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  

Mechanisms of platelet-derived growth factor-BB regulation of hypoxia-inducible factor-1αexpression in pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension

作　　者：杨延青 巴依尔才次克[2] 郭鑫 王乐[2] Yang Yanqing;Caicike Bayer;Guo Xin;Wang Le(Academy of Pediatrics,Xinjiang Medical University,Urumqi 830054,China;Department of Neonatology,First Affiliated Hospital of Xinjiang Medical University,Urumqi 830054,China;Department of Pediatrics,Shangqiu Hospital of Traditional Chinese Medicine,Shangqiu 476000,China)

机构地区：[1]新疆医科大学儿科学院,乌鲁木齐830054 [2]新疆医科大学第一附属医院新生儿科,乌鲁木齐830054 [3]商丘市中医院儿科,商丘476000

出　　处：《中华新生儿科杂志（中英文）》2024年第3期168-176,共9页Chinese Journal of Neonatology

基　　金：国家自然科学基金(82060287)。

摘　　要：目的探讨血小板源性生长因子BB(platelet-derived growth factor-BB,PDGF-BB)是否通过调控缺氧诱导因子1α(hypoxia induced factor-1 alpha,HIF-1α)表达促进肺动脉平滑肌细胞增殖以及参与缺氧性肺动脉高压(hypoxic pulmonary hypertension,HPH)的肺血管重塑。方法160只Wistar新生大鼠按随机数字表法分为常氧组、HPH组、常氧+PDGF-BB组、HPH+PDGF-BB组、HPH+PDGF-BB抑制剂(STI571)组,每组各32只,每组再分为第3、7、14、21天4个亚组,每组8只。PDGF-BB组经尾静脉注射载有PDGF-BB的腺病毒、HPH+STI571组给予STI571灌胃;缺氧建立新生大鼠HPH模型,建模后第3、7、14、21天检测平均右心室收缩压(right ventricular systolic pressure,RVSP),苏木素-伊红染色观察肺小动脉形态变化及检测肺血管重塑指标,免疫组化测定各组PDGF-BB、HIF-1α及增殖相关蛋白核蛋白Ki67在肺血管中的表达部位和表达水平,实时荧光定量聚合酶链反应检测肺组织中PDGF-BB、HIF-1α及Ki67的mRNA水平。结果各时间点HPH组RVSP均高于常氧组(P<0.05),HPH+PDGF-BB组RVSP均高于HPH组(P<0.05),HPH+STI571组RVSP均低于HPH+PDGF-BB组与HPH组(P<0.05);建模后第3天HPH+PDGF-BB组发生肺血管重塑,第7天常氧+PDGF-BB组和HPH组发生肺血管重塑,HPH+STI571组肺血管重塑出现较晚且程度较其他缺氧组轻;第3、7、21天HPH+PDGF-BB组PDGF-BB、HIF-1α、Ki67蛋白及mRNA表达水平均高于其他组(P<0.05),各时间点HPH+STI571组PDGF-BB、HIF-1α、Ki67蛋白及mRNA表达水平均低于HPH+PDGF-BB组和HPH组(P<0.05)。结论PDGF-BB通过上调HIF-1α表达水平促进肺动脉平滑肌细胞增殖、加重肺血管重塑,从而提高HPH新生大鼠肺动脉压力。Methods A total of 160 Wistar neonatal rats were assigned into normoxia group,HPH group,normoxia+PDGF-BB group,HPH+PDGF-BB group and HPH+PDGF-BB inhibitor(STI571)group using random number table method(32 rats in each group),each group was further assigned into 4 subgroups on d3,d7,d14 and d21(8 rats in each subgroup).HPH model was established using nitrogen-oxygen mixture with an oxygen concentration of 10%±0.5%.PDGF-BB groups were injected with adenovirus encoding PDGF-BB in the tail vein.HPH+STI571 group was given STI571 intragastrically.On d3,d7,d14 and d21 after modeling,mean right ventricular systolic pressure(RVSP)was examined.Morphological changes of small pulmonary arteries were observed using HE staining and indicators of pulmonary vascular remodeling calculated.Immunohistochemistry was used to determine the protein levels of PDGF-BB,HIF-1αand proliferation-associated protein nuclear protein Ki67 in the pulmonary vasculature of each group.RT-qPCR was used to determine the mRNA levels of PDGF-BB,HIF-1αand Ki67 in lung tissue.Results At all time points,RVSP was higher in the HPH group than the normoxia group(P<0.05),higher in the HPH+PDGF-BB group than the HPH group(P<0.05),and lower in the HPH+STI571 group than both the HPH+PDGF-BB group and the HPH group(P<0.05).On d3 after modeling,pulmonary vascular remodeling occurred in the HPH+PDGF-BB group;on d7,pulmonary vascular remodeling occurred in the PDGF-BB group and the HPH group.Pulmonary vascular remodeling appeared later and to a lesser extent in the HPH+STI571 group than the other hypoxic groups.On d3,d7 and d21 after modeling,protein and mRNA levels of PDGF-BB,HIF-1αand Ki67 in the HPH+PDGF-BB group were higher than the other groups(P<0.05).The protein and mRNA expression levels of PDGF-BB,HIF-1αand Ki67 in the HPH+STI571 group were lower than the HPH+PDGF-BB group and the HPH group at all timepoints(P<0.05).Conclusions PDGF-BB up-regulates HIF-1αexpression,participates in PASMC proliferation,exacerbates pulmonary vascular remodeling and increas

关 键 词：血小板源性生长因子BB 缺氧诱导因子1Α 肺动脉高压 血管重塑 新生大鼠 

分 类 号：R722.1[医药卫生—儿科] R-332[医药卫生—临床医学]