title: Stabilization of HIF-1α modulates VEGF and Caspase-3 in the hippocampus of rats following transient global ischemia induced by asphyxial cardiac arrest.
abstract: OBJECTIVE
  Hypoxia inducible factor-1 (HIF-1) contributes to pathophysiological changes of homeostasis under conditions of oxygen deprivation as well as ischemia. In this study, we examined protein expression of subtype HIF-1α and its downstream product, namely vascular endothelial growth factor (VEGF) in the rat hippocampus after transient global ischemia induced by asphyxial cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We also examined the effects of stabilization of HIF-1α by systemic administration of dimethyloxalylglycine (DMOG) and ML228 on expression of VEGF receptor subtype 2 (VEGFR-2), Caspase-3 and NF-kB in the hippocampus.
  
  
  METHODS
  Ninety-six adult Sprague-Dawley rats were used in this study. The animals surviving from CPR were sacrificed 0, 3, 6 and 24h following CPR and the protein levels of HIF-1α and VEGF in the hippocampus were determined. VEGFR-2, Caspase-3 and NF-kB were also examined in control rats, and rats that survived for 24h after CPR and were given with DMOG/ML228. Moreover, neurological functions were estimated in control rats and rats with DMOG/ML228.
  
  
  RESULTS
  Our results show that HIF-1α and VEGF were significantly increased in the hippocampus 3-24h after CA. Significant increases in VEGFR-2, Caspase-3 and NF-κB were observed in the hippocampus 24h after CA (P<0.05 vs. control group). Nonetheless, DMOG and ML228 significantly augmented VEGFR-2, attenuated Caspase-3 and neuronal apoptosis, and improved neurological Severity Score and tissue edema (P<0.05 vs. saline group), without affecting expression of NF-κB.
  
  
  CONCLUSIONS
  Our data revealed specific signaling pathways in alleviating CA-evoked global cerebral ischemia by elucidating that HIF-1α plays an important role in regulating expression of VEGFR-2 and Caspase-3 as well as improving neurological functions and neuronal edema. The subsequent induction of HIF-1α and its target signal pathways is likely a part of the intrinsic neuroprotective effects aimed at attenuating damage as a result of global cerebral ischemia. Thus, targeting one or more of these signaling molecules has clinical implications for treatment and management of CA-evoked global cerebral ischemia often observed in clinics.
authors.affiliation: Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Department of Abdominal Surgery, Jilin Province Carcinoma Hospital, Changchun, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, China. Electronic address: jhxing79@gmail.com.
authors.forename: Jihong
authors.initials: J
authors.lastname: Xing
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D016887:Cardiopulmonary Resuscitation; D053148:Caspase 3 / Q000378:metabolism*; D006323:Heart Arrest / Q000150:complications / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D014227:Triazines / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C573773:ML228 probe; D016328:NF-kappa B; D011725:Pyridines; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D053148:Caspase 3; C040947:oxalylglycine
keywords: Cardiac arrest; Cardiopulmonary resuscitation; Caspase-3; HIF-1α; Hippocampus; VEGF