HIF-2α attenuates intracerebral hemorrhage injury in rats by inhibiting inflammatory response

Abstract:

Objective：To investigate the role of hypoxia-inducible factor 2α（HIF-2α） in intracerebral hemorrhage（ICH） injury，and to determine whether HIF-2α is involved in the regulation of inflammatory response after ICH. Methods：There were 95 healthy male Sprague-Dawley rats，and 35 of them were randomly assigned to seven groups for different data collection time points：Sham，12 h，24 h，48 h，3 d，5 d，and 7 d，with 5 rats in each group. The other 60 rats were randomly divided into Sham group（sham operation group with injection of the same amount of normal saline），ICH group（ICH model group with collagenase-induced ICH），Vehicle group（empty vector group with injection of empty lentiviral vector before modeling），and Oe-HIF-2α group（HIF-2α over－expression group with injection of HIF-2α overexpression lentiviral vector before modeling） for brain water content mea－surement，neurological function scoring，Western blot analysis，and immunofluorescence detection. The severity of brain injury was assessed by brain water content and Garcia neurological deficit scores. The expression levels of HIF-2α，tumor necrosis factor α（TNF-α），interleukin 18（IL-18），and interleukin 1 beta（IL-1β） were determined by Western blot，and the expression of myeloper－oxidase（MPO） was determined by immunofluorescence assay. Results：The expression of HIF-2α began to increase at 24 hours after ICH（0.555 4±0.070 2，P=0.000），peaked on day 3（2.368 4±0.346 6，P=0.000），and then decreased. Compared with the ICH group on day 3，the Oe-HIF-2α group had significantly decreased brain water content（0.793 5±0.002 5，P=0.000），significantly improved neurological function（14.700 0±0.674 9，P=0.000），and significantly reduced expression of inflammatory mediators including TNF-α（1.350 4±0.191 5，P=0.000），IL-1β（1.158 4±0.070 8，P=0.000），and IL-18（0.784 2±0.073 9，P=0.000）；the expression of MPO in the surrounding area of lesion was significantly lower in the Oe-HIF-2α group than in the ICH group（3.500 0±0.534 5 vs. 5.125 0±0.991 0，P=0.002）. Conclusion：After ICH，HIF-2α is upregulated，and it can suppress the expression of inflammatory factors includ－ing TNF-α，IL-1β，and IL-18 to reduce inflammatory response and ICH injury in rats.