Targeting endothelial thioredoxin-interacting protein (TXNIP) attenuates pulmonary vascular remodeling

Pulmonary hypertension (PH) is a severe cardiopulmonary disease with high morbidity and mortality worldwide. Pulmonary vascular endothelial cell dysfunction is a core component of the etiology and progression of PH. Here we address the hypothesis that the thioredoxin-interacting protein (TXNIP), known to play a pivotal role in cellular growth, survival, and homeostasis in various diseases, plays a key role in the pathogenesis of pulmonary vascular remodeling, which characterizes PH. Expression of TXNIP was measured in lung tissue from patients with PH and animal surrogates. Global and endothelial-specific TXNIP inhibition or overexpression were used to explore the roles of TXNIP in PH. Small hairpin RNA and plasmids were used to examine functional behavior in human pulmonary artery endothelial cells. Histological, transcriptomic, proteomic, and single-cell RNA sequencing (scRNA-seq) were used to investigate the mechanisms by which TXNIP contributes to the pathogenesis of PH. Multiomics analyses revealed elevated TXNIP expression in the lung tissues of animal surrogates of PH and from human patients with PH. In the surrogates, global deletion of TXNIP attenuated the development of PH and pulmonary vascular remodeling. In vitro, TXNIP was upregulated in endothelial cells rather than smooth muscle cells and neutrophils. Furthermore, in mice, endothelial-specific inhibition of TXNIP attenuated the progression of pulmonary hypertension. Conversely, TXNIP overexpression accelerated disease progression. Mechanistically, TXNIP induced endothelial dysfunction by promoting cell proliferation, angiogenesis, and adhesion. E-twenty-six-specific sequence variant 4 (ETV4) induced TXNIP transcription and nuclear translocation. Subsequently, TXNIP bonded with annexin A2 (ANXA2) to promote endothelial dysfunction. Moreover, pharmacological inhibition of TXNIP attenuated pulmonary vascular remodeling and PH development. TXNIP plays a crucial role in endothelial homeostasis during the development of PH and is a promising therapeutic target for PH.