Activation of ecto-5'-nucleotidase by protein kinase C and its role in ischaemic tolerance in the canine heart.
1. Ischaemic preconditioning (IP) protects the myocardium against irreversible ischaemic injury by activating protein kinase C (PKC). The mechanism by which PKC protects the myocardium is unknown. We have shown that PKC increases the activity of ecto-5'-nucleotidase (ecto-5'-N) and thereby the production of adenosine in cardiomyocytes which may protect the myocardium against ischaemia-reperfusion injury in vivo. 2. The objective of this study was to elucidate the possible role of PKC-induced activation of ecto-5'-N in the cardioprotection associated with IP in the canine heart. 3. IP increased the activities of both ecto-5'-N and PKC, and minimized ischaemic damage (infarct size: 7.5 +/- 1.8 vs. 42.3 +/- 2.8%, P < 0.01 vs. the control group). Treatment with the PKC activator (4 beta-phorbol 12-myristate-13-acetate) also reduced infarct size (13.5 +/- 2.9%, P < 0.01 vs. the control group). 8-Sulfophenyltheophylline (an antagonist of adenosine receptors) or alpha,beta-methyleneadenosine 5'-diphosphate (an inhibitor of ecto-5'-N) eliminated the cardioprotective effect of the PKC activator (infarct size: 36.6 +/- 3.9 and 34.7 +/- 4.2%, respectively), suggesting that PMA limits infarct size by increasing the activity of ecto-5'-N and the adenosine level. 4. The PMA-induced cardioprotection was blunted by GF109203X (an inhibitor of PKC, infarct size: 36.2 +/- 3.1%), but not by pretreatment with dexamethasone (infarct size, 14.2 +/- 2.6%). 5. We conclude that the PMA- and IP-induced cardioprotection is attributable to phosphorylation and activation of ecto-5'-N.
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K
K
First Department of Medicine, Osaka University School of Medicine, Japan.
Kitakaze
M
M
Minamino
T
T
Tada
M
M
Inoue
M
M
Hori
M
M
Kamada
T
T
D015720:5'-Nucleotidase / Q000502:physiology*; D000818:Animals; D004285:Dogs; D004789:Enzyme Activation; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000517:prevention & control*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007211:Indoles; D008301:Maleimides; D011493:Protein Kinase C; D015720:5'-Nucleotidase; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate