HIF-1α在间歇低氧合并肺气肿大鼠肝细胞凋亡中的机制研究

Mechanism Underlying the Role of HIF-1α during Hepatocyte Apoptosis in Intermittent Hypoxia with Pulmonary Emphysema in Rats

目的探讨间歇低氧(IH)合并肺气肿对大鼠肝脏低氧诱导因子-1α(HIF-1α)、Bax、Bcl-2表达的影响及HIF-1α在肝细胞凋亡中的作用机制。方法将60只大鼠按随机数字表法均分为4组:正常对照组,正常饲养;IH组,每天9:00—17:00于低氧舱内交替通入30 s氮气和90 s空气,8 h/d;肺气肿组,每天8:00和18:00于熏箱内熏烟各30 min;IH合并肺气肿组,上述IH组和肺气肿组方法的联合。暴露14周后,处死大鼠,采用荧光实时定量(qRT)-PCR法测定肝组织中HIF-1α、Bax、Bcl-2表达水平。结果 IH合并肺气肿组HIF-1αmRNA、Bax mRNA、Bax/Bcl-2水平较正常对照组、IH组、肺气肿组升高(均P<0.05),Bcl-2 mRNA水平较正常对照组、肺气肿组降低(均P<0.05),较IH组无显著差异(P>0.05);HIF-1α与Bax、Bax/Bcl-2呈正相关(r分别为0.732、0.699),与Bcl-2呈负相关(r=-0.705)。结论 IH合并肺气肿可诱导肝细胞HIF-1αmRNA、Bax mRNA、Bax/Bcl-2表达上调,HIF-1α与Bax、Bcl-2相关,HIF-1α可能通过调控凋亡基因Bax、Bcl-2的表达来参与肝细胞的凋亡。

Objective To investigate the effect of intermittent hypoxia （IH） with pulmonary emphysema on the ex-pression of hypoxia inducible factor-1α（HIF-1α）,Bax and Bcl-2, and the mechanism underlying the role of HIF-1αin he-patocyte apoptosis thereof. Methods Sixty rats were randomly divided into four groups： normal control group, rats were treated normally;IH group, rats were treated by 30 s nitrogen and then 90 s air, and rats were treated by from 9：00-17：00 daily;pulmonary emphysema group, rats were treated by smudging for half an hour, twice a day （8：00 and 18：00）;IH with pul-monary emphysema group, rats were treated by 30 s nitrogen and then 90 s air from 9：00-17：00 daily. After exposure four-teen weeks, rats were killed. qRT-PCR assay was conducted to detect the expression of HIF-1α mRNA, Bax mRNA and Bcl-2 mRNA in live tissues. Results The expressions of HIF-1αmRNA, Bax mRNA and Bax/Bcl-2 were significantly higher in IH with pulmonary emphysema group than those in control group,IH group and pulmonary emphysema group （P〈0.05）. The expression level of Bcl-2 mRNA was significantly lower in IH with pulmonary emphysema group than that of con-trol group and pulmonary emphysema group （P 〈 0.05）, but no significant difference compared with that of IH group （P ＆gt;0.05）. The levels of HIF-1αand Bax were positively correlated with the level of Bax/Bcl-2 （r=0.732 and 0.699）,but the lev-els of HIF-1αand Bax were negatively correlated with the level of Bcl-2 （r=-0.705）. Conclusion The expression levels of HIF-1αmRNA, Bax mRNA and Bcl-2 mRNA were over-regulated in hepatocytes induced by intermittent hypoxia with pul-monary emphysema. The HIF-1αexpression was correlated with Bax and Bcl-2, suggesting that HIF-1αmay promote the hepatocyte apoptosis through transcriptional co-activators, Bax and Bcl-2.