Molcular Mechanisms and Clinical Role of the Phosphorylation and Activation of Ecto-5'-Nucleotidase, Adenosine Producing Enzyme in Cardioprotection.

我们之前已经报道，通过α1-肾上腺素能刺激激活蛋白激酶C会激活ECTO-5‘-核苷酸酶，从而产生腺苷。因此，我们研究了外周-5‘-核苷酸酶的激活是否通过腺苷的产生在活体心脏保护中发挥作用。首先，我们发现冠脉内给药，迅速代谢为腺苷，缩小了犬心脏的梗死范围。我们还建立了外向-5‘-核苷酸酶过度表达的小鼠模型，目前正在研究外向-5’-核苷酸酶保护心脏的分子机制。此外，我们正在进行一项名为COAT研究的临床大规模试验，以评估腺苷对心脏保护的临床影响。我们已经初步报道了这种作用。第二，我们发现AICA核苷、Na+/H+交换抑制剂和ATP敏感性钾通道开放剂可以提高外向-5‘-核苷酸酶的活性。由于这些化合物在犬体内模型中具有心脏保护作用，我们建议腺苷参与这些药物的作用。第三，我们证实尼古丁预处理通过激活尼古丁受体和α1-肾上腺素受体对心肌坏死和顿抑具有心脏保护作用，从而增加外周-5‘-核苷酸酶的活性，增加局部腺嘌呤的产生(已提交)。这些基础和临床证据表明，腺苷和外周-5’-核苷酸酶在心脏病学中具有有益的作用。

We have previously reported that activation of protein kinase C via α 1-adrenergic stimulation activates ecto-5'-nucleotidase, which produces adenosine. Therefore, we investigated whether the activation of ecto-5'-nucleotidase plays a role in cardioprotection in vivo via the adenosine production.First, we found that an intracoronary administration of ATP, metabolized rapidly to adenosine, reduces infarct size in canine hearts. We also establish the mice overexpressional model of ecto-5'-nucleotidase, and now under the examination on the molecular mechanisms for cardioprotection of ecto-5'-nucleotidase.Furthermore, we are now proceeding a clinical large-scale trial named COAT study to estimate the clinical impact of adenosine on cardioprotection. We have preliminarily reported this efficacy.Second, we found that AICA riboside, Na+/H+ exchanger inhibitors, and ATP-sensitive potassium channel openers can increase the activity of ecto-5'-nucleotidase. Since these compounds have the cardioprotective effect in canine model in vivo, we suggest the involvement of adenosine in the effects of these drugs.Third, we established that the pretreatment with nicotine has cardioprotecitive effects against myocardial necrosis and stunning via nicotinic receptor activation, and the α1-adrenoceptor activation, which increases ecto-5'-nucleotidase activity and enhances the regional adenine production (submitted).These basic and clinical evidence indicates the beneficial action of adenosine and ecto-5'-nucleotidase in cardiology.