Arginine attenuates bronchopulmonary dysplasia-associated pulmonary hypertension via RARS1-mediated arginylation of HES1
Yubin Li, Dongmei Zhou, Xiaona Dai, Yujie Han, Yunxia Li, Xiaoying Li, Lili KangBackground:
Bronchopulmonary dysplasia (BPD) is a complex chronic lung disease caused by the interaction between lung development and prenatal and postnatal injury events. Up to one-third of infants with BPD further develop pulmonary vascular dysfunction, leading to chronic pulmonary hypertension (PH). Infants with BPD-PH face increased mortality, a higher risk of adverse neurodevelopmental outcomes, and a lack of effective treatments.
Methods:
A total of 30 study participants were recruited from the Children’s Hospital Affiliated to Shandong University, with the data collection period spanning from January 2023 to May 2025. Through metabolite analysis, we observed significant differences in arginine concentration. Subsequently, in vitro experiments were conducted to investigate the effects of arginine on the proliferation and migration abilities of vascular endothelial cells and to elucidate the underlying molecular mechanisms. Finally, in vivo experiments were performed to validate the protective role of arginine in BPD-PH.
Results:
The results of the in vitro experiments indicate that arginine inhibits the proliferation and migration of vascular endothelial cells. Molecular mechanism studies revealed that arginine reduces the expression of α-smooth muscle actin, hypoxia-inducible factor-1α, and related proteins through the arginyl-tRNA synthetase-1 (RARS1)-hairy and enhancer of split homologue-1 (HES1) pathway, RARS1 directly interacts with HES1, and this process is enhanced by arginine, thereby alleviating vascular endothelial cell dysfunction. Further in vivo experiments demonstrated that arginine supplementation protects against hyperoxia-induced lung injury and PH in neonatal rats.
Conclusion:
Our results indicate that arginine alleviates BPD-PH by promoting vascular endothelial cell remodeling through the RARS1-HES1 pathway. Arginine supplementation may represent a novel therapeutic alternative for preventing BPD.