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

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Reichelt, Melissa E
Shanu, Anu
Willems, Laura
Witting, Paul K
Ellis, Natasha A
Blackburn, Michael R
Headrick, John P
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2009
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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 8.2ᰮ7 IU/g of lactate dehydrogenase (LDH). A1AR deletion worsened dysfunction and LDH efflux (15.2Ხ6 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 a-tocopherylquinone (a-TQ; oxidation product of a-tocopherol (a-TOH)) increased 6-fold. Elevations in a-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 占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 a-TOH/a-TQ levels may contribute to A1AR-dependent cardioprotection.

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Antioxidants & Redox Signaling

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11

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11

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© 2009 Mary Ann Liebert, Inc., publishers. Self-archiving of the author-manuscript version is not yet supported by this publisher. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.

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Biochemistry and cell biology

Biochemistry and cell biology not elsewhere classified

Animal physiology - cell

Medical biochemistry and metabolomics

Cardiology (incl. cardiovascular diseases)

Pharmacology and pharmaceutical sciences

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