Open AccessSilencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway
Author(s) -
RuoMin Di,
Zhongzhou Yang,
Peng Xu,
Yanhong Xu
Publication year - 2019
Publication title -
experimental and therapeutic medicine
Language(s) - English
Resource type - Journals
eISSN - 1792-1015
pISSN - 1792-0981
DOI - 10.3892/etm.2019.7627
Subject(s) - protein kinase b , hypoxia (environmental) , phosphorylation , knockout mouse , right ventricular hypertrophy , western blot , signal transduction , biology , medicine , pulmonary hypertension , endocrinology , chemistry , microbiology and biotechnology , biochemistry , receptor , oxygen , organic chemistry , gene
The present study aimed to investigate the effect of phosphoinositide-dependent protein kinase-1 (PDK1) on hypoxia-induced pulmonary arterial hypertension (PAH). A mouse model of hypoxia-induced PAH was generated using normal or PDK1 -knockout mice. Histological analysis and hemodynamic evaluations were performed to identify the progression of PAH. The expression and phosphorylation of PDK1/protein kinase B (Akt) signaling pathway associated proteins were detected by western blot analysis. Increased lung vessel thickness, right ventricular (RV) systolic pressure (RVSP), RV hypertrophy index (RVHI) values [the RV weight- to -left ventricular (LV) plus septum (S) weight ratio] and PDK1 expression were observed in the hypoxia-induced PAH model compared with the normal control. The phosphorylation of Akt T308 , proline-rich Akt1 substrate 1 (PRAS40) and S6KT 229 was also notably increased in the PAH model compared with the control. The changes of proteins were not observed in the hypoxia treated PDK1 flox/+ : Tie2-Cre mice. Similarly, the RVSP and RVHI values, and PDK1 expression were reduced in the hypoxia treated PDK1 flox/+ : Tie2-Cre mice to a level comparable with those in the control, suggesting that PDK1 partial knockout significantly limited hypoxia-induced PAH. The results of the present study indicate that PDK1 is essential for hypoxia-induced PAH through the PDK1/Akt/S6K signaling cascades.