李珊珊,王乐,谢鸥,罗洋,赵婷

• 1:新疆医科大学儿科学院
• 2:新疆医科大学第一附属医院新生儿科

摘要(Abstract)：

目的 探讨缺氧诱导因子-1α(Hypoxia-inducible factor-1α,HIF-1α)调控内皮-间充质转化(Endothelial to mesenchymal transition, EndoMT)在缺氧性肺动脉高压(Hypoxia induced pulmonary hypertension, HPH)新生大鼠肺血管重塑(Pulmonary vascular remodeling, PVR)中的作用机制。方法 96只Wistar新生大鼠随机分为常氧组、缺氧组、缺氧+YC-1(HIF-1α抑制剂)组和缺氧+HIF-1α组，每组再按不同观察时间点随机分为3、7、14 d亚组，每个亚组8只新生大鼠。常氧组给予空病毒尾静脉注射1 d后，每日给予生理盐水腹腔内注射；缺氧组给予空病毒尾静脉注射1 d后，每日生理盐水腹腔注射后开始8 h缺氧处理；缺氧+YC-1组给予空病毒尾静脉注射1 d后，每日YC-1(10 mg/kg)腹腔注射后开始8 h缺氧处理；缺氧+HIF-1α组尾静脉注射8×10~9PFU/mL的腺病毒(标有绿色荧光信号，携带HIF-1α的重组腺病毒载体)1 d后，每日生理盐水腹腔注射后开始8 h缺氧处理。在干预处理后3、7、14 d时，用直接测压法测量右心室收缩压(Right ventricular systolic pressure, RVSP);荧光显微镜观察腺病毒转染情况；苏木精-伊红染色观察肺血管形态，计算肺血管重塑指标肺小动脉中层血管壁厚度占血管外径的百分比(MT%)和肺小动脉中层截面积的百分比(MA%);间接免疫荧光双标法检测肺组织中内皮标志物CD31和α平滑肌肌动蛋白(α smooth muscle actin, αSMA)的表达水平；实时荧光定量聚合酶链反应检测CD31、αSMA和HIF-1α mRNA表达水平。结果 与常氧组相比，干预处理后3、7、14 d时，通过缺氧处理的各组RVSP均升高，MA%、MT%增加(P<0.05),CD31表达降低，而αSMA表达升高，HIF-1α mRNA表达升高(P<0.05);与缺氧组相比，干预后7 d、14 d时，缺氧+YC-1组RVSP降低，MA%、MT%减少，CD31表达升高，αSMA表达降低，HIF-1α mRNA表达降低(P<0.05);干预后7 d、14 d时，缺氧+HIF-1α组RVSP进一步升高，MA%、MT%增加，CD31表达降低，αSMA表达升高，HIF-1α mRNA表达升高(P<0.05)。结论 缺氧及HIF-1α的抑制及过表达影响了EndoMT的过程，HIF-1α可能通过调控EndoMT促进HPH新生大鼠的PVR。

关键词(KeyWords)： 缺氧性肺动脉高压;内皮-间充质转化;缺氧诱导因子-1α;新生大鼠

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(82060287)

作者(Author): 李珊珊,王乐,谢鸥,罗洋,赵婷

参考文献(References)：

• [1] JAIN A,EL-KHUFFASH A F,VAN H C,et al.Cardiac function and ventricular interactions in persistent pulmonary hypertension of the newborn[J].Pediatr Crit Care Med,2021,22(2):e145-e157.
• [2] 杨延青，巴依尔才次克，郭鑫，等.血小板源性生长因子BB调控缺氧诱导因子1α表达在缺氧性肺动脉高压新生大鼠肺血管重塑中的机制研究[J].中华新生儿科杂志(中英文),2024,39(3):168-176.
• [3] 赵婷，王彦梅，王乐.谷氨酰胺诱导热休克蛋白70在缺氧性肺动脉高压新生大鼠中的保护作用研究[J].新疆医科大学学报，2019,42(12):1538-1543,1548.
• [4] AKIYAMA T,SADAHIRO T,YAMADA Y,et al.Flk1 deficiency and hypoxia synergistically promote endothelial dysfunction,vascular remodeling,and pulmonary hypertension[J].Arterioscler Thromb Vasc Biol,2023,43(9):1668-1683.
• [5] NOVOYATLEVA T,KOJONAZAROV B,OWCZAREK A,et al.Evidence for the fucoidan/P-selectin axis as a therapeutic target in hypoxia-induced pulmonary hypertension[J].Am J Respir Crit Care Med,2019,199(11):1407-1420.
• [6] RANCHOUX B,ANTIGNY F,RUCKER-MARTIN C,et al.Endothelial-to-mesenchymal transition in pulmonary hypertension[J].Circulation,2015,131(11):1006-1018.
• [7] WANG E L,ZHANG J J,LUO F M,et al.Cerebellin-2 promotes endothelial-mesenchymal transition in hypoxic pulmonary hypertension rats by activating NF-κB/HIF-1α/Twist1 pathway[J].Life Sci,2023,328:121879.
• [8] XING Y,HOU Y,FAN T,et al.Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension[J].Acta Pharm Sin B,2024,14(4):1726-1741.
• [9] LEE H W,ADACHI T,PAK B,et al.BMPR1A promotes ID2-ZEB1 interaction to suppress excessive endothelial to mesenchymal transition[J].Cardiovasc Res,2023,119(3):813-825.
• [10] TANG B,LIU Y,ZHANG J,et al.Ginsenoside Rg1 ameliorates hypoxia-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition and inflammation by regulating CCN1[J].Biomed Pharmacother,2023,164:114920.
• [11] PULLAMSETTI S S,MAMAZHAKYPOV A,WEISSMANN N,et al.Hypoxia-inducible factor signaling in pulmonary hypertension[J].J Clin Invest,2020,130(11):5638-5651.
• [12] WANG L,LI M.Roles of heat shock protein 70 toward hypoxia-inducible factor 1 alpha (HIF-1 alpha) blockade in newborn rats with hypoxia-induced pulmonary hypertension[J].Int J Clin Exp Med,2018,11(12):13520-13527.
• [13] XU X,TAN X,TAMPE B,et al.Snail is a direct target of hypoxia-inducible factor 1α (HIF1α) in hypoxia-induced endothelial to mesenchymal transition of human coronary endothelial cells[J].J Biol Chem,2015,290(27):16653-16664.
• [14] ZHANG B,NIU W,DONG H,et al.Hypoxia induces endothelialmesenchymal transition in pulmonary vascular remodeling[J].Int J Mol Med,2018,42(1):270-278.