缺氧诱导因子-1α对失血性休克血管反应性的调控作用及机制

Regulatory role and mechanism of hypoxia-inducible factor 1α(HIF-1α) in vascular hyporeactivity after hemorrhagic shock

目的探讨失血性休克(hemorrhagic shock,HS)后大鼠肠系膜上动脉血管组织缺氧诱导因子-1α(hypoxia-inducible factor 1α,HIF-1α)表达变化规律及其调控血管低反应性发生的相关机制。方法取大鼠HS模型肠系膜上动脉(superior mensenteric artery,SMA),离体血管环技术检测SMA血管反应性,RT-PCR法分析HIF-1α及内皮型一氧化氮合酶(endothelial-nitro oxide nitroxide synthase,eNOS)和环氧合酶-2(cy-clooxygenase-2,COX-2)的mRNA表达变化规律。分别采用硝酸还原酶法和放射免疫法测定其血浆NO和PGI含量变化。结果与正常组相比,HS后HIF-1α、eNOS和COX-2 mRNA表达及其相应血浆产物NO和PGI含量显著增加。血管反应性表现为早期增高、晚期降低的双相变化。寡霉素处理可使eNOS和COX-2mRNA及其产物NO和PGI表达表现不同程度受抑,对血管反应性表现为对早期的升高趋势的部分抑制和晚期低反应性的改善作用。结论HIF-1α可能通过对eNOS-NO和COX-2-PGI通路,在休克后血管反应性双相向变化的形成中发挥重要调节作用。

Objective To observe the changes of HIF-1α expression of SMA tissue in rats,and its regulatory role and mechanism in vascular reactivity following hemorrhagic shock （ HS ）. Methods Rats models of HS were divided into 3 groups： normal,HS and oligomycin treated groups. The superior mensenteric artery （SMA） from HS rats was adopted to analyze the mRNA expression of HIF-1 α, eNOS （ endothelial - nitro oxide synthase ） and COX-2 （ cyclooxygenase-2 ）. Vascular reactivity was determined with the contractile response of SMA to nor-epinephrine （ NE） in isolated organ bath. Plasma NO and PGI were measured by means of nitrate reductase method and radio- immunoassay. Results HIF-1α,eNOS and COX-2 mRNA exhibited a time-dependent increase following HS,and peaked at 4h, 1 h and 3h respectively, the peak expression was 2.25,2.10 and 2.12-folds respectively as compared with normal group（P 〈0.05）. Serum NO and PGI showed 3.41 and 2.45-fold increase. Vascular reactivity of SMA was increased compensatorily at the early stage of HS, and decreased gradually at the decompensated period. Oligomycin treatment partly inhibited the vascular reactivity at early stage with a 30.77% drop,while improved at decompensated period with an increase of 52.51%. eNOS and COX-2 mRNA expression fluctuated in the normal range and plasma CO,NO were oppressed at a low level following oligomycin administration. Conclusion HS can elicit a biphasic changes of vascular reactivity as previously described ,and HIF-1α seems to play an important role in vascular hyporeactivity following HS by regulating the pathway of eNOS-NO and COX-2-PGI selectively.