title: Beta-estradiol attenuates hypoxic pulmonary hypertension by stabilizing the expression of p27kip1 in rats.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, PR China.
authors.forename: Dun-Quan
authors.initials: DQ
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Wang
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Dong
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Dong
authors.forename: Peng-Tao
authors.initials: PT
authors.lastname: Zhao
authors.forename: Wen
authors.initials: W
authors.lastname: Niu
authors.forename: Man-Ling
authors.initials: ML
authors.lastname: Liu
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: Gao
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Li
mesh_terms: D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D004958:Estradiol