Liang B T
Department of Medicine, Cardiovascular Division, and Pharmacology, 504 Johnson Pavilion, University of Pennsylvania Medical Center, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
Biochem J. 1998 Dec 1;336 ( Pt 2)(Pt 2):337-43. doi: 10.1042/bj3360337.
Prior activation of protein kinase C (PKC) can precondition the cardiac cell against injury during subsequent ischaemia. By using cultured chick ventricular cell model for simulated ischaemia and preconditioning, the present study investigated the biochemical mechanism underlying the PKC-mediated preconditioning. A 5 min exposure to PMA enhanced the ability of pinacidil to mediate cardioprotection during a subsequent 90 min period of ischaemia, which is consistent with a sustained activation of the KATP channel initiated by PKC. The brief prior exposure to PMA was also associated with an enhanced ability of the adenosine A1 or A3 receptor agonist 2-chloro-N6-cyclopentyladenosine or N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide to elicit a cardioprotective response during the subsequent ischaemia. In myocytes pretreated with PMA, the cardioprotection mediated by receptor agonist was blocked by the concomitant presence of KATP-channel antagonists glibenclamide or 5-hydroxydecanoic acid during the ischaemia. Thus the KATP channel acts downstream of the adenosine A1 and A3 receptors in mediating the protective effect due to prior PMA exposure. KATP channel activation is responsible for the adenosine receptor-mediated effect. PMA treatment had no effect on other A1 or A3 receptor-mediated effects such as the inhibition of adenylate cyclase, ruling out a direct stimulation of the receptor or G-protein by PMA. The present results indicate that prior stimulation of PKC causes a sustained KATP channel activation, which in turn renders the myocyte more responsive to the protective action of adenosine A1 and A3 receptor agonists during the subsequent ischaemia.
蛋白激酶C（PKC）的预先激活可使心脏细胞在随后的缺血过程中对损伤产生预处理作用。本研究利用培养的鸡心室细胞模型进行模拟缺血和预处理，探讨了PKC介导的预处理的生化机制。用佛波酯（PMA）处理5分钟可增强吡那地尔在随后90分钟缺血期间介导心脏保护的能力，这与PKC引发的ATP敏感性钾通道（KATP通道）的持续激活一致。预先短暂暴露于PMA还与腺苷A1或A3受体激动剂2-氯-N6-环戊基腺苷或N6-（3-碘苄基）腺苷-5'-N-甲基脲苷在随后缺血期间引发心脏保护反应的能力增强有关。在用PMA预处理的心肌细胞中，受体激动剂介导的心脏保护在缺血期间被KATP通道拮抗剂格列本脲或5-羟基癸酸的同时存在所阻断。因此，KATP通道在介导由于预先暴露于PMA而产生的保护作用中位于腺苷A1和A3受体的下游。KATP通道激活负责腺苷受体介导的效应。PMA处理对其他A1或A3受体介导的效应如腺苷酸环化酶的抑制没有影响，排除了PMA对受体或G蛋白的直接刺激。目前的结果表明，预先刺激PKC会导致KATP通道持续激活，这反过来又使心肌细胞在随后的缺血期间对腺苷A1和A3受体激动剂的保护作用更敏感。
