TY - JOUR
T1 - Pharmacological and genetic accumulation of hypoxia-inducible factor-1α enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor
AU - Huang, Yu Fei
AU - Yang, Chih Hao
AU - Huang, Chiung Chun
AU - Tai, Ming Hong
AU - Hsu, Kuei Sen
PY - 2010/4/28
Y1 - 2010/4/28
N2 - Hypoxia-inducible factor-1 (HIF-1) is an important transcriptional factor in mammalian cells for coordination of adaptive responses to hypoxia. It consists of a regulatory subunit HIF-1α, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1β. In addition to the well characterized oxygen-dependent mode of action of HIF-1, recent work has shown that various growth factors and cytokines stimulate HIF-1α expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. In this study, we examined whether accumulation of HIF-1α induced by insulin-like growth factor-1 (IGF-1) has a regulatory role in excitatory synaptic transmission in hippocampal neuron cultures. Our results show that IGF-1 induced a time- and dose-dependent increase in HIF-1α expression that was blocked by pretreatment with selective IGF-1 receptor antagonist, transcriptional inhibitor, and translational inhibitors. In addition, pharmacological blockade of the phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin signaling pathway, but not extracellular signal-regulated kinase, inhibited IGF-1-induced HIF-1α expression. More importantly, the increase in HIF-1α expression induced by IGF-1 was accompanied by increasing levels of vascular endothelial growth factor (VEGF) mRNA and protein, which enhanced excitatory synaptic transmission. In parallel, blockade of HIF-1α activity by echinomycin or lentiviral infection with dominant-negative mutant HIF-1α or short hairpin RNA targeting HIF-1α inhibited the increase in expression of VEGF and the enhancement of synaptic transmission induced by IGF-1. Conversely, transfection of constitutively active HIF-1α into neurons mimicked the effects of IGF-1 treatment. Together, these results suggest that HIF-1α accumulation can enhance excitatory synaptic transmission in hippocampal neurons by regulating production of VEGF.
AB - Hypoxia-inducible factor-1 (HIF-1) is an important transcriptional factor in mammalian cells for coordination of adaptive responses to hypoxia. It consists of a regulatory subunit HIF-1α, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1β. In addition to the well characterized oxygen-dependent mode of action of HIF-1, recent work has shown that various growth factors and cytokines stimulate HIF-1α expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. In this study, we examined whether accumulation of HIF-1α induced by insulin-like growth factor-1 (IGF-1) has a regulatory role in excitatory synaptic transmission in hippocampal neuron cultures. Our results show that IGF-1 induced a time- and dose-dependent increase in HIF-1α expression that was blocked by pretreatment with selective IGF-1 receptor antagonist, transcriptional inhibitor, and translational inhibitors. In addition, pharmacological blockade of the phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin signaling pathway, but not extracellular signal-regulated kinase, inhibited IGF-1-induced HIF-1α expression. More importantly, the increase in HIF-1α expression induced by IGF-1 was accompanied by increasing levels of vascular endothelial growth factor (VEGF) mRNA and protein, which enhanced excitatory synaptic transmission. In parallel, blockade of HIF-1α activity by echinomycin or lentiviral infection with dominant-negative mutant HIF-1α or short hairpin RNA targeting HIF-1α inhibited the increase in expression of VEGF and the enhancement of synaptic transmission induced by IGF-1. Conversely, transfection of constitutively active HIF-1α into neurons mimicked the effects of IGF-1 treatment. Together, these results suggest that HIF-1α accumulation can enhance excitatory synaptic transmission in hippocampal neurons by regulating production of VEGF.
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U2 - 10.1523/JNEUROSCI.5493-09.2010
DO - 10.1523/JNEUROSCI.5493-09.2010
M3 - Article
C2 - 20427666
AN - SCOPUS:77951653933
SN - 0270-6474
VL - 30
SP - 6080
EP - 6093
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -