HIF-1α contributes to hypoxia adaptation of the naked mole rat

Abstract

Background/AimsNaked 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 hypoxia-tolerant species. The mechanisms underlying NMRs hypoxia tolerance remain poorly understood. In this study, we explored whether hypoxia inducible factor 1α (HIF-1α), and vascular endothelial growth factor A (VEGFA) play a role in NMRs adaption to hypoxia.MethodsPrimary hepatic stellate cells (HSCs) isolated from NMRs and mice were treated with 50 μM YC-1, 50 μM KC7F2 or VEGFA siRNA. HIF-1α 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.ResultsOur results showed that HIF-1α and VEGFA expression in NMRs was significantly higher than in hypoxia-sensitive mice. Inhibition of HIF-1α 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 LC3ΙΙ/LC3Ι = 9.6) than mouse HSCs (relative ratio of LC3ΙΙ/ LC3Ι = 4.9) under hypoxic conditions.ConclusionWe conclude that HIF-1α activation may be an important mechanism for hypoxia adaption. However, high expression of VEGFA follows HIF-1α activation in NMRs.

Naked mole rats activate neuroprotective proteins during hypoxia

“…NMRs have evolved a HIF1α protein with a unique mutation that relieves the constant state of HIF1α protein degradation and that is specifically adapted to chronic low oxygen availability (Kim et al, ). While the upregulation of HIF1α observed herein did not match the downregulation of HIF1α in a similar timeframe for 5% O 2 exposed NMR in a previous study, it did match HIF1α levels when the animals were exposed to 5% O 2 for 9 hr and longer (Xiao et al, ). Thus, increased HIF1α may be a robust NMR response to hypoxia with temporal and oxygen‐specific nuances.…”

“…Both of these results signal that exposure for less than 4 hr to hypoxic conditions may show interesting HIF1α dynamics, after which HIF1α shows consistent upregulation. An interesting NMR‐specific adaptation reported by Xiao et al () was that HIF1α was expressed at a higher level in NMR brains as compared to mouse brains, possibly contributing to their elevated hypoxia tolerance and likely due to their unique HIF1α protein sequence (Xiao et al, ). This activation of HIF1α has also been observed in other animal models of metabolic rate depression and anoxia/hypoxia tolerance, an observation that has been made at the protein, mRNA, and noncoding RNA levels (English, Hadj‐Moussa, & Storey, ; Gorr, ; Maistrovski, Biggar, & Storey, ; Morin, McMullen, & Storey, ).…”

Naked mole-rat cortical neurons are resistant to acid-induced cell death

“…it is established that ASICs play a key role in acidotoxicity. Considering the similar prevalence of ASIC currents, we suggest that the reduced ASIC-mediated current amplitude observed in NMR neurons may be an additional neuroprotective mechanism in NMR brains, alongside the previously described increased hypoxia-inducible transcription factor (HIF1-α) expression [ 65 ] or more efficient in vivo CO 2 buffering [ 47 ]. One possible mechanism for the decreased amplitude observed is reduced ASIC plasma membrane trafficking which is known to be modulated by an extracellular acidic environment [ 64 ].…”

The Janus Face of VEGF in Stroke

“…VEGF-A has multiple protective effects, including the promotion of angiogenesis, neurogenesis, and neuroprotection, leading to improved functional recovery [ 45 ]. VEGF-A is significantly upregulated in the brain of the naked mole rat ( Heterocephalus glaber ), where it contributes to their exceptional intrinsic hypoxia tolerance [ 46 , 47 ]. VEGF-A is therefore a very interesting candidate for therapeutic treatment in ischemic stroke [ 48 ].…”