Thioredoxin‐Interacting Protein‐Regulated in Development and DNA Damage‐Response 1‐Driven Macrophage Senescence Promotes Hypoxia‐Induced Pulmonary Hypertension
4 affiliations
- 1Nanjing Medical University
- 2The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University
- 3the First Affiliated Hospital of Nanjing Medical University
- 4the Affiliated Hospital of Jiangsu University
Abstract
Background 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. Methods 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. Results 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. Conclusions 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.
Related
- Macrophage senescence and senescence-like states in senile osteoporosis: cellular cross-talk and therapeutic perspectives
- Macrophage pyroptosis drives luminal senescence and club-cell reprogramming in 5α-reductase inhibitor-treated prostatic hyperplasia
- Macrophage immunometabolic programming in pulmonary arterial hypertension: prioritizing TET2 and METTL3/m⁶A
- Immune architecture of oocyte competence: from development to senescence
- Development of a predictive model and nomogram using CTPA parameters for the identification of group 1 pulmonary arterial hypertension
BibTeX
@article{li2026thioredoxininteracting,
title = {{Thioredoxin‐Interacting Protein‐Regulated in Development and DNA Damage‐Response 1‐Driven Macrophage Senescence Promotes Hypoxia‐Induced Pulmonary Hypertension}},
author = {Yan Li and Tianfan Zhu and Donghai Lin and Chenhao Cao and Qiang Wang and Jie Wang and Li Hu and Yanfang Yu and Huijie Huang and Dong Wei and Feng Chen},
journal = {Journal of the American Heart Association},
year = {2026},
month = oct,
doi = {10.1161/jaha.126.049236},
url = {https://www.ahajournals.org/doi/10.1161/JAHA.126.049236},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Thioredoxin‐Interacting Protein‐Regulated in Development and DNA Damage‐Response 1‐Driven Macrophage Senescence Promotes Hypoxia‐Induced Pulmonary Hypertension
AU - Yan Li
AU - Tianfan Zhu
AU - Donghai Lin
AU - Chenhao Cao
AU - Qiang Wang
AU - Jie Wang
AU - Li Hu
AU - Yanfang Yu
AU - Huijie Huang
AU - Dong Wei
AU - Feng Chen
PY - 2026
DA - 2026/10/23
JO - Journal of the American Heart Association
DO - 10.1161/jaha.126.049236
UR - https://www.ahajournals.org/doi/10.1161/JAHA.126.049236
AB - Background 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. Methods 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. Results 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. Conclusions 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.
SN - 2047-9980
ER -