Endogenous Adenosine Selectively Modulates Oxidant Stress via the A1 Receptor in Ischemic Hearts

We tested the impact of A(1) adenosine receptor (AR) deletion on injury and oxidant damage in mouse hearts subjected to 25-min ischemia/45-min reperfusion (I/R). Wild-type hearts recovered similar to 50% of contractile function and released 8.2 +/- 0.7 IU/g of lactate dehydrogenase (LDH). A(1)AR deletion worsened dysfunction and LDH efflux (15.2 +/- 2.6 IU/g). Tissue cholesterol and native cholesteryl esters were unchanged, whereas cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased threefold, and alpha-tocopherylquinone [alpha-TQ; oxidation product of alpha-tocopherol (alpha-TOH)] increased sixfold. Elevations in alpha-TQ were augmented by two-to threefold by A(1)AR deletion, whereas CE-O( O) H was unaltered. A(1)AR deletion also decreased glutathione redox status ([GSH]=[GSSG + GSH]) and enhanced expression of the antioxidant response element heme oxygenase-1 (HO-1) during I/R: fourfold elevations in HO-1 mRNA and activity were doubled by A(1)AR deletion. Broad-spectrum AR agonism (10 mu M 2-chloroadenosine; 2-CAD) countered effects of A(1)AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A(2A), A(2B), and/or A(3)) can mediate similar actions. These data reveal that local adenosine engages A(1)ARs during I/R to limit oxidant damage and enhance outcome selectively. Control of alpha-TOH/alpha-TQ levels may contribute to A(1)AR-dependent cardioprotection. Antioxid. Redox Signal. 11, 2641-2650.