Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1.
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. It consists of a regulatory subunit HIF-1alpha, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1beta. In this study we analyzed HIF-1alpha expression in the rat cerebral cortex after transient global ischemia induced by cardiac arrest and resuscitation. Our results showed that HIF-1alpha accumulates as early as 1 hr of recovery and persists for at least 7 d. In addition, the expression of HIF-1 target genes, erythropoietin and Glut-1, were induced at 12 hr to 7d of recovery. A logical explanation for HIF-1alpha accumulation might be that the brain remained hypoxic for prolonged periods after resuscitation. By using the hypoxic marker 2-(2-nitroimidazole-1[H]-y1)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), we showed that the brain is hypoxic during the first hours of recovery from cardiac arrest, but the tissue is no longer hypoxic at 2 d. Thus, the initial ischemic episode must have activated other nonhypoxic mechanisms that maintain prolonged HIF-1alpha accumulation. One such mechanism might be initiated by insulin-like growth factor-1 (IGF-1). Our results showed that IGF-1 expression was upregulated after cardiac arrest and resuscitation. In addition, we showed that IGF-1 was able to induce HIF-1alpha in pheochromocytoma cells and cultured neurons as well as in the brain of rats that received intracerebroventricular and systemic IGF-1 infusion. Moreover, infusion of a selective IGF-1 receptor antagonist abrogates HIF-1alpha accumulation after cardiac arrest and resuscitation. Our study suggest that activation of HIF-1 might be part of the mechanism by which IGF-1 promotes cell survival after cerebral ischemia.
Chavez
Juan C
JC
Department of Anatomy, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4938, USA.
LaManna
Joseph C
JC
D000818:Animals; D016887:Cardiopulmonary Resuscitation; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017341:Etanidazole / Q000031:analogs & derivatives*; D006324:Heart Arrest, Induced; D006845:Hydrocarbons, Fluorinated; D002534:Hypoxia, Brain / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008025:Ligases / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D005466:Fluorocarbons
D004268:DNA-Binding Proteins; D017341:Etanidazole; D006845:Hydrocarbons, Fluorinated; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I; D008025:Ligases; D009687:Nuclear Proteins; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D017526:Receptor, IGF Type 1; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497444:Hif1a protein, rat; C096011:2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide; D005466:Fluorocarbons; C061553:ATP dependent 26S protease