The Modulation Of NF-κB On Insulin-like Growth Factor-Ⅰ(IGF-Ⅰ)/Insulin-like Growth Factor Binding Protein-1 (IGFBP-1) Under Hypoxia

Ochotona curzoniae,Microtus oeconomus and Myospalax Baileyi are native mammals resident at Qinghai-Tibetan plateau,and they have well acclimatized to the environmental hypoxia,but the adaptive principle has not been entirely explored.IGF-I (Insulin-like Growth Factorâ… ),an endocrinal and paracrinal/autocrinal factor,is linked to hypoxia closely.Recently more and more papers showed that IGF may play protective roles in hypoxic model.This study reports the effects of hypoxia on IGF-I/IGFBP-1 expressions in both the prefrontal cortex and the liver of Ochotona curzoniae,Microtus oeconomus,Myospalax haileyi and mice,and the potential involvement of nuclear factor kappa-B(NF-κB)in mediating the effects of normobaric hypoxia.IGF-1 work as a key regulator of cellular apoptosis and play an important role in preventing tissue damage.In the plateau mammal study,hypoxia was simulated by two methods:the cobalt chloride(CoCl₂)treatment and the normobaric chamber. PDTC,an inhibitor of NF-κB,was injected just before the hypoxia exposure in the normobaric hypoxia study.IGF-I/IGFBP-1 protein was determined by Elisa.Results:1.Six hours after the injection of CoCl₂,IGF-I in the prefrontal cortex of M.Baileyi (20,40 mg/kg)dose not change evidently;IGF-I/IGFBP-1 in the liver of M.Baileyi (20,40 mg/kg)significantly increased.During normobaric hypoxia(10.8%O₂ or 8.0%O₂),IGF-I expressions in the liver of M.oeconomus and the IGFBP-1 expressions in the liver of O.curzoniae has been greatly enhanced;16.0%,10.8% O₂ or 8.0%O₂ hypoxia remarkably enhanced IGF-I/IGFBP-1 expressions in the liver of mice.Under the hypoxic induction(10.8%and 8,0%O₂),hepatic IGF-I of Microtus oeconomus significantly enhanced,but hepatic IGFBP-1 did not show such change.Hepatic IGF-I and IGFBP-1 of Ochotona curzoniae showed reverse changes of hepatic IGF-I and IGFBP-1 from Microtus oeconomus.2.IGF-I expressions of the PDTC treatment during hypoxia in prefrontal cortex of M. Baileyi reduced remarkedly;PDTC treatment during hypoxia significantly reversed the hypoxia-enhanced IGF-I expressions in the liver of mice,M.Baileyi and M. oeconomus,PDTC treatment during hypoxia significantly reversed the hypoxia-enhanced IGFBP-1 expressions in the liver of mice,M.Baileyi and O. curzoniae;3.Six hours after the injection of CoCl₂,HIF-1αin the prefrontal cortex and liver of M. Baileyi(20 mg/kg)increased significantly compared to the control group.We did not detect any expression of HIF-1,however,in the cortex of M.Baileyi.4.The coding region of M.cansus HIF-1αcDNA was 2457 bp,encoding 818 amino acids.The amino acid sequence of M.cansus HIF-1αhas 93%,92%,93%,98% identities of those from mice,rat,human and M.Baileyi.Conclusions:1.Ochotona curzoniae,Microtus oeconomus and Myospalax Baileyi are well acclimatized to the environmental hypoxia.Ochotona curzoniae,Microtus oeconomus and Myospalax Baileyi may have different signaling pathways to prevent the hypoxic damage.These differences might be caused by their living environments or the differences of their species.2.NF-κB may play important,but different roles in the regulation of IGF-I/IGFBP-1 expressions of different animals.The IGF-I/IGFBP-1 expressions of Ochotona curzoniae,Microtus oeconomus and Myospalax Bailevi linked to NF-κB.NF-κB also partly participates in the regulation of IGFBP-1 expression of mice.3.As an oxygen-sensitive transcription factor,NIF-1αis important for the response of ischemia-hypoxia.Although some transcription factors,like AP-1,Egr-1,may mediate some special gene's expressions under hypoxia,HIF-1αplays an indispensable role in the oxygen balance.Expression of HIF-1αof Ochotona curzoniae did not show changes under hypoxia,expression of HIF-1αof Microtus oeconomus enhanced only in the circumstance of dramatic hypoxia,while expression of hepatic HIF-1αof Myospalax Baileyi enhanced significantly during hypoxia.Moreover,NF-κB may mediate the hepatic expression of HIF-1αof Myospalax Baileyi.After injection of the antagonist of NF-κB,we did not detect the basic expression and the expression of HIF-1αunder hypoxia. 4.The homology of M.cansus HIF-1αcDNA sequence shows 98%identity to M. Baileyi and 97%identity to M.judaei.The amino acids alignment exhibits 100% identity in all key domain between M.Baileyi and M.cansus which lived in Western China,but there are four different amino acids in TAD(N)domain of M. judaei which lived in Israel,The amino acids in ODD domain of M.baileyi and M. cansus is S.but R instead of S in M.judaei.