogenesis, its underlying molecular mechanisms remain elusive.

We employed multiomics database analysis, cross-species validation, and functional studies in hypoxia-induced PH models. Myeloid-specific Txnip deletion was achieved via bone marrow transplantation in mice. Mechanistic insights were evaluated through protein-binding assays, cellular senescence analyses in bone marrow-derived macrophages, and co-culture experiments with pulmonary artery smooth muscle cells.

We identified that cellular senescence in pulmonary adventitial macrophages was involved in the pathogenesis of hypoxia-induced PH. Integrated multiomics analysis revealed elevated TXNIP (thioredoxin-interacting protein) expression in perivascular macrophages during hypoxia-induced PH. Myeloid-specific Txnip deletion attenuated hypoxia-induced pulmonary vascular remodeling in mice. Mechanistically, TXNIP binds to and stabilizes the REDD1 (regulated in development and DNA damage-response 1) protein, promoting hypoxia-induced senescence in bone marrow-derived macrophages. Conditioned medium from senescent macrophages subsequently enhanced the proliferation and migration of pulmonary artery smooth muscle cells.

The TXNIP-REDD1 axis drives hypoxia-induced macrophage senescence, which promotes pulmonary artery smooth muscle cell dysfunction and pulmonary vascular remodeling in hypoxia-induced PH. Targeting the TXNIP-REDD1 pathway may provide a novel therapeutic strategy for hypoxia-induced PH.