title: 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 approximately 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, 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 A1AR 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 A1AR deletion. Broad-spectrum AR agonism (10 microM 2-chloroadenosine; 2-CAD) countered effects of A1AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A(2A), A(2B), and/or A3) can mediate similar actions. These data reveal that local adenosine engages A1ARs during I/R to limit oxidant damage and enhance outcome selectively. Control of alpha-TOH/alpha-TQ levels may contribute to A1AR-dependent cardioprotection.
authors: Heart Foundation Research Center, Griffith University , Southport, Queensland, Australia. mreichelt@ucsd.edu
authors: Melissa E
authors: ME
authors: Reichelt
authors: Anu
authors: A
authors: Shanu
authors: Laura
authors: L
authors: Willems
authors: Paul K
authors: PK
authors: Witting
authors: Natasha A
authors: NA
authors: Ellis
authors: Michael R
authors: MR
authors: Blackburn
authors: John P
authors: JP
authors: Headrick
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism*; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D014810:Vitamin E / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D058907:Adenosine A1 Receptor Agonists; D002788:Cholesterol Esters; D006878:Hydroxides; D008054:Lipid Peroxides; D043682:Receptor, Adenosine A1; D014810:Vitamin E; D015762:2-Chloroadenosine; C002421:tocopherylquinone; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D005978:Glutathione; D000241:Adenosine