Recombinant Adenovirus-Mediated HIF-lα Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats

Abstract

Wenmei Zhou,1 Tao Tao,1 Wenfeng Yu,2 Wanfu Wu,3 Zhirong Hui,1 Hongliang Xu,1 Yaqi Li,4 Ying Zhang,5 Xiaohui Yang1,6 1Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China; 2Department of Human Anatomy, Basic Medical College, Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China; 3Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA; 4Emergency Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China; 5Department of Chinese Traditional Medicine, Zunyi Medical and Pharmaceutical College, Zunyi, Guizhou, 563006, People’s Republic of China; 6Department of Rehabilitation Medicine, The Affiliated Hospital Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of ChinaCorrespondence: Tao Tao, Tel [phone], Email [email protected]: Hypoxia inducible factor-1α (HIF-1α) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1ɑ on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model.Methods: Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1α (AdHIF-1α) group. The AdHIF-1α group and the Ad group were injected with AdHIF-1α and Ad in the lateral ventricle. The mNSS was performed at post-ischemia day 0 (P0) and P1, P14 and P28. At P14, the cerebral infarct volume was compared. At P28, HE staining, Nissl stains and TUNEL staining were performed. The expression of HIF-1α, GLUT1 and PFKFB3 were evaluated by Western Blot and immunohistochemistry. High performance liquid chromatography (HPLC) was used to determine the expression of GLUT1 and PFKFB3, and the level of energy metabolites: ATP, ADP and AMP.Results: mNSS scores in the AdHIF-1α group were consistently lower than those in the CIR and Ad groups from P14 (P < 0.05) and Ad groups (P < 0.05). The cerebral infarct volume was reduced in the AdHIF-1α group compared with that in CIR group and Ad group (P < 0.05). At P28, HE showed better pathological changes in AdHIF-1α group. The number of Nissl bodies was increased in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The number of apoptotic cells in the AdHIF-1α group was fewer than that in the CIR and Ad groups (P < 0.05). The expression of HIF-1α, GLUT1 and PFKFB3 was significantly higher in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The ATP, ADP and AMP in the ischemic penumbra were also higher in the AdHIF-1α group (P < 0.05).Conclusion: HIF-lα promoted neurological function recovery and decreased cerebral infarct volume in rats after cerebral ischemia-reperfusion injury by improving energy metabolism.Keywords: cerebral ischemia-reperfusion injury, HIF-lα, energy metabolism, glucose transporter protein-1, GLUT1, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3, PFKFB3

Keywords

• cerebral ischemia-reperfusion injury
• hif-lα
• energy metabolism
• glucose transporter protein-1 (glut1)
• 6-phosphofructo-2-kinase/fructose-2
• 6-biphosphatase 3 (pfkfb3)