Hypoxia Pathway Gene Expression in Aging and Periodontitis Gingival Tissues

Hypoxia (i.e., oxygen deprivation) occurs in a diverse range of disease states and depending on the severity, permanent damage to tissues and cells may occur.  Low oxygen conditions activate the hypoxia-signaling pathway, primarily via the hypoxia inducible factor-1 (HIF-1). It is a transcription factor for numerous target genes, which mediate angiogenesis, metabolism, coagulation, among other processes to try to replenish tissues with blood and oxygen.  Hypoxia signaling dysregulation also commonly occurs during chronic inflammation.  Objective: This report hypothesized that gingival tissues in aging animals demonstrate enhanced expression of genes in physiologic pathways consistent with hypoxic stress in the tissues prior to a disease process.  Methods:   We sampled gingival tissues in health (n=23) from rhesus monkeys (M. mulatta) from 3-25 years, and naturally occurring periodontitis samples from animals 12-23 years (n=10).  Total RNA was isolated and the Rhesus GeneChip (Affymetrix) was used for microarray analysis.  Results:   HIF-1 was significantly increased in healthy aged tissues, and both HIF-1 and HIF-3 positively correlated with aging.  Multiple co-transcription factors were also increased (ARNT, COPS5). Metabolic hypoxia-inducible genes were generally increased, while angiogenesis genes were decreased in healthy aging tissues.  During periodontitis, aging tissues showed decreases in metabolic gene expression, with up-regulation of hypoxia-inducible transcription genes and proliferation genes.  MMP9 gene levels were significantly increased with healthy aging and up-regulated with periodontitis in both adult and aging tissues.  Conclusions:   The results supported that hypoxic stress exists in aging gingival tissues prior to clinical assessment of periodontitis.  These changes might be anticipated to provide a risk for the tissues to express destructive processes in response to a pathogenic microbial challenge.