Modulation Of Hypoxia On Insulin-like Growth Factor-â…  (IGF-â… ) And Its Binding Protein (IGFBP)

Ochotona curzoniae and Microtus oeconomus are native mammals resident at Qinghai-Tibetan plateau, and well acclimatized to environmental hypoxia, but the adaptive principle has not been entirely explored. This study reports the acute response of HIF-1α, IGF-I in brain and HIF-1α, IGF-I, IGFBP-1 and key metabolic enzyme genes of LDH, ICD in liver to hypoxia.The parameters were tested 6 h after exposure to hypoxia (CoCl₂ injection i.p. 20, 40 and 60 mg/kg or exposure to16%, 10.8% and 8% O₂). Protein of HIF-lcc was determined by Western blot, IGF-I and IGFBP-1 proteins were assayed by RIA or Elisa, mRNAs were determined by RT-PCR. Results:a) The results firstly demonstrated that HIF-1α expression (transcriptional factor, steady and inducible under hypoxia) in mice was markedly increased during hypoxia (i.p. 20 or 40mg/kg CoCl₂ or exposure to 10.8% or 8% O₂), and no response in either O. curzoniae or M. oeconomus at any dose CoCl₂ or exposure to 10.8% O₂.b) CoCl₂ significantly increased hepatic IGF-I expression in a dose-dependent manner in M. oeconomus, but not in O. curzoniae and mice; CoCl₂ induced an increased hepatic IGFBP-1 in dose dependent reducing in mice, and not in M. oeconomus. In the contrast, a dramatic increased IGFBP-1 was caused by all doses of CpCl₂ in O. curzoniae, and 40 mg/kg CoCl₂-induced IGFBP-1 increase maintained up to 12h (last point of observation),c) Hypoxia (i.p.CoCl₂ at any dose or exposure to 10.8% and 8% O₂) stimulated LDH-A mRNA but reduced ICD mRNA in mice and no change was seen inplateau native mammals at any dose C0CI2 or exposure to 10.8% O2. d) IGF-I mRNA was significantly up-regulated by CoC^-induced hypoxia in thebrain of the native mammals. And IGF-I mRNA was markedly increased in thebrain of O. curzoniae exposured to 10.8% and 8% O2. Conclusions or suggestion:a) In contrast with lowland lab animal, plateau-acclimated native mammals might be de-sensitive or high endurance to hypoxia. And between the two kind of native animals, O. curzoniae might be more de-sensive to hypoxia.b) Maintaining the aerobic TCA may be of the characteristic manner of energy metabolism for the hypoxia-well-acclimatized plateau mammals, but the increased anaerobic LDH and reduced TCA may be the signal for triggered glycolysis pathway and/or hepatic damage for lowland mice.c) The IGF-I/IGFBP-1 systems are distinguishing for those classes, and may differentially contribute to hypoxic protection at cellular or molecular levels in the liver and brain.d) Considering that IGF-I/IGFBP-1 increased but not HIF-la in the native mammals, we postulate that other transcription factors for IGFBP-1 are likely involved in the native mammals.