Reduced selenium levels may represent a novel risk factor and a promising preventive target for pulmonary arterial hypertension
B Liang, T Li, Y Tang, M Zhang, W Lin, X Li, N Zhou, L Zha, Z YuAbstract
Background
Although selenium deficiency is implicated in some cardiovascular diseases, its role in pulmonary arterial hypertension (PAH) remains unclear.
Objective
This study aimed to determine whether reduced selenium levels are associated with an increased risk of PAH and to investigate whether preventive selenium supplementation can attenuate PAH in preclinical models.
Methods
Serum selenium concentrations were measured by inductively coupled plasma mass spectrometry in PAH patients and matched hospital-based controls to evaluate its association with disease risk and prognosis. Next, PAH rat models with preventive supplementation of selenium-rich feed were established, and single-cell sequencing of the pulmonary arteries was performed. Key findings were validated through ex vivo lung tissue analyses and in vitro cellular experiments.
Results
Figure 1A summarizes the baseline characteristics of the PAH patients and matched controls. Serum selenium levels were significantly lower in PAH patients (P < 0.01). In multivariable-adjusted logistic regression, higher selenium levels were associated with a significantly reduced risk of PAH (P for trend < 0.05, Figure 1B), identifying reduced selenium as a potential risk factor. Among PAH patients, lower selenium levels correlated with higher risk stratification, worse WHO functional class, and shorter 6-minute walking distance, indicating poor prognosis (all P < 0.05, Figure 1C-H). Furthermore, lung tissue selenium levels were decreased in monocrotaline (MCT)-induced PAH rats, which were restored by preventive selenium supplementation (Figure 2A). Selenium-supplemented MCT rats exhibited improved hemodynamics and attenuated pulmonary vascular remodeling compared to MCT controls, characterized by markedly reduced collagen fiber deposition and vessel wall thickness (Figure 2B-F). Single-cell sequencing revealed that selenium supplementation decreased the proportion of MCT-induced myofibroblasts and inflammatory fibroblasts (Figure 2G-I). In vitro experiments further confirmed that selenium supplementation attenuated TGF-β-induced fibroblast activation (Figure 2J-K), suggesting a key mechanism by which selenium may regulate pulmonary vascular remodeling.
Conclusion
This study identified reduced selenium levels as a novel risk factor for PAH. It likely promoted pulmonary vascular remodeling by inducing fibroblast activation, but preventive selenium supplementation could attenuate it. Further studies are warranted to elucidate the precise molecular mechanisms by which selenium regulates fibroblast activation and to evaluate the efficacy of preventive selenium supplementation in clinical practice.Figure_1Figure_2