Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion.
Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion.
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DOI：
10.1007/s00395-010-0124-1
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发表时间：
2010-11
影响因子：
9.5
通讯作者：
Schulz R
中科院分区：
文献类型：
--
作者：
Boengler K;Hilfiker-Kleiner D;Heusch G;Schulz R
信号转导和转录激活因子3（STAT3）通过缺血预处理和后处理对心脏起到保护作用。线粒体是心脏保护信号传导的核心要素，很可能是通过延迟线粒体通透性转换孔（MPTP）的开放来实现的，并且最近在线粒体中发现了STAT3。我们现在对STAT3在线粒体中的定位及其对呼吸和MPTP开放的影响进行了研究。STAT3主要存在于心肌细胞肌膜下和肌原纤维间线粒体的基质中。在生理条件下，在线粒体中也检测到了STAT1，但未检测到STAT5。与野生型相比，心肌细胞特异性缺失STAT3的小鼠（STAT3 - KO）的线粒体以及用STAT3抑制剂Stattic（STAT3抑制化合物，6 - 硝基苯并[b]噻吩1,1 - 二氧化物）处理的大鼠线粒体中，ADP刺激的呼吸作用减弱。在MPTP开放之前，STAT3 - KO小鼠的线粒体和用Stattic处理的大鼠线粒体能够耐受的钙更少。STAT3与亲环蛋白D发生免疫共沉淀，亲环蛋白D是心脏保护剂和MPTP抑制剂环孢素A（CsA）的作用靶点。然而，在体内，CsA使野生型和STAT3 - KO小鼠的梗死面积减少程度相似。因此，STAT3可能通过刺激呼吸和抑制MPTP开放对心脏起到保护作用。
The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening.
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