Jichu yixue yu linchuang (Oct 2021)
Nrf2 activator relieves pulmonary vascular remodeling in rats with hypoxic pulmonary arterial hypertension
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.
