{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T22:21:43Z","timestamp":1773267703478,"version":"3.50.1"},"reference-count":116,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T00:00:00Z","timestamp":1650672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms23094683","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"4683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Acute Hypoxia Alters Extracellular Vesicle Signatures and the Brain Citrullinome of Naked Mole-Rats (Heterocephalus glaber)"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7586-5939","authenticated-orcid":false,"given":"Stefania","family":"D\u2019Alessio","sequence":"first","affiliation":[{"name":"Tissue Architecture and Regeneration Research Group, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London W1W 6 UW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5251-640X","authenticated-orcid":false,"given":"Hang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liam","family":"Eaton","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-278X","authenticated-orcid":false,"given":"Igor","family":"Kraev","sequence":"additional","affiliation":[{"name":"Electron Microscopy Suite, Faculty of Science, Technology, Engineering and Mathematics, Open University, Walton Hall, Milton Keynes MK7 6AA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-9555","authenticated-orcid":false,"given":"Matthew E.","family":"Pamenter","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada"},{"name":"Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-3102","authenticated-orcid":false,"given":"Sigrun","family":"Lange","sequence":"additional","affiliation":[{"name":"Tissue Architecture and Regeneration Research Group, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London W1W 6 UW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/brv.12791","article-title":"The naked truth: A comprehensive clarification and classification of current \u2018myths\u2019 in naked mole-rat biology","volume":"97","author":"Buffenstein","year":"2022","journal-title":"Biol. 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