Normoxic induction of HIF?1? by adenosine?A _2B R signaling in epicardial stromal cells formed after myocardial infarction

Myocardial infarction (MI) activates the epicardium to form epicardial stromal cells (EpiSC) that reside in hypoxic microenvironment. Paracrine factors secreted by EpiSC were shown modulate injury response of post-MI heart and improve cardiac function. We have previously reported expression angiogenic cytokines vascular endothelial growth factor A (VEGFA) IL-6 is strongly upregulated adenosine acting via A2B receptor (A2BR). Since tissue hypoxia well known be a potent stimulus for generation extracellular adenosine, present study explored crosstalk A2BR activation hypoxia-hypoxia-inducible 1 alpha (HIF-1?) signaling cultured EpiSC, isolated from rat hearts 5 days after MI. found substantial nuclear accumulation HIF-1? even absence hypoxia. This normoxic induction was PKC-dependent involved upregulation mRNA expression. While influence on only minor, cumulatively increased VEGFA Normoxic triggered an HIF-1?-associated cell-protective metabolic switch reduced oxygen consumption. targets negative regulators PHD2 PHD3 weakly induced signaling, which may result sustained activity. The A2BR-mediated also observed fibroblasts healthy mouse hearts, suggesting this mechanism functional other A2BR-expressing cell types. Altogether, we identified as novel aspect HIF-1?-adenosine crosstalk, modulates activity can amplify HIF-1?-mediated cardioprotection.