关键词: 活性氧, 氧化应激, 核因子E2相关因子2/血红素氧合酶1通路

Abstract: Objective To investigate the effect of activation of nuclear factor E2-related factor 2 (Nrf2) on vascular remodeling in hypoxic-induced pulmonary hypertension (PAH) rats and its mechanism. Methods The rats were divided into four groups with eight in each: control group, hypoxic group (hypoxic treatment of rats), Nrf2 activated group (gavage 5 mg/kg Nrf2 agonist sulforaphane every day for 4 weeks before hypoxic treatment). The cardiopulmonary hemodynamics and right ventricular hypertrophy index mean pulmonary artery pressure (mPAP) were measured, the right ventricular hypertrophy index=right ventricle (RV)/(left ventricle+interventricular septum) (LV+S) were calculated; the related indexes of pulmonary vascular remodeling were measured and the wall area (WA)/total area (TA) of pulmonary arterioles and the thickness of vascular mesothelium (MT)/external diameter (ED) of pulmonary arterioles were calculated; malondialdehyde (MDA) and superoxide dismutase (SOD) were measured by thiobarbituric acid method and nitrogen blue tetrazole method; the mRNA of matrix metalloproteinase (MMP) and MMP-9 in pulmonary artery were detected by qRT-PCR; and the protein level of Nrf2, antioxidant response element (ARE), NADPH quinineoxidoreductase-1 (NQO-1) and heme oxygenase1 (HO1) were measured by Western blot. Results Compared with the control group, the level of mPAP, RV/(LV+S), WA/TA and MT/ED, MDA and mRNA level of MMP-2 and MMP-9 in pulmonary artery tissue, the level of Nrf2, ARE, NQO1 and HO1 proteins in the nucleus of the hypoxic group were all increased (P＜0.05); and SOD activity in pulmonary artery tissue and level of Nrf2 protein in plasma were decreased (P＜0.05). Compared with hypoxia group, the levels of mPAP, RV/(LV+S), levels of WA/TA and MT/ED, level of MDA and mRNA levels of MMP-2 and MMP-9 in pulmonary artery tissue, the level of Nrf2 protein in cytoplasm of the Nrf2 activation group were decreased (P＜0.05); and SOD activity in pulmonary artery tissue and levels of Nrf2, ARE, NQO1 and HO1 proteins in the nucleus were increased (P＜0.05). Conclusions Nrf2 activation may delay the vascular remodeling induced by PAH, and potential mechanism is the pathway of Nrf2/ARE activation.

Key words: reactive oxygen species, oxidative stress, nuclear factor E2-associated factor 2/ heme oxygenase 1 pathway