Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice
Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice
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DOI：
10.1152/ajpheart.00379.2008
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发表时间：
2008-10-01
影响因子：
4.8
通讯作者：
Ghaleh, Bijan
中科院分区：
文献类型：
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作者：
Bouhidel, Omar;Pons, Sandrine;Ghaleh, Bijan
缺血后处理（IPCD）可显著减少健康动物的梗死面积并保护人类心脏。由于肥胖是心血管疾病的主要危险因素，因此在8至10周龄的瘦素缺陷型肥胖（ob/ob）小鼠中研究了IPCD的作用，并与野生型C57 BL/6 J（WT）小鼠进行了比较。所有动物均经历30分钟的冠状动脉闭塞，随后再灌注24小时，与IPCD相关或不相关（6个循环的10秒闭塞，10秒再灌注）。在再灌注10分钟时处死另外的小鼠用于蛋白质印迹。IPCD使WT小鼠的梗死面积减少了58%（对照组和IPCD分别为33 +/- 1%和14 +/- 3%，P < 0.05），但未能诱导ob/ob小鼠的心脏保护作用（对照组和IPCD分别为53 +/- 4%和56 +/- 5%）。在WT小鼠中，IPCD显著增加了Akt（+77%），ERK 1/2（+41%）及其共同靶点p70 S6 K1（Thr 389为+153%，Thr 421/Ser 424为+57%）的磷酸化。此外，IPCD还增加了WT小鼠磷酸化AMP活化蛋白激酶（AMPK）与总AMPK的比例（+64%，P < 0.05）。这伴随着10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）、MAP激酶磷酸酶（MKP）-3和蛋白磷酸酶（PP）2C水平的降低。相反，IPCD未能增加ob/ob小鼠中所有这些激酶的磷酸化状态，并且三种磷酸酶的水平显著增加。因此，虽然IPCD减少了健康动物的心肌梗死面积，但其心脏保护作用随着肥胖而消失。IPCD对Akt、ERK 1/2、p70 S6 K1和AMPK磷酸化的增强缺乏可能部分解释了肥胖小鼠实验模型中心脏保护作用的丧失。
Ischemic postconditioning (IPCD) significantly reduces infarct size in healthy animals and protects the human heart. Because obesity is a major risk factor of cardiovascular diseases, the effects of IPCD were investigated in 8- to 10-wk-old leptin-deficient obese (ob/ob) mice and compared with wild-type C57BL/6J (WT) mice. All animals underwent 30 min of coronary artery occlusion followed by 24 h of reperfusion associated or not with IPCD (6 cycles of 10-s occlusion, 10-s reperfusion). Additional mice were killed at 10 min of reperfusion for Western blotting. IPCD reduced infarct size by 58% in WT mice (33 +/- 1% vs. 14 +/- 3% for control and IPCD, respectively, P < 0.05) but failed to induce cardioprotection in ob/ob mice (53 +/- 4% vs. 56 +/- 5% for control and IPCD, respectively). In WT mice, IPCD significantly increased the phosphorylation of Akt (+77%), ERK1/2 (+41%), and their common target p70S6K1 (+153% at Thr389 and +57% at Thr421/Ser424). In addition, the phosphorylated AMP-activated protein kinase (AMPK)-to-total AMPK ratio was also increased by IPCD in WT mice (+64%, P < 0.05). This was accompanied by decreases in phosphatase and tensin homolog deleted on chromosome 10 (PTEN), MAP kinase phosphatase (MKP)-3, and protein phosphatase (PP)2C levels. In contrast, IPCD failed to increase the phosphorylation state of all these kinases in ob/ob mice, and the level of the three phosphatases was significantly increased. Thus, although IPCD reduces myocardial infarct size in healthy animals, its cardioprotective effect vanishes with obesity. The lack of enhanced phosphorylation by IPCD of Akt, ERK1/2, p70S6K1, and AMPK might partly explain the loss of cardioprotection in this experimental model of obese mice.