Hypoxia‐inducible transcription factors, HIF1A and HIF2A, increase in aging mucosal tissues

Abstract

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.

Integrative Analysis of lncRNAs, miRNAs, and mRNA-Associated ceRNA Network in Lung Tissue of Aging Mice and Changes after Intervention of Codonopsis pilosula

“…Aging is correlated with a reduction of cellular oxygen supply, which is characterized by decreased oxygen supply to tissue, a reduction of tissue PO2, and the activity of several enzymes and metabolic factors [29]. Hif3a (hypoxia-inducible factor 3A gene) has been reported to show significant differences in elderly tissues and is positively correlated with aging [30]. In the present study, we found that Hif3a was significantly upregulated in the model group.…”

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…Besides its role as an essential factor in VEGF-mediated effects on ECs, HIF-1 also has critical cell-autonomous functions in ECs [43,85]. In this regard, HIF participates in the formation of new vessels, enhancing the delivery of oxygenated blood to tissues [63]. In support of this, ECs under hypoxic conditions generate tube formation, which is negatively regulated by melatonin treatment.…”

“…Results have reported that the loss of epidermal HIF-1α accelerates epidermal aging and affects re-epithelialization in humans and mice [62]. Notably, significant elevations in both hypoxia-inducible transcription factors HIF-1α and HIF-1β gene expression have also been found in the gingival tissues of aged animals, even though these tissues were deemed clinically healthy [63]. In a model of limb ischemia in mice, HIF-1 was found to mediate angiogenesis and, therefore, has been proposed to contribute to the pathological aging process [54].…”

Transcriptome analysis of common and diverged circulating miRNAs between arterial and venous during aging

“…These cellular behaviors and response pathways were influenced by the aging process. EMT has been shown to decrease in senescent cells [ 33 ], whereas mTOR [ 34 , 35 ] and hypoxia-related pathways [ 36 , 37 ] have been shown to be induced. Apoptosis and senescence are cellular responses to damage with different mechanisms; both are involved in aging, and their relationship may vary under different conditions [ 38 , 39 ].…”