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The Journal of Neuroscience, October 15, 2002, 22(20):8922-8931
Activation of Hypoxia-Inducible Factor-1 in the Rat Cerebral
Cortex after Transient Global Ischemia: Potential Role of Insulin-Like
Growth Factor-1
Juan C.
Chavez1 and
Joseph C.
LaManna1, 2
Departments of 1 Anatomy and 2 Neurology,
Case Western Reserve University, School of Medicine, Cleveland, Ohio
44106
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-1 , which accumulates under
hypoxic conditions, and a constitutively expressed subunit HIF-1 .
In this study we analyzed HIF-1 expression in the rat cerebral
cortex after transient global ischemia induced by cardiac arrest and
resuscitation. Our results showed that HIF-1 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-1 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-1 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-1 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-1 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.
Key words:
global cerebral ischemia; hypoxia-inducible factor-1; insulin-like growth factor-1; hypoxia-inducible genes; cardiac arrest; brain hypoxia
Copyright © 2002 Society for Neuroscience 0270-6474/02/22208922-10$05.00/0
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