title: Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats.
abstract: Resveratrol, a plant-derived polyphenolic compound and a phytoestrogen, was shown to possess multiple protective effects including anti-inflammatory response and anti-oxidative stress. Hypoxic pulmonary hypertension (HPH) is a progressive disease characterized by sustained vascular resistance and marked pulmonary vascular remodeling. The exact mechanisms of HPH are still unclear, but inflammatory response and oxidative stress was demonstrated to participate in the progression of HPH. The present study was designed to investigate the effects of resveratrol on HPH development. Sprague-Dawley rats were challenged by hypoxia exposure for 28 days to mimic hypoxic pulmonary hypertension along with treating resveratrol (40 mg/kg/day). Hemodynamic and pulmonary pathomorphology data were then obtained, and the anti-proliferation effect of resveratrol was determined byin vitroassays. The anti-inflammation and anti-oxidative effects of resveratrol were investigatedin vivoandin vitro. The present study showed that resveratrol treatment alleviated right ventricular systolic pressure and pulmonary arterial remodeling induced by hypoxia.In vitroexperiments showed that resveratrol notably inhibited proliferation of pulmonary arterial smooth muscle cells in an ER-independent manner. Data showed that resveratrol administration inhibited HIF-1 α expressionin vivoandin vitro, suppressed inflammatory cells infiltration around the pulmonary arteries, and decreased ROS production induced by hypoxia in PAMSCs. The inflammatory cytokines' mRNA levels of tumor necrosis factor α, interleukin 6, and interleukin 1β were all suppressed by resveratrol treatment. Thein vitroassays showed that resveratrol inhibited the expression of HIF-1 α via suppressing the MAPK/ERK1 and PI3K/AKT pathways. The antioxidant axis of Nuclear factor erythroid-2 related factor 2/ Thioredoxin 1 (Nrf-2/Trx-1) was up-regulated both in lung tissues and in cultured PASMCs. In general, the current study demonstrated that resveratrol may prevent pulmonary hypertension through its anti-proliferation, anti-inflammation and antioxidant effects. Hence, the present data may offer novel targets and promising pharmacological perspective for treating hypoxic pulmonary hypertension.
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.; Clinical laboratory, the Eighth Hospital of PLA, Xigaze, 857000, PR China.
authors.forename: Dunquan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Physical Examination Center of Beijing Military Region General Hospital, Beijing, 100700, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Niu
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Mingqing
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Manling
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Pengtao
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Fourth Military Medical University, Xi`an, 710032, PR China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism*; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D013267:Stilbenes; D013879:Thioredoxins; D000077185:Resveratrol
keywords: estrogen receptor; hypoxia inducible factor 1 α; hypoxic pulmonary hypertension; inflammation; nuclear factor erythroid-2 related factor 2; reactive oxygen species; resveratrol; thioredoxin 1.