Regulation of HIF-1α and p53 in stress responses in the subterranean rodents Lasiopodomys mandarinus and Lasiopodomys brandtii (Rodentia: Cricetidae)

ABSTRACT The response mechanism and interaction patterns of HIF-1α and p53 in animals in an hypoxic environment are crucial for their hypoxic tolerance and adaptation. Many studies have shown that underground rodents have better hypoxic adaptation characteristics. However, the mechanism by which HIF-1α and p53 in underground rodents respond to hypoxic environments compared with in ground rodents remains unclear. Further, whether a synergy between HIF-1α and p53 enables animals tolerate extremely hypoxic environments is unclear. We studied HIF-1α and p53 expression in the brain tissue and cell apoptosis in the hippocampal CA1 region during 6 hours of acute hypoxia (5% oxygen) in Lasiopodomys mandarinus (Milne-Edwards, 1871) and Lasiopodomys brandtii (Radde, 1861), two closely related small rodents with different life characteristics (underground and aboveground, respectively), using a comparative biology method to determine the mechanisms underlying their adaptation to this environment. Our results indicate that HIF-1α and p53 expression is more rapid in L. mandarinus than in L. brandtii under acute hypoxic environments, resulting in a significant synergistic effect in L. mandarinus. Correlation analysis revealed that HIF-1α expression and the apoptotic index of the hippocampal CA1 regions of the brain tissues of L. mandarinus and L. brandtii, both under hypoxia, were significantly negatively and positively correlated, respectively. Long-term existence in underground burrow systems could enable better adaptation to hypoxia in L. mandarinus than in L. brandtii. We speculate that L. mandarinus can quickly eliminate resulting damage via the synergistic effect of p53 and HIF-1α in response to acute hypoxic environments, helping the organism quickly return to a normal state after the stress.摘要 缺氧诱导因子-1α（Hypoxia-inducible factor 1α，HIF-1α）与肿瘤蛋白p53（tumor protein p53，p53）在动物体内的响应机制及相互作用模式，对于动物的低氧耐受与适应能力至关重要。多项研究表明，地下栖息啮齿类动物具备更优异的低氧适应特性。然而，相较于地面栖息啮齿类，地下栖息啮齿类体内的HIF-1α与p53如何响应低氧环境，其具体机制仍未阐明。此外，HIF-1α与p53的协同作用是否能帮助动物耐受极端低氧环境，这一问题也尚未明确。 本研究以两种亲缘关系密切但生活习性截然不同的小型啮齿类——地下栖息的东方鼢鼠（Lasiopodomys mandarinus，Milne-Edwards, 1871）与地面栖息的布氏田鼠（Lasiopodomys brandtii，Radde, 1861）为研究对象，采用比较生物学方法，探究二者在急性低氧（5%氧浓度）环境下暴露6小时过程中，脑组织内HIF-1α与p53的表达水平，以及海马CA1区的细胞凋亡情况，以阐明其适应低氧环境的潜在机制。 研究结果显示，在急性低氧环境下，东方鼢鼠体内HIF-1α与p53的表达响应速度快于布氏田鼠，这使得东方鼢鼠体内产生了显著的协同效应。相关性分析结果表明，在低氧条件下，东方鼢鼠脑组织海马CA1区的HIF-1α表达水平与凋亡指数呈显著负相关，而布氏田鼠则呈显著正相关。长期栖息于地下洞穴系统，可能是东方鼢鼠相较于布氏田鼠具备更优异低氧适应能力的原因。我们推测，东方鼢鼠可通过p53与HIF-1α的协同作用，快速清除急性低氧应激所造成的损伤，帮助机体在应激后迅速恢复至正常生理状态。