Activation of Hypoxia-Inducible Factor-1 in the Rat Cerebral Cortex after Transient Global Ischemia: Potential Role of Insulin-Like Growth Factor-1

Abstract

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.

Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit

“…HIF-1 is an oxygen-regulated transcriptional complex that controls a large number of oxygen-regulated genes. An increase in HIF-1α activity would result in metabolic, angiogenic and apoptotic adaptive responses, contributing to neuroprotection [52,55]. HIF-1α accumulation and HIF-1 target gene activation were triggered by systemic administration of IGF-1 in the adult rat brain [55].…”

“…An increase in HIF-1α activity would result in metabolic, angiogenic and apoptotic adaptive responses, contributing to neuroprotection [52,55]. HIF-1α accumulation and HIF-1 target gene activation were triggered by systemic administration of IGF-1 in the adult rat brain [55]. Because the level of hypoxia was profound in our model (1% oxygen), we can speculate that the neuroprotective action of IGF-1 played a role in the increase of survival rate seen in our model.…”

Notch signaling in the brain: In good and bad times

“…3). It is currently unknown whether high levels of Hif-1␣ can activate Notch, in the mammalian brain, following cerebral ischemia (Chavez and LaManna, 2002).…”

“…3). It is possible that Hif-1␣, which is strongly induced by ischemia (Chavez and LaManna, 2002), can potentiate Notch signaling in injury.…”

Erythropoietin in post-resuscitation neurological recovery: is there light at the end of the tunnel?

“…During the first few hours of recovery from cardiac arrest, the brain remains hypoxic, but for no more than 2 days (23). After a hypoxic-ischemic insult, hypoxia inducible factor (HIF) isoforms, HIF-1 alpha and HIF-2 alpha, stimulate the expression of EPO in brain astrocytes (23)(24)(25).…”