Sun Jiayan, Lin Jiancheng, Yin Di, Pan Zetao, Ye Yuheng, Wang Yi, Wang Xiaowan, Guo Qiang
Medical College of Soochow Universuty, Soochow University, Suzhou, Jiangsu, China.
Medical Center of Soochow University, Soochow University, Suzhou, Jiangsu, China.
Front Pharmacol. 2025 Apr 28;16:1572489. doi: 10.3389/fphar.2025.1572489. eCollection 2025.
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.
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) mice were also utilized to investigate the role of androgen receptors in disease progression. Key indicators were compared across groups. The mechanisms through which androgen receptors influence PAH were examined in both rat and mouse models. Additionally, mouse pulmonary artery endothelial cells (PAECs) were cultured under hypoxic conditions to create an model of PAH, facilitating further investigation into the role of androgen receptors in disease pathogenesis.
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 and . Furthermore, activation of the Notch3/Hes5 signaling pathway was observed. However, treatment with androgen receptor inhibitors or gene knockout significantly ameliorated these pathological changes. Apoptosis levels increased both and , and the activation of the Notch3/Hes5 signaling pathway was effectively inhibited.
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.
肺动脉高压（PAH）在预后方面存在显著的性别差异，男性患者的预后通常比女性更差。这些差异可能源于雄激素受体表达和活性的不同。临床研究表明，雄激素受体在PAH的病理生理学中起关键作用，影响疾病进展和治疗反应。尽管缺乏针对PAH的靶向治疗方法，但这些发现促使人们对雄激素受体的潜在治疗作用进行研究。本研究探讨雄激素受体在PAH中的作用，并评估其治疗潜力。
通过腹腔注射野百合碱（MCT）诱导大鼠发生PAH。模型建立后，每3天以10mg/kg的剂量给予恩杂鲁胺，共给药7次（21天）。通过皮下注射SU5416并使小鼠暴露于低氧环境建立PAH小鼠模型。还利用雄激素受体敲除（AR）小鼠研究雄激素受体在疾病进展中的作用。比较各实验组的关键指标。在大鼠和小鼠模型中研究雄激素受体影响PAH的机制。此外，在低氧条件下培养小鼠肺动脉内皮细胞（PAECs）以建立PAH模型，便于进一步研究雄激素受体在疾病发病机制中的作用。
与正常组相比，模型组大鼠、小鼠和mPAECs中的雄激素受体表达显著增加。同时伴有明显的肺动脉壁增厚、右心室肥大、肺纤维化、肺动脉压力升高以及体内和体外凋亡水平降低。此外，观察到Notch3/Hes5信号通路的激活。然而，用雄激素受体抑制剂治疗或基因敲除可显著改善这些病理变化。体内和体外的凋亡水平均升高，Notch3/Hes5信号通路的激活被有效抑制。
我们的研究结果表明，在动物模型和低氧mPAECs中，抑制雄激素受体表达可通过抑制Notch3/Hes5信号通路导致凋亡增加。这一机制可能是观察到的治疗效果的原因，为肺动脉高压中针对雄激素受体的潜在治疗策略提供了思路。
