Endogenous adenosine selectively modulates oxidant stress via the A1 receptor in ischemic hearts.
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.
Reichelt
Melissa E
ME
Heart Foundation Research Center, Griffith University , Southport, Queensland, Australia. mreichelt@ucsd.edu
Shanu
Anu
A
Willems
Laura
L
Witting
Paul K
PK
Ellis
Natasha A
NA
Blackburn
Michael R
MR
Headrick
John P
JP
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
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