Post-ischemic cardioprotection by A2A adenosine receptors: dependent of phosphatidylinositol 3-kinase pathway.
Activation of myocardial A2A adenosine receptors during reperfusion has been shown to be cardioprotective. The intracellular mechanisms underlying this protection remain unknown. To understand the beneficial effects of activated A2A adenosine receptors in such a state, we investigated whether the enzymes phosphatidylinositol 3-kinase (PI3K) and caspase-3 can account for this post-ischemic cardioprotective effect in an anesthetized rabbit model of myocardial infarction (30 minutes ischemia; 5 hours reperfusion). Administration of the A2A agonist CGS21680 (0.2 microg/kg/min) 5 minutes before reperfusion began (Early) reduced infarct size expressed as a percentage of the area at risk (25.7 +/- 5.3% versus 46.5 +/- 5.3% for the control group; * P < 0.05). Treatment with the A2A agonist 5 minutes after the onset of reperfusion (Late) had no effect on infarct size (38.2 +/- 6.2%). In the presence of a selective inhibitor of PI3K (LY294002), the beneficial effects of CGS21680 on infarct size was no longer observed (43.9 +/- 7.9%). After 5 hours of reperfusion, higher PI3K activity in the ischemic region was observed in the Early group compared with the other experimental groups. Caspase-3 activity was not observed in these different groups. In another set of experiments, PI3K activity was significantly higher during the first 15 minutes of reperfusion in the Early group as compared with the Control group. Caspase-3 activity increased rapidly during the first 15 minutes of reperfusion in the Control group and remained stable in the Early group. These results indicated that post-ischemic cardioprotection afforded by A2A adenosine receptor activation is PI3K-dependent and modulate rapidly other signaling pathways such as caspase-3.
Boucher
Matthieu
M
Centre de Biomédecine, Hôpital du Sacré-Coeur de Montréal, Département de pharmacologie and Groupe de Recherche sur le Système Nerveux Autonome, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
Pesant
Stéphanie
S
Falcao
Stéphanie
S
de Montigny
Chantal
C
Schampaert
Erick
E
Cardinal
René
R
Rousseau
Guy
G
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010627:Phenethylamines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011817:Rabbits; D043705:Receptor, Adenosine A2A / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D000241:Adenosine; D058908:Adenosine A2 Receptor Agonists; D053148:Caspase 3; D020169:Caspases; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010627:Phenethylamines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one