N6-(3-iodobenzyl)-adenosine-5′-N-methylcarboxamide confers cardioprotection at reperfusion by inhibiting mitochondrial permeability transition pore opening via glycogen synthase kinase 3β
N6-(3-iodobenzyl)-adenosine-5′-N-methylcarboxamide confers cardioprotection at reperfusion by inhibiting mitochondrial permeability transition pore opening via glycogen synthase kinase 3β
复制标题
N6-(3-碘苄基)-腺苷-5′-N-甲基甲酰胺通过糖原合酶激酶 3β 抑制线粒体通透性转换孔开放，从而在再灌注时提供心脏保护作用
DOI：
10.1124/jpet.106.101477
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发表时间：
2006-07-01
影响因子：
3.5
通讯作者：
Xu, Zhelong
中科院分区：
文献类型：
--
作者：
Park, Sung-Sik;Zhao, Hong;Xu, Zhelong
腺苷A3受体激动剂N-6-（3-碘苄基）腺苷-5 '-N-甲基甲酰胺（IB-MECA）在再灌注时具有心肌保护作用，但其机制尚不清楚。我们假设IB-MECA可能通过糖原合成酶激酶（GSK）3 β失活阻止线粒体通透性转换孔（mPTP）开放来保护再灌注时的心脏。在再灌注期间应用IB-MECA（1 μ M）可减少离体大鼠心脏的梗死面积，这种作用可被选择性A3受体拮抗剂1，4-二氢-2-甲基-6-苯基-4-（苯乙炔基）-3，5-吡啶二羧酸3-乙基-5-[（3-硝基苯基）甲基]酯（MRS 1334）（100 nM）所消除。IB-MECA的作用被mPTP开放剂甘草酸苷（20 μ M）消除，这意味着IB-MECA的作用可能是通过抑制mPTP开放来介导的。在心肌细胞中，IB-MECA减弱了氧化剂诱导的线粒体膜电位损失（Delta Psi（m）），这被MRS 1334逆转。IB-MECA也减少了Ca 2+诱导的线粒体肿胀。IB-MECA增强了再灌注时GSK-3 β（Ser（9））的磷酸化，GSK-3抑制剂3-（2，4-二氯苯基）-4-（1-甲基-1H-吲哚-3-基）-1H-吡咯-2，5-二酮（SB 216763）（3 μ M）通过减弱梗死和Δ Psi（m）的损失模拟了IB-MECA的保护作用。此外，IB-MECA对GSK-3 β的作用被渥曼青霉素（100 nM）逆转，IB-MECA显示在再灌注后增强Akt磷酸化。相比之下，雷帕霉素（2 nM）未能通过IB-MECA影响GSK-3 β磷酸化，IB-MECA也未改变mTOR（Ser（2448））或70 s6 K（Thr（389））的磷酸化。总之，这些数据表明，IB-MECA通过在再灌注时GSK-3 β的失活抑制mPTP开放来防止心肌再灌注损伤。IB-MECA诱导的GSK-3 β抑制由PI 3-激酶/Akt信号通路介导，但不由mTOR/p70 s6 K通路介导。
Although the adenosine A 3 receptor agonist N-6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) has been reported to be cardioprotective at reperfusion, little is known about the mechanisms underlying the protection. We hypothesized that IB-MECA may protect the heart at reperfusion by preventing the opening of mitochondrial permeability transition pore (mPTP) through inactivation of glycogen synthase kinase (GSK) 3 beta. IB-MECA (1 mu M) applied during reperfusion reduced infarct size in isolated rat hearts, an effect that was abrogated by the selective A 3 receptor antagonist 1,4-dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3,5-pyridinedicarboxylic acid 3-ethyl-5-[(3-nitrophenyl)methyl] ester (MRS1334) (100 nM). The effect of IB-MECA was abrogated by the mPTP opener atractyloside (20 mu M), implying that the action of IB-MECA may be mediated by inhibition of the mPTP opening. In cardiomyocytes, IB-MECA attenuated oxidant-induced loss of mitochondrial membrane potential (Delta Psi(m)), which was reversed by MRS1334. IB-MECA also reduced Ca2+-induced mitochondrial swelling. IB-MECA enhanced phosphorylation of GSK-3 beta (Ser(9)) upon reperfusion, and the GSK-3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) (3 mu M) mimicked the protective effect of IB-MECA by attenuating both infarction and the loss of Delta Psi(m). In addition, the effect of IB-MECA on GSK-3 beta was reversed by wortmannin (100 nM), and IB-MECA was shown to enhance Akt phosphorylation upon reperfusion. In contrast, rapamycin (2 nM) failed to affect GSK-3 beta phosphorylation by IB-MECA, and IB-MECA did not alter phosphorylation of either mTOR (Ser(2448)) or 70s6K (Thr(389)). Taken together, these data suggest that IB-MECA prevents myocardial reperfusion injury by inhibiting the mPTP opening through the inactivation of GSK-3 beta at reperfusion. IB-MECA-induced GSK-3 beta inhibition is mediated by the PI3-kinase/Akt signal pathway but not by the mTOR/p70s6K pathway.