Abstract:

Objective   To explore the effects and potential mechanism of PS-341 on nuclear factor E2-realated factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) in remodeling vascular of rats with high-flow pulmonary arterial hypertension (PAH).  Methods  Forty-eight female Wistar rats were randomly assigned to the vehicle/sham group, PS-341/sham group, vehicle/shunt group, and PS-341-treated group.The model of aorto-caval shunting (ACS) was established by surgical Methods   to produce a high blood flow-induced pulmonary hypertension rats. The vehicle/sham and PS-341/sham  groups  performed the sham operation. After operation for 3 days, the rats received an intraperitoneal injection of PS-341 (50μg/kg·d) or vehicle for 8 weeks.  The hemodynamic data and right ventricular injury were evaluated. The protein expressions of NF-κB, Nrf2, Nqo1 and MMP-2 were analyzed by immunohistochemisty and Western blotting. RT-PCR  analysis was performed to detect the mRNA expression level of NF-κB.  Results  Compared with the vehicle/sham group, the vehicle/shunt group had the higher levels of the right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI),  WT% and WA% (P＜0.05), and the expressions of Nrf2，NF-κB-P65, Nqo1 and MMP-2 increased (P＜0.05). Compared with the vehicle/sham group, the PS-341-treated group deceased the levels of RVSP, RVHI, WT% and WA% (P＜0.05), and the activation of NF-κB-P65 and MMP-2 were inhibited, but the expressions of Nrf2 and Nqo1 significantly increased (P＜0.05).  Conclusion  PS-341 might delay vascular remodeling of high-flow PAH through promoting the expressions of Nrf2 and Nqo1, and inhibiting the expressions of NF-κB and MMP-2.

Key words: PS-341, Pulmonary arterial hypertension, Nuclear factor E2-realated factor 2; , Nuclear factor-kappa B； Rats