Peptidylarginine deiminases (PADs) and extracellular vesicles (EVs) may be indicative
biomarkers of physiological and pathological status and adaptive responses, including to diseases and disorders of the central nervous system (CNS) and related to
hypoxia. While these markers have been studied in
hypoxia-intolerant mammals, in vivo investigations in
hypoxia-tolerant species are lacking. Naked mole-rats (NMR) are among the most
hypoxia-tolerant mammals and are thus a good model organism for understanding natural and beneficial adaptations to
hypoxia. Thus, we aimed to reveal CNS related roles for PADs in
hypoxia tolerance and identify whether circulating EV signatures may reveal a fingerprint for adaptive whole-body
hypoxia responses in this species. We found that following in vivo acute
hypoxia, NMR: (1) plasma-EVs were remodelled, (2) whole
proteome EV cargo contained more
protein hits (including citrullinated
proteins) and a higher number of associated KEGG pathways relating to the total
proteome of plasma-EVs Also, (3) brains had a trend for elevation in PAD1, PAD3 and PAD6
protein expression, while PAD2 and PAD4 were reduced, while (4) the brain citrullinome had a considerable increase in deiminated
protein hits with
hypoxia (1222 vs. 852 hits in normoxia). Our findings indicate that circulating EV signatures are modified and proteomic content is reduced in hypoxic conditions in naked mole-rats, including the circulating EV citrullinome, while the brain citrullinome is elevated and modulated in response to
hypoxia. This was further reflected in elevation of some PADs in the brain tissue following acute
hypoxia treatment. These findings indicate a possible selective role for PAD-
isozymes in
hypoxia response and tolerance.