TXNDC5 Governs Extracellular Matrix Homeostasis in Pulmonary Hypertension
Abstract
BACKGROUND
Pulmonary hypertension (PH) is characterized by vascular remodeling without effective treatments. Thioredoxin domain containing 5 (TXNDC5), a member of the protein disulfide isomerases (PDI) family, regulates protein folding and vascular homeostasis, yet its role in PH remains unknown.
METHODS
Label-free proteomics was used to profile PDI expression in hypoxic PH patients. TXNDC5 expression and localization were examined by multiplex immunofluorescence and Western blot. Gain- and loss-of-function approaches, including adeno-associated virus-mediated lung endothelial overexpression, global knockout, and endothelial ablation of TXNDC5, were used in Sugen5416/hypoxia (SuHx)-induced rodent PH models. In vitro endothelial cell assays, RNA sequencing, protein-protein interaction analysis, and pharmacological intervention were conducted to elucidate underlying mechanisms and therapeutic potential.
RESULTS
TXNDC5 was significantly upregulated in the lungs of both PH patients and experimental PH models, predominantly in endothelial cells of remodeled distal pulmonary arteries. Endothelial TXNDC5 overexpression exacerbated pulmonary vascular remodeling, elevated right ventricular systolic pressure, and promoted right ventricular hypertrophy, whereas global or endothelial-specific TXNDC5 deficiency conferred protection against SuHx-induced PH. RNA sequencing and protein-protein interaction analysis revealed that TXNDC5 regulated extracellular matrix homeostasis through biglycan (BGN), which was required for TXNDC5-mediated inhibition of HIF-1α/2α ubiquitination, leading to pathological HIF accumulation. Pharmacological inhibition of TXNDC5 with E64FC26 and endothelial-targeted TXNDC5 gene therapy significantly attenuated PH severity in SuHx rats.
CONCLUSIONS
Our study reveals that TXNDC5 is a main modulator to regulate ECM homeostasis and may serve as a promising target for the treatment of PH.
Abstract Figure
<fig id="figa1" position="float" orientation="portrait" fig-type="figure"> <label>Graphic Abstract</label> <caption>The role of TXNDC5 in regulating ECM homeostasis during PH. In the healthy state, BGN folding is properly maintained and HIF-1α/2α is rapidly degraded. During PH, TXNDC5 is upregulated, leading to excessive accumulation of BGN and impaired ubiquitination-mediated degradation of HIF-1α/2α, resulting in an imbalance in ECM homeostasis and contributing to vascular remodeling. Pharmacological or genetic inhibition of TXNDC5 restores BGN folding capacity and facilitates HIF-1α/2α degradation, thereby reestablishing ECM homeostasis and attenuating PH progression.
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