Inosine and equilibrative nucleoside transporter 2 contribute to hypoxic preconditioning in the murine cardiomyocyte HL-1 cell line

The purine nucleoside adenosine is a physiologically important molecule in the heart. Brief exposure of cardiomyocytes to hypoxic challenge results in the production of extracellular adenosine, which then interacts with adenosine receptors to activate compensatory signaling pathways that lead to cellular resistance to subsequence hypoxic challenge. This phenomenon is known as preconditioning (PC), and, while adenosine is clearly involved, other components of the response are less well understood. Flux of nucleosides, such as adenosine and inosine, across cardiomyocyte membranes is dependent on equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2). We have previously shown in the murine cardiomyocyte HL-1 cell line that hypoxic challenge leads to an increase in intracellular adenosine, which exits the cell via ENT1 and preconditions via A1 and A3 adenosine receptor-dependent mechanisms. However, the role and contribution of inosine and ENT2 are unclear. In this study, we confirmed that ENT1 and ENT...