Ischemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3
Ischemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3
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DOI：
10.1152/ajpheart.00749.2016
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发表时间：
2017-03-01
影响因子：
4.8
通讯作者：
Heusch, Gerd
中科院分区：
文献类型：
--
作者：
Gent, Sabine;Skyschally, Andreas;Heusch, Gerd
缺血预处理（IPC），即在持续缺血和随后的再灌注之前短暂的非致死性心肌缺血-再灌注（I/R）发作，在迄今为止测试的所有物种中，包括人类，都减少了梗死面积。在啮齿类动物中，心脏保护信号转导涉及Akt、ERK1/2和STAT3的激活。然而，啮齿动物和猪等大型哺乳动物之间的信号转导存在明显的物种差异，Akt和ERK1/2的IPC信号转导数据不一致。STAT3的作用尚未被分析。猪接受60分钟的左冠状动脉前降支闭塞和180分钟的无IPC或有IPC的再灌注（2个周期，3分钟闭塞，2分钟再灌注，在持续I/R前15分钟）。采用氯化三苯四唑染色分析梗死面积，并在基线和早期再灌注心肌活检中定量检测Akt、ERK1/2和STAT3磷酸化水平。AG490用于阻断STAT3信号通路。IPC降低了梗死面积（危险面积%；平均+/- SE， I/R, 45 +/- 3 vs IPC, 18 +/- 3, P < 0.05）。Akt和ERK1/2磷酸化在无IPC和有IPC的早期再灌注时升高。相比之下，早期再灌注时STAT3磷酸化仅随IPC升高（基线%；平均+/- SE， I/R, 126 +/- 29， IPC, 408 +/- 147, P < 0.05）。AG490阻止再灌注时IPC相关的STAT3磷酸化增加（基线%，平均+/- SE， 82 +/- 12），并消除IPC的心脏保护作用（危险面积%，平均+/- SE， 35 +/- 4）。在猪中，STAT3磷酸化的增加与IPC的心脏保护有关，而Akt和ERK1/2似乎在IPC的心脏保护中没有作用。在猪原位心脏中，缺血预处理（IPC）与STAT3磷酸化升高有关，而Akt和ERK1/2在心脏保护中没有作用。IPC的心脏保护信号转导与猪缺血后适应和远端IPC相似。
Ischemic preconditioning (IPC), i.e., brief episodes of nonlethal myocardial ischemia-reperfusion (I/R) before sustained ischemia with subsequent reperfusion, reduces infarct size in all species tested so far, including humans. In rodents, the cardioprotective signal transduction causally involves an activation of Akt, ERK1/2, and STAT3. However, there are apparent species differences in the signal transduction between rodents and larger mammals such as pigs, where data on IPC's signal transduction are inconsistent for Akt and ERK1/2. The role of STAT3 has not yet been analyzed. Pigs were subjected to 60 min of left anterior descending coronary artery occlusion and 180 min of reperfusion without or with IPC (2 cycles of 3-min occlusion separated by 2 min of reperfusion 15 min before sustained I/R). Infarct size was analyzed by triphenyl tetrazolium chloride staining, and Akt, ERK1/2, and STAT3 phosphorylation was quantified in myocardial biopsies taken at baseline and early reperfusion. AG490 was used to block the STAT3 signaling pathway. IPC reduced infarct size (% area at risk; mean +/- SE, I/R, 45 +/- 3 vs. IPC, 18 +/- 3, P < 0.05). Akt and ERK1/2 phosphorylation was increased at early reperfusion without and with IPC. In contrast, STAT3 phosphorylation at early reperfusion was only increased with IPC (% baseline; mean +/- SE, I/R, 126 +/- 29 vs. IPC, 408 +/- 147, P < 0.05). AG490 prevented the IPC-related increase of STAT3 phosphorylation at reperfusion (% baseline; mean +/- SE, 82 +/- 12) and abolished IPC's cardioprotection (% area at risk; mean +/- SE, 35 +/- 4). In pigs, increased phosphorylation of STAT3 is causally involved, whereas Akt and ERK1/2 seem to play no role in IPC's cardioprotection.NEW & NOTEWORTHY In pig hearts in situ, ischemic preconditioning (IPC) causally involves increased phosphorylation of STAT3, whereas Akt and ERK1/2 play no role for cardioprotection. The cardioprotective signal transduction of IPC is similar to that of ischemic postconditioning and remote IPC in pigs.