Protective effect of hypoxia inducible factor-1α gene therapy using recombinant adenovirus in cerebral ischaemia-reperfusion injuries in rats

摘要

Context: Hypoxia-inducible factor-1α (HIF-1α)-induced genes can improve blood circulation. Objective: To investigate brain protective effect of recombinant adenovirus-mediated HIF-1α (AdHIF-1α) expression and its mechanism. Materials and methods: Male SD rats were used to establish focal cerebral ischaemia-reperfusion (CIR) injury models and randomly divided into normal, sham, CIR, Ad and AdHIF-1α groups. Ad or AdHIF-1α (10sup8/sup pfu/10?μL) were administered into lateral ventricle of rats in Ad and AdHIF-1α groups. Modified neurological severity score (mNSS), brain water content (BWC) and cerebral infarct volumes (CIVs) were analyzed, and HE staining was performed using the brain tissues. Furthermore, the expression of caspase-3 and HSP90 was analyzed using qRT-PCR and Western blotting. Results: Compared to CIR (mNSS, 8.52?±?0.52; CIV, 0.22?±?0.01) and Ad groups (mNSS, 8.83?±?0.41; CIV, 0.22?±?0.02), mNSS and CIV were significantly decreased in AdHIF-1α group (mNSS, 6.03?±?0.61; CIV, 0.11?±?0.01) at 72?h (p??0.05). With prolonged reperfusion time (6?h to 72?h), BWC of all rats increased gradually, although the increase was markedly less in AdHIF-1α group (78.15?±?0.16 to 87.01?±?0.31) compared to that in CIR (78.77?±?0.60 to 89.74?±?0.34) and Ad groups (78.77?±?0.35 to 89.71?±?0.27) (p??0.01). There were significantly greater pathological changes in the neurons in AdHIF-1α group at 72?h following CIR. Furthermore, expression of caspase-3 (p??0.01) down-regulated and HSP90 up-regulated (p??0.05) at mRNA and protein levels in AdHIF-1α group. Discussion and conclusions: HIF?1α gene therapy is neuroprotective towards the CIR rat model. HIF-1α may be a candidate gene for the treatment of ischaemic brain injury.