Endogenous adenosine selectively modulates oxidant stress via the A1 receptor in ischemic hearts

Abstract

We tested the impact of A1 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 ~50% of contractile function, and released 8.2±0.7 IU/g of lactate dehydrogenase (LDH). A1AR deletion worsened dysfunction and LDH efflux (15.2±2.6 IU/g). Tissue cholesterol and native cholesteryl esters were unchanged, while cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased 3-fold, and α-tocopherylquinone (α-TQ; oxidation product of α-tocopherol (α-TOH)) increased 6-fold. Elevations in α-TQ were augmented 2- to 3-fold by A1AR deletion, whereas CE-O(O)H was unaltered. A1AR 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: 4-fold elevations in HO-1 mRNA and activity were doubled by A1AR deletion. Broad-spectrum AR agonism (10 µM 2-chloroadenosine; 2-CAD) countered effects of A1AR deletion on oxidant damage, HO-1, and tissue injury, indicating additional ARs (A2A, A2B and/or A3) can mediate similar actions. These data reveal local adenosine engages A1ARs during I/R to selectively limit oxidant damage and enhance outcome. Control of α-TOH/α-TQ levels may contribute to A1AR-dependent cardioprotection.