Silencing PDK1 limits hypoxia-induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway.

Abstract

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 AktT308, proline-rich Akt1 substrate 1 (PRAS40) and S6KT229 was also notably increased in the PAH model compared with the control. The changes of proteins were not observed in the hypoxia treated PDK1flox/+ : Tie2-Cre mice. Similarly, the RVSP and RVHI values, and PDK1 expression were reduced in the hypoxia treated PDK1flox/+: 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.