Acquirement of the Ischemic Cardioprotection and ecto-5'-nucleotidase : Investigation of the Receptor Activation and Subsequent Signal Transduction

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We had completed in preparing the ecto-5'-nucleotidase overexpression mice. The infarct size in the in vivo model afforded by 30-min ischemia and 2-hour reperfusion was significantly smaller (24 %) than that in the control (49 %). The ecto-5'-nucleotidase was rapidly activated early in the ischemic phase, which resulted in the increase in adenosine production. We also examined using these mice the changes in mRNA expression pattern by micro-array system, which revealed that adenosine in the ischemic phase plays cardioprotective roles.In healthy beagle dog model, ischemic preconditioning caused marked reduction in infarct size afforded by 90-min ischemia and 6-hour reperfusion, which was blunted by 1)PKC inhibition, 2) ecto-5'-nucleotidase inhibition, 3)adenosine A1 receptor blockade and 4)p38MAPK inhibition during preconditioning period, or partially attenuated by either sarcolemmal or mitochondrial KATP channel blockade. Furthermore, p70S6 kinase inhibition abolished the second-window … More protection after 48 hours of the preconditioning ischemia. These data indicate that the immediate and second-window preconditioning protect myocardium by different mechanisms.Now we are establishing the cDNA micro-array system in dogs, which can analyze the changes in as much as 10000 mRNA expression patterns at once. On this process, we prepared a pilot system that can analyze 100 known mRNA at once. Using this system, we tested the effect of 3-hour low flow ischemia on the 100 mRNA expression patterns and found that about 15 kinds of mRNA among them showed significant changes.In clinical settings, we are now operating some open or double-blind randomized case-control multi-center trials to examine the effect of an ATP derivative, a KATP channel opener, and a human hAMP derivative on acute myocardial infarction (COAT and J-WIND studies) and the effect of dipyridamol on stable mild chronic heart failure (ROAD study), under the approval of the ethical committee. COAT study now revealed that the acute phase treatment with ATP derivative resulted in better outcome 1-year later. Interestingly, ROAD study now showed that the chronic treatment with dipyridamol resulted in the increase in ADL, reduction in plasma BNP and aldosterone levels. These studies are now going on further toward the final results. Less