{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T07:26:45Z","timestamp":1778830005193,"version":"3.51.4"},"reference-count":70,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P 31083\u2010B34"],"award-info":[{"award-number":["P 31083\u2010B34"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia\u2013reperfusion (IR) injury (24\u201372\u2009h), but the mechanisms underlying extended\u00a0cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor\u2010induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mice were administered an ADK inhibitor, ABT\u2010702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24\u2013120\u2009h later. Theophylline or bortezomib was administered 24\u2009h after ABT\u2010702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72\u2009h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac\u2010specific ADK KO (cADK<jats:sup>+\/\u2212<\/jats:sup>) mice. Cardiac ADK expression was also examined after A<jats:sub>1<\/jats:sub> or A<jats:sub>3<\/jats:sub> receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>ABT\u2010702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72\u2009h. ADK mRNA upregulation restored ADK protein after 96\u2013120\u2009h. Adenosine receptor or proteasome inhibition at 24\u2009h reversed ABT\u2010702\u2010induced ADK protein deficit and cardioprotection at 72\u2009h. cADK<jats:sup>+\/\u2212<\/jats:sup> hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>A positive feedback loop driven by adenosine receptor\u2010induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT\u2010702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK<jats:sup>+\/\u2212<\/jats:sup> hearts.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17331","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T04:51:02Z","timestamp":1726030262000},"page":"4920-4936","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An adenosinergic positive feedback loop extends pharmacological cardioprotection duration"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2552-1999","authenticated-orcid":false,"given":"Gerald","family":"W\u00f6lkart","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Graz  Graz Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Gissing","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Graz  Graz Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"Stessel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Graz  Graz Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin K.","family":"Fassett","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Graz  Graz Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Burkhard","family":"Kl\u00f6sch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Graz  Graz Austria"},{"name":"Ludwig Boltzmann Institute for Arthritis and Rehabilitation University of Graz  Graz Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.","family":"Greene","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuroscience, Peter O'Donnell 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