Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, University of Duisburg-Essen, Essen, Germany.
Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
Am J Physiol Heart Circ Physiol. 2022 Dec 1;323(6):H1365-H1375. doi: 10.1152/ajpheart.00580.2022. Epub 2022 Nov 11.
Ischemic preconditioning (IPC; brief cycles of coronary occlusion/reperfusion) is operative in all species tested so far and reduces infarct size through the release of trigger molecules and activation of signal transducer and activator of transcription (STAT)3 in pigs. We have recently demonstrated that IPC failed to protect Ossabaw minipigs, which had a genetic predisposition to, but not yet established a metabolic syndrome, from infarction and did not activate STAT3. We now subjected Ossabaw minipigs to remote ischemic conditioning (RIC; 4 × 5 min/5 min bilateral hindlimb ischemia-reperfusion) and analyzed the release of cardioprotective triggers into the circulation with the aim to distinguish whether IPC failed to stimulate trigger release or to activate intracellular signaling cascades upstream of STAT3. RIC or a placebo protocol, respectively, was induced in anesthetized pigs before 60 min/180 min coronary occlusion/reperfusion. Plasma, prepared from Ossabaw minipigs after RIC or placebo, was infused into isolated rat hearts subjected to 30 min/120 min global ischemia-reperfusion. In the Ossabaw minipigs, RIC did not reduce infarct size (49.5 ± 12.1 vs. 56.0 ± 11.8% of area at risk with placebo), and STAT3 was not activated. In isolated rat hearts, infusion of RIC plasma reduced infarct size (19.7 ± 6.7 vs. 33.2 ± 5.5% of ventricular mass with placebo) and activated STAT3. Pretreatment of rat hearts with the STAT3 inhibitor stattic abrogated such infarct size reduction and STAT3 activation. In conclusion, Ossabaw minipigs release cardioprotective triggers in response to RIC into the circulation, and lack of cardioprotection is attributed to myocardial nonresponsiveness. Ischemic conditioning reduces myocardial infarct size in all species tested so far. In the present study, we used Ossabaw minipigs that had a genetic predisposition to, but not yet established a metabolic syndrome. In these pigs, remote ischemic conditioning (RIC) induced the release of cardioprotective triggers but did not reduce infarct size. Transfer of their plasma, however, reduced infarct size in isolated recipient rat hearts, along with signal transducer and activator of transcription (STAT)3 activation.
缺血预处理（IPC；短暂的冠状动脉闭塞/再灌注循环）在迄今为止测试的所有物种中均有效，并且通过释放触发分子和激活信号转导和转录激活因子 3（STAT3）来减少猪的梗塞面积。我们最近证明，IPC 未能保护 Ossabaw 小型猪免受梗塞的侵害，这些小型猪具有遗传倾向，但尚未建立代谢综合征，并且未能激活 STAT3。我们现在使 Ossabaw 小型猪接受远程缺血预处理（RIC；4×5 分钟/5 分钟双侧后肢缺血-再灌注），并分析循环中保护性触发物的释放，目的是区分 IPC 是否未能刺激触发物释放或激活 STAT3 上游的细胞内信号级联。在麻醉猪中，在 60 分钟/180 分钟冠状动脉闭塞/再灌注之前，分别进行 RIC 或安慰剂方案。在 Ossabaw 小型猪中，在 RIC 或安慰剂后，从 Ossabaw 小型猪中提取的血浆被输注到接受 30 分钟/120 分钟全缺血-再灌注的分离大鼠心脏中。在 Ossabaw 小型猪中，RIC 并未减少梗塞面积（安慰剂组为 49.5±12.1%，RIC 组为 56.0±11.8%），并且 STAT3 未被激活。在分离的大鼠心脏中，输注 RIC 血浆可减少梗塞面积（安慰剂组为 33.2±5.5%，RIC 组为 19.7±6.7%）并激活 STAT3。预先用 STAT3 抑制剂 stattic 处理大鼠心脏会消除这种梗塞面积减少和 STAT3 激活。总之，Ossabaw 小型猪在循环中释放保护性触发物以响应 RIC，并且缺乏心脏保护作用归因于心肌反应性降低。缺血预处理在迄今为止测试的所有物种中均可减少心肌梗塞面积。在本研究中，我们使用了 Ossabaw 小型猪，这些猪具有遗传倾向，但尚未建立代谢综合征。在这些猪中，远程缺血预处理（RIC）诱导了保护性触发物的释放，但并未减少梗塞面积。然而，它们的血浆转移可减少分离的受体大鼠心脏中的梗塞面积，并激活信号转导和转录激活因子 3（STAT3）。
