Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, KY, USA.
School of Dentistry, University of Puerto Rico, Sabana Seca, PR, USA.
Immunology. 2018 Jul;154(3):452-464. doi: 10.1111/imm.12894. Epub 2018 Feb 14.
Hypoxia (i.e. oxygen deprivation) activates the hypoxia-signalling pathway, primarily via hypoxia-inducible transcription factors (HIF) for numerous target genes, which mediate angiogenesis, metabolism and coagulation, among other processes to try to replenish tissues with blood and oxygen. Hypoxia signalling dysregulation also commonly occurs during chronic inflammation. We sampled gingival tissues from rhesus monkeys (Macaca mulatta; 3-25 years old) and total RNA was isolated for microarray analysis. HIF1A, HIF1B and HIF2A were significantly different in healthy aged tissues, and both HIF1A and HIF3A were positively correlated with aging. Beyond these transcription factor alterations, analysis of patterns of gene expression involved in hypoxic changes in tissues showed specific increases in metabolic pathway hypoxia-inducible genes, whereas angiogenesis pathway gene changes were more variable in healthy aging tissues across the animals. With periodontitis, aging tissues showed decreases in metabolic gene expression related to carbohydrate/lipid utilization (GBE1, PGAP1, TPI1), energy metabolism and cell cycle regulation (IER3, CCNG2, PER1), with up-regulation of transcription genes and cellular proliferation genes (FOS, EGR1, MET, JMJD6) that are hypoxia-inducible. The potential clinical implications of these results are related to the epidemiological findings of increased susceptibility and expression of periodontitis with aging. More specifically the findings describe that hypoxic stress may exist in aging gingival tissues before documentation of clinical changes of periodontitis and, so, may provide an explanatory molecular risk factor for an elevated capacity of the tissues to express destructive processes in response to changes in the microbial biofilms characteristic of a more pathogenic microbial challenge.
缺氧（即氧气剥夺）激活缺氧信号通路，主要通过缺氧诱导转录因子（HIF）对许多靶基因进行调节，这些基因调节血管生成、代谢和凝血等过程，试图为组织补充血液和氧气。慢性炎症期间也常发生缺氧信号失调。我们从恒河猴（Macaca mulatta；3-25 岁）的牙龈组织中取样，并分离总 RNA 进行微阵列分析。在健康老年组织中，HIF1A、HIF1B 和 HIF2A 存在显著差异，HIF1A 和 HIF3A 均与衰老呈正相关。除了这些转录因子的改变之外，对涉及组织缺氧变化的基因表达模式的分析表明，代谢途径的缺氧诱导基因特异性增加，而血管生成途径的基因变化在健康衰老组织中在动物之间更加多变。患有牙周炎时，衰老组织中与碳水化合物/脂质利用（GBE1、PGAP1、TPI1）、能量代谢和细胞周期调节（IER3、CCNG2、PER1）相关的代谢基因表达减少，与缺氧诱导的转录基因和细胞增殖基因（FOS、EGR1、MET、JMJD6）上调。这些结果的潜在临床意义与牙周炎随年龄增长易感性和表达增加的流行病学发现有关。更具体地说，这些发现描述了在牙周炎临床变化出现之前，衰老的牙龈组织中可能存在缺氧应激，因此可能为组织在微生物生物膜变化的更具致病性微生物挑战下表现出破坏性过程的能力升高提供了一个解释性的分子风险因素。
