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CARDIOVASCULAR

The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase C in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1

Department of Biology, York University, Toronto, Ontario, Canada

Brief exposure of the heart to hypoxia results in less cellular damage after subsequent hypoxia, an effect known as preconditioning (PC). PC has been widely studied but is still not fully understood. Adenosine (Ado), adenosine receptors, and protein kinase C (PKC) have been implicated as integral components of PC. Adenosine (nucleoside) transporters (NTs) facilitate flux of Ado across cell membranes, but their role in PC is unknown. Therefore, we used the murine cardiomyocyte cell line, HL-1, and asked if there was feedback regulation of NTs by Ado, Ado receptors, and PKC following either hypoxic or pharmacological PC. Activation (by specific agonists) of A₁ or A₃ Ado receptors or PKC resulted in PC in HL-1. The A₁ (but not A₃) receptor is coupled to PKC, and activation of PKC (by specific peptide agonist) resulted in PC. Moreover, PKC stimulates Ado uptake via the predominant NT in HL-1, mouse equilibrative nucleoside transporter 1 (mENT1). Studies in primary neonatal mouse cardiomyocytes confirmed our observations in HL-1 cells. Hypoxic challenge led to a rapid increase in, and efflux of, intracellular Ado from cells, which was blocked by NT inhibitors (dipyridamole/nitrobenzylthioinosine). Moreover, NT inhibition during hypoxia or PC was highly protective, suggesting that Ado loss contributes to decreased cell viability. Our data suggest that hypoxic challenge causes an efflux of Ado via ENTs, activation of A₁ and/or A₃ receptors, signaling through PKC, and activation of ENT1. Since Ado is required for ATP synthesis on reperfusion, this feedback regulation of mENT1 would promote reuptake of Ado.

Address correspondence to: Imogen R. Coe, Department of Biology, York University, 4700 Keele St., Toronto, Ontario, Canada M3J 1P3. E-mail: coe{at}yorku.ca

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