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Paracrine factors secreted by EpiSC were shown to modulate the injury response of the post\u2010MI heart and improve cardiac function. We have previously reported that the expression of the angiogenic cytokines vascular endothelial growth factor A (VEGFA) and IL\u20106 is strongly upregulated in EpiSC by adenosine acting via the A\n                    <jats:sub>2B<\/jats:sub>\n                    receptor (A\n                    <jats:sub>2B<\/jats:sub>\n                    R). Since tissue hypoxia is well known to be a potent stimulus for the generation of extracellular adenosine, the present study explored the crosstalk of A\n                    <jats:sub>2B<\/jats:sub>\n                    R activation and hypoxia\u2010hypoxia\u2010inducible factor 1 alpha (HIF\u20101\u03b1) signaling in cultured EpiSC, isolated from rat hearts 5\u00a0days after MI. We found substantial nuclear accumulation of HIF\u20101\u03b1 after A\n                    <jats:sub>2B<\/jats:sub>\n                    R activation even in the absence of hypoxia. This normoxic HIF\u20101\u03b1 induction was PKC\u2010dependent and involved upregulation of HIF\u20101\u03b1 mRNA expression. While the influence of hypoxia on adenosine generation and A\n                    <jats:sub>2B<\/jats:sub>\n                    R signaling was only minor, hypoxia and A\n                    <jats:sub>2B<\/jats:sub>\n                    R activation cumulatively increased VEGFA expression. Normoxic A\n                    <jats:sub>2B<\/jats:sub>\n                    R activation triggered an HIF\u20101\u03b1\u2010associated cell\u2010protective metabolic switch and reduced oxygen consumption. HIF\u20101\u03b1 targets and negative regulators PHD2 and PHD3 were only weakly induced by A\n                    <jats:sub>2B<\/jats:sub>\n                    R signaling, which may result in a sustained HIF\u20101\u03b1 activity. The A\n                    <jats:sub>2B<\/jats:sub>\n                    R\u2010mediated normoxic HIF\u20101\u03b1 induction was also observed in cardiac fibroblasts from healthy mouse hearts, suggesting that this mechanism is also functional in other A\n                    <jats:sub>2B<\/jats:sub>\n                    R\u2010expressing cell types. Altogether, we identified A\n                    <jats:sub>2B<\/jats:sub>\n                    R\u2010mediated HIF\u20101\u03b1 induction as novel aspect in the HIF\u20101\u03b1\u2010adenosine crosstalk, which modulates EpiSC activity and can amplify HIF\u20101\u03b1\u2010mediated cardioprotection.\n                  <\/jats:p>","DOI":"10.1096\/fj.202002545r","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T07:49:20Z","timestamp":1619682560000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Normoxic induction of HIF\u20101\u03b1 by adenosine\u2010A\n                    <sub>2B<\/sub>\n                    R signaling in epicardial stromal cells formed after myocardial infarction"],"prefix":"10.1096","volume":"35","author":[{"given":"Julia","family":"Hesse","sequence":"first","affiliation":[{"name":"Department of Molecular Cardiology, Medical Faculty and University Hospital 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