Institut für Pathophysiologie, Universitätsklinikum Essen, Germany.
Circ Res. 2011 Nov 11;109(11):1302-8. doi: 10.1161/CIRCRESAHA.111.255604. Epub 2011 Oct 6.
Timely restoration of coronary blood flow is the only way to salvage myocardium from infarction, but reperfusion per se brings on additional injury. Such reperfusion injury and the resulting size of myocardial infarction is attenuated by ischemic postconditioning, ie, the repeated brief interruption of coronary blood flow during early reperfusion. The signal transduction of ischemic postconditioning is under intense investigation, but no signaling step has yet been identified as causal for such protection in larger mammals in situ.
We have now in an in situ pig model of regional myocardial ischemia/reperfusion addressed the role of mitochondrial signal transducer and activator of transcription 3 (STAT3).
We demonstrated reduction of infarct size by ischemic postconditioning (26 ± 3% of area at risk versus 38 ± 2% in controls with immediate full reperfusion) along with more markedly increased tyrosine(705) phosphorylation of STAT3 in myocardial biopsies (at 10 minutes reperfusion: 9.2 ± 3.0-fold from baseline versus 6.6 ± 2.9-fold in controls with immediate full reperfusion). Increased tyrosine(705) phosphorylation of STAT3 and better preservation of complex 1 respiration and calcium retention capacity were also present in isolated mitochondria from postconditioned myocardium in vitro. Prior janus kinase/STAT inhibition with AG490 in vivo abrogated the infarct size reduction and the better preservation of mitochondrial function, and the STAT3 inhibitor Stattic in vitro also abrogated better preservation of mitochondrial function.
Our data support a causal role for mitochondrial STAT3 activation to mediate cardioprotection through better mitochondrial function.
及时恢复冠状动脉血流是挽救梗塞心肌的唯一方法，但再灌注本身会带来额外的损伤。缺血后处理（即在再灌注早期反复短暂中断冠状动脉血流）可以减轻这种再灌注损伤和由此导致的心肌梗死的范围。缺血后处理的信号转导正在深入研究，但在较大的哺乳动物原位模型中，尚未确定任何信号步骤是这种保护作用的因果关系。
我们现在在局部心肌缺血/再灌注的猪原位模型中研究了线粒体信号转导物和转录激活因子 3（STAT3）的作用。
我们在缺血后处理（缺血后处理组梗塞面积为 26%±3%，而即刻完全再灌注组为 38%±2%）中证明了梗塞面积的减少，同时在心肌活检中观察到 STAT3 的酪氨酸（705）磷酸化明显增加（再灌注 10 分钟时：与即刻完全再灌注组的 6.6±2.9 倍相比，为基线的 9.2±3.0 倍）。体外从缺血后处理的心肌中分离的线粒体也存在 STAT3 的酪氨酸（705）磷酸化增加和复合物 1 呼吸以及钙保留能力更好的保存。体内用 Janus 激酶/STAT 抑制剂 AG490 进行预先抑制，可消除梗塞面积的减少和线粒体功能的更好保存，体外使用 STAT3 抑制剂 Stattic 也可消除线粒体功能的更好保存。
我们的数据支持线粒体 STAT3 激活在通过更好的线粒体功能介导心脏保护中起因果作用。
