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Resveratrol inhibits hypoxia-induced oxidative stress and proliferation in pulmonary artery smooth muscle cells through the HIF-1α/NOX4/ROS signaling pathway

HE Li-Nan¹, LAN Yu-Ru¹, HE Guang-Ming², GUO Shu-Jin³, WEN Fu-Qiang¹, WANG Tao^1,*

¹Laboratory of Pulmonary Diseases, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610041, China；²Department of Critical Care Medicine, Sichuan Cancer Hospital & Institute, Chengdu 610041, China；³Sichuan Research Hospital of Translational Medicine, Chinese Academy of Sciences, University of Electronic Science and Technology of China, Chengdu 610054, China

Abstract

The purpose of the present study was to determine the effects of resveratrol on hypoxia-induced oxidative stress and proliferation in pulmonary artery smooth muscle cells (PASMCs) and the underlying mechanism. Primary rat PASMCs were isolated and cultured in vitro and pretreated with different concentrations of resveratrol (10, 20, and 40 µmol/L) or the NADPH oxidase (NOX) inhibitor VAS2870 (10 µmol/L) for 0.5 h. The cells were then cultured under normoxia (21% O2, 5% CO2) or hypoxia (2% O2, 5% CO2) for 24 h. The proliferation of cells was measured using the CCK-8 method and the expression of proliferating cell nuclear antigen (PCNA). The production of reactive oxygen species (ROS) was detected by DCFH-DA. The expression of rat NOX1, NOX4 and hypoxia inducible factor 1α (HIF-1α) was detected by real-time RT-PCR and Western blotting assays. The related signaling pathways were determined using the small interference RNAs (siRNAs) specifically targeting Hif-1α and Nox4. The results showed that resveratrol and VAS2870 significantly inhibited hypoxia-induced cell proliferation and ROS production in rat PASMCs. Resveratrol also effectively prevented hypoxia-induced increase of HIF-1α protein levels and NOX4 up-regulation, but had little effect on NOX1. After the knocking down of Hif-1α or Nox4 with siRNAs, hypoxia-induced cell proliferation and ROS accumulation were significantly decreased, and both were further inhibited by resveratrol treatment. These results suggest that resveratrol inhibits hypoxia-induced oxidative stress and cell proliferation in rat PASMCs possibly through blocking the HIF-1α/NOX4/ROS pathway.

Key words: resveratrol; hypoxia; hypoxia inducible factor 1α; NADPH oxidase 4; reactive oxygen species

Received: 2019-10-30　　Accepted: 2020-05-04

Corresponding author: 汪涛　　E-mail: tao.wang@scu.edu.cn

DOI: 10.13294/j.aps.2020.0067

Citing This Article：

HE Li-Nan, LAN Yu-Ru, HE Guang-Ming, GUO Shu-Jin, WEN Fu-Qiang, WANG Tao. Resveratrol inhibits hypoxia-induced oxidative stress and proliferation in pulmonary artery smooth muscle cells through the HIF-1α/NOX4/ROS signaling pathway. Acta Physiol Sin 2020; 72 (5): 551-558 (in Chinese with English abstract).