Androgen receptor inhibitor ameliorates pulmonary arterial hypertension by enhancing the apoptosis level through suppressing the Notch3/Hes5 pathway.

Background: Pulmonary arterial hypertension (PAH) exhibits significant gender differences in prognosis, with male patients typically showing worse outcomes than females. These disparities may stem from differences in androgen receptor expression and activity. Clinical studies suggest that the androgen receptor plays a crucial role in the pathophysiology of PAH, influencing disease progression and treatment response. Despite the lack of targeted therapies for PAH, these findings have spurred investigations into the potential therapeutic role of androgen receptors. This study explores the role of androgen receptors in PAH and evaluates their therapeutic potential. Methods: PAH was induced in rats via intraperitoneal injection of monocrotaline (MCT). Following model establishment, Enzalutamide was administered every 3 days at 10 mg/kg once for a total of 7 times (21 days). A mouse model of PAH was developed by subcutaneously injecting SU5416 and exposing the mice to hypoxia. Androgen receptor knockout (AR Results: Compared to the normal group, the model group exhibited significantly increased androgen receptor expression in rats, mice, and mPAECs. This was accompanied by pronounced pulmonary artery wall thickening, right ventricular hypertrophy, pulmonary fibrosis, elevated pulmonary artery pressure, and a reduced level of apoptosis both Conclusion: Our findings suggest that in both animal models and the hypoxic mPAECs, inhibition of androgen receptor expression leads to increased apoptosis via suppression of the Notch3/Hes5 signaling pathway. This mechanism likely contributes to the therapeutic effects observed, providing insights for potential treatment strategies targeting androgen receptors in pulmonary arterial hypertension.