Beta-estradiol attenuates hypoxic pulmonary hypertension by stabilizing the expression of p27kip1 in rats

• Published in: Respiratory research 2010-12, Vol.11 (1), p.182-182, Article 182
• Main Authors: Xu, Dun-Quan, Luo, Ying, Liu, Yi, Wang, Jing, Zhang, Bo, Xu, Min, Wang, Yan-Xia, Dong, Hai-Ying, Dong, Ming-Qing, Zhao, Peng-Tao, Niu, Wen, Liu, Man-Ling, Gao, Yu-Qi, Li, Zhi-Chao
• Format: Article
• Language: English
• Subjects: Animals; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Dose-Response Relationship, Drug; Estradiol; Estradiol - administration & dosage; Gene Expression - drug effects; Hypertension; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; Hypoxia; Hypoxia - complications; Hypoxia - drug therapy; Hypoxia - metabolism; Male; Medical research; Nuclear nonproliferation; Phenols (Class of compounds); Proteins; Pulmonary arteries; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Rodents; Signal Transduction - drug effects; Studies; Treatment Outcome; Veins & arteries
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/1465-9921-11-182

Pulmonary vascular structure remodeling (PVSR) is a hallmark of pulmonary hypertension. P27(kip1), one of critical cyclin-dependent kinase inhibitors, has been shown to mediate anti-proliferation effects on various vascular cells. Beta-estradiol (β-E2) has numerous biological protective effects including attenuation of hypoxic pulmonary hypertension (HPH). In the present study, we employed β-E2 to investigate the roles of p27(kip1) and its closely-related kinase (Skp-2) in the progression of PVSR and HPH. Sprague-Dawley rats treated with or without β-E2 were challenged by intermittent chronic hypoxia exposure for 4 weeks to establish hypoxic pulmonary hypertension models, which resemble moderate severity of hypoxia-induced PH in humans. Subsequently, hemodynamic and pulmonary pathomorphology data were gathered. Additionally, pulmonary artery smooth muscle cells (PASMCs) were cultured to determine the anti-proliferation effect of β-E2 under hypoxia exposure. Western blotting or reverse transcriptional polymerase chain reaction (RT-PCR) were adopted to test p27(kip1), Skp-2 and Akt-P changes in rat lung tissue and cultured PASMCs. Chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of right ventricle/left ventricle plus septum (RV/LV+S) ratio, medial width of pulmonary arterioles, accompanied with decreased expression of p27(kip1) in rats. Whereas, β-E2 treatment repressed the elevation of RVSP, RV/LV+S, attenuated the PVSR of pulmonary arterioles induced by chronic hypoxia, and stabilized the expression of p27(kip1). Study also showed that β-E2 application suppressed the proliferation of PASMCs and elevated the expression of p27(kip1) under hypoxia exposure. In addition, experiments both in vivo and in vitro consistently indicated an escalation of Skp-2 and phosphorylated Akt under hypoxia condition. Besides, all these changes were alleviated in the presence of β-E2. Our results suggest that β-E2 can effectively attenuate PVSR and HPH. The underlying mechanism may partially be through the increased p27(kip1) by inhibiting Skp-2 through Akt signal pathway. Therefore, targeting up-regulation of p27(kip1) or down-regulation of Skp-2 might provide new strategies for treatment of HPH.