Abstract
BackgroundPulmonary vascular structure remodeling (PVSR) is a hallmark of pulmonary hypertension. P27kip1, 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 p27kip1 and its closely-related kinase (Skp-2) in the progression of PVSR and HPH.MethodsSprague-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 p27kip1, Skp-2 and Akt-P changes in rat lung tissue and cultured PASMCs.ResultsChronic 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 p27kip1 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 p27kip1. Study also showed that β-E2 application suppressed the proliferation of PASMCs and elevated the expression of p27kip1 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.ConclusionsOur results suggest that β-E2 can effectively attenuate PVSR and HPH. The underlying mechanism may partially be through the increased p27kip1 by inhibiting Skp-2 through Akt signal pathway. Therefore, targeting up-regulation of p27kip1 or down-regulation of Skp-2 might provide new strategies for treatment of HPH.
Highlights
Pulmonary vascular structure remodeling (PVSR) is a hallmark of pulmonary hypertension
Beta-estradiol treatment attenuated chronic hypoxia-induced pulmonary artery remodeling and pulmonary hypertension in rats The right ventricular systolic pressure (RVSP) was measured by catheterization via jugular vein to right ventricle, which substitutes for the pulmonary artery pressure
There was no significant difference of the right ventricular systolic pressures (RVSP) between the normoxia group and the normoxia treated with b-E2 group (24.90 ± 1.66 vs. 25.17 ± 1.20 mmHg; Table 1, n = 7, P < 0.01)
Summary
Pulmonary vascular structure remodeling (PVSR) is a hallmark of pulmonary hypertension. We employed b-E2 to investigate the roles of p27kip and its closely-related kinase (Skp-2) in the progression of PVSR and HPH. Pulmonary hypertension is a common complication of chronic hypoxic lung diseases, characterized by sustained elevation of pulmonary artery pressure and treatment of pulmonary hypertension [4]. Among these 5 subsets, pulmonary arterial hypertension (PAH), whose inducements including idiopathic, heritable, and connective tissue diseases, is predominantly suffered by women. Compared with PAH, the pathological changes of pulmonary hypertension due to lung diseases and/or hypoxia are characterized by medial hypertrophy and intimal obstructive proliferation of the distal pulmonary arteries [4,9]. The severity of pulmonary hypertension due to lung diseases and/ or hypoxia is usually from mild to moderate compared with PAH [4,10]
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