A1 adenosine receptor overexpression attenuates ischemia-reperfusion-induced apoptosis and caspase 3 activity.
We tested the hypothesis that myocardial ischemia-reperfusion (I/R)-induced apoptosis is attenuated in transgenic mice overexpressing cardiac A(1) adenosine receptors. Isolated hearts from transgenic (TG, n = 19) and wild-type (WT, n = 22) mice underwent 30 min of ischemia and 2 h of reperfusion, with evaluation of apoptosis, caspase 3 activity, function, and necrosis. I/R-induced apoptosis was attenuated in TG hearts. TG hearts had less I/R-induced apoptotic nuclei (0.88 +/- 0.10% vs. 4.22 +/- 0.24% terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in WT, P < 0.05), less DNA fragmentation (3.30 +/- 0.38-fold vs. 4.90 +/- 0.39-fold over control in WT, P < 0.05), and less I/R-induced caspase 3 activity (145 +/- 25% over nonischemic control vs. 234 +/- 31% in WT, P < 0.05). TG hearts also had improved recovery of function and less necrosis than WT hearts. In TG hearts pretreated with LY-294002 (3 microM) to evaluate the role of phosphosinositol-3-kinase in acute signaling, there was no change in the functional protection or apoptotic response to I/R. These data suggest that cardioprotection with transgenic overexpression of A(1) adenosine receptors involves attenuation of I/R-induced apoptosis that does not involve acute signaling through phosphoinositol-3-kinase.
Regan
Sara E
SE
Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Broad
Michael
M
Byford
Anne M
AM
Lankford
Amy R
AR
Cerniway
Rachael J
RJ
Mayo
Marty W
MW
Matherne
G Paul
GP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis* / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
D053148:Caspase 3; D020169:Caspases; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018047:Receptors, Purinergic P1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat