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

• Published in: Pharmaceutical biology Vol. 58; no. 1; pp. 438 - 446
• Main Authors: Li, Ya-Qi, Hui, Zhi-Rong, Tao, Tao, Shao, Kang-Yu, Liu, Zhi, Li, Min, Gu, Li-Ling
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Adenoviridae - genetics; Adenoviruses; Animals; Blood circulation; Brain injury; Brain Ischemia - genetics; Brain Ischemia - therapy; brain water content; Caspase-3; cerebral infarct volumes; Cerebral infarction; Gene therapy; Genetic Therapy - methods; Hsp90 protein; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - administration & dosage; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-inducible factor 1a; Infusions, Intraventricular; Ischemia; Male; modified neurological severity score; mRNA; Neuroprotection; Neuroprotection - genetics; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant AdHIF-1α; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - therapy; Rodents; Ventricle; Ventricles (cerebral); Water content; Western blotting; Recombinant AdHIF-1α; brain water content; cerebral infarct volumes; modified neurological severity score
• ISSN: 1388-0209; 1744-5116
• DOI: 10.1080/13880209.2020.1762667

Hypoxia-inducible factor-1α (HIF-1α)-induced genes can improve blood circulation. To investigate brain protective effect of recombinant adenovirus-mediated HIF-1α (AdHIF-1α) expression and its mechanism. 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 (10 8 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. 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. 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.