HIF-1a contributes to Hypoxia adaptation of the naked mole rat

Abstract

Background/Aims: Naked mole rats (NMRs) spend their lives in burrow systems containing very low levels of oxygen, indicating long-term hypoxic exposure, and suggesting that pathological changes caused by hypoxia are attenuated or absent in this hypoxiatolerant species. The mechanisms underlying NMRs hypoxia tolerance remain poorly understood. In this study, we explored whether hypoxia inducible factor 1a (HIF-1a), and vascular endothelial growth factor A (VEGFA) play a role in NMRs adaption to hypoxia. Methods: Primary hepatic stellate cells (HSCs) isolated from NMRs and mice were treated with 50 μM YC-1, 50 μM KC7F2 or VEGFA siRNA. HIF-1a or VEGFA expression was detected by Western blot and real-time PCR. Apoptosis was determined by flow cytometry. The expression of autophagy markers (LC3 and p62) was detected by Western blot. Results: Our results showed that HIF-1a and VEGFA expression in NMRs was significantly higher than in hypoxia-sensitive mice. Inhibition of HIF-1a expression induced apoptosis in both NMR and mouse HSCs following hypoxia. However, blocking VEGFA transcription results in a significant increase of apoptosis in both NMR and mouse HSCs before and after hypoxia. In addition, NMR HSCs displayed higher levels of autophagy (ratio of LC3??/LC3? = 9.6) than mouse HSCs (relative ratio of LC3??/ LC3? = 4.9) under hypoxic conditions. Conclusion: We conclude that HIF-1a activation may be an important mechanism for hypoxia adaption. However, high expression of VEGFA follows HIF-1a activation in NMRs.