Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade
Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade
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DOI：
10.1016/j.cardiores.2006.02.014
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发表时间：
2006-05-01
影响因子：
10.8
通讯作者：
Cohen, Michael V.
中科院分区：
文献类型：
--
作者：
Philipp, Sebastian;Yang, Xi-Ming;Cohen, Michael V.
目的：缺血后处理可保护再灌注心脏免于梗死，这种保护作用依赖于腺苷受体的占据。方法：兔心脏缺血30 min，再灌注3 h，缺血结束后再灌注30 s/冠状动脉阻断30 s共4个循环，观察腺苷受体对缺血后心肌保护作用的影响。后处理将梗死面积从未处理心脏的40.2 +/- 3.4%降低到15.5 +/-2.5%。在再灌注前5 min静脉注射非选择性腺苷受体阻断剂8-对-（磺苯基）茶碱或A（2b）选择性拮抗剂MRS 1754可阻断后处理的保护作用。蛋白激酶C（PKC）拮抗剂白屈菜红碱也中止后处理的补救，表明PKC依赖的机制。A（1）选择性拮抗剂8-环戊基-1，3-二丙基黄嘌呤和A（2a）选择性拮抗剂8-（13-氯苯乙烯基）咖啡因均无保护作用。从再灌注前5分钟至再灌注后1小时输注非选择性但A（2b）有效的腺苷激动剂5 '-（N-乙基甲酰氨基）腺苷（NECA）模拟后处理对梗死面积（17.2 +/- 2.7%梗死）的影响，MRS 1754阻断了NECA诱导的心脏保护作用，证实A（2b）活化具有保护作用。再灌注前给予PKC激活剂佛波醇12-肉豆蔻酸酯13-乙酸酯也复制了后处理的保护作用（16.3 +/- 4.1%梗死），同时给予PKC拮抗剂白屈菜红碱使PMA的保护作用无效，证实了保护作用是PKC激活的结果。NECA的保护作用不受白屈菜红碱的影响，但MRS 1754阻断了PMA的有益作用（42.8 +/- 1.0%梗死），表明A（2b）受体的作用受PKC控制。最后，wortmannin，磷脂酰肌醇3-激酶的阻断剂，也废除了保护PMA.Conclusions：挽救缺血心肌的后处理是依赖于激活A（2b）受体，这反过来又依赖于激活PKC。目前还不清楚为什么PKC激活需要使心脏的腺苷成为保护。(c)2006年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Ischemic postconditioning protects the reperfused heart from infarction, and this protection is dependent on the occupancy of adenosine receptors. We further explored the role of adenosine receptors in this salvage.Methods: In situ rabbit hearts underwent 30min of regional ischemia and 3h of reperfusion, and postconditioning was effected with four cycles of 30-s reperfusion/30-s coronary artery occlusion at the end of ischemia.Results: Postconditioning reduced infarct size from 40.2 +/- 3.4% of the risk zone in untreated hearts to 15.5 +/- 2.5%. Protection by postconditioning was blocked by either the non-selective adenosine receptor blocker 8-p-(sulfophenyl)theophylline or the A(2b)-selective antagonist MRS 1754, injected intravenously 5min before reperfusion. The protein kinase C (PKC) antagonist chelerythrine also aborted postconditioning's salvage, indicating a PKC-dependent mechanism. Neither the A(1)-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine nor the A(2a)-selective antagonist 8-(13-chlorostyryl)caffeine had an effect on protection. The non-selective but A(2b)-potent adenosine agonist 5'-(N-ethylcarboxamido)adenosine (NECA) infused from 5 min before to I h after reperfusion mimicked postconditioning's effect on infarct size (17.2 +/- 2.7% infarction) and MRS 1754 blocked the NECA-induced cardioprotection, confirming that A(2b) activation was protective. The PKC activator phorbol 12-myristate 13-acetate delivered just before reperfusion also duplicated the protective effect of postconditioning (16.3 +/- 4.1% infarction), and co-administration of the PKC antagonist chelerythrine aborted PMA's protection, confirming that the protection was the result of PKC activation. NECA's protective effect was not affected by chelerythrine, but rather MRS 1754 blocked PMA's salutary effect (42.8 +/- 1.0% infarction), suggesting that the A(2b) receptor's effect is under control of PKC. Finally, wortmannin, a blocker of phosphatidylinositol 3-kinase, also abrogated protection by PMA.Conclusions: Salvage of ischemic myocardium by postconditioning is dependent on activation of A(2b) receptors, which in turn depends on activation of PKC. It is still unclear why PKC activation is required to make the heart's adenosine become protective. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.