Stat3: its role in cardiomyocyte mitochondria and in the cardioprotection by ischemic postconditioning

STAT 3（信号转导子和转录激活子3）将应激信号从质膜转导到细胞核，导致基因转录的变化。除了在心肌细胞肥大和凋亡中的作用外，STAT 3还参与缺血预处理（IP）减少梗死面积（IS）。虽然IP的详细信号转导级联和末端效应仍有待阐明，但已提出通过糖原合成酶3 β（GSK 3）磷酸化的延迟线粒体通透性转换孔（MPTP）开放参与IP的心脏保护作用。在初步实验中，我们现在表明，STAT 3存在于心肌细胞线粒体。由于GSK 3（也位于线粒体中，并且可能代表STAT 3的下游靶标，我们将进一步分析两种线粒体蛋白是否相互作用以及STAT 3是否通过修饰GSK 3（磷酸化影响MPTP开放。还将研究线粒体STAT 3输入及其精确的亚线粒体定位。虽然STAT 3有助于IP的心脏保护，但仍不清楚STAT 3是否也参与通过缺血后处理（iPoco）减少IS，这是一种临床上可行的减少心肌缺血/再灌注损伤的方法。因此，将研究iPoco减少具有心肌细胞特异性STAT 3缺失的小鼠中IS的潜力。由于初步数据表明心肌STAT 3表达也随着年龄的增长而降低，因此将在老年小鼠的原位心脏中评估缺血后处理的重要性。(1596字符）

STAT3 (signal transducer and activator of transcription 3) transduces stress signals from the plasma membrane to the nucleus, leading to changes in gene transcription. Besides its role in cardiomyocyte hypertrophy and apoptosis, STAT3 is involved in the infarct size (IS) reduction by ischemic preconditioning (IP). Although the detailed signal transduction cascade and the end-effector of IP remain to be elucidated, a delayed mitochondrial permeability transition pore (MPTP) opening via phosphorylation of the glycogen synthase 3 beta (GSK3() has been proposed to be involved in IP’s cardioprotection. In preliminary experiments we now show that STAT3 is present in cardiomyocyte mitochondria. Since GSK3( is also localized in mitochondria and may represent a downstream target of STAT3, we will further analyze whether or not the two mitochondrial proteins interact and whether STAT3 by modifying GSK3( phosphorylation impacts on MPTP opening. Also the mitochondrial STAT3 import and its exact submitochondrial localization will be investigated. While STAT3 contributes to IP’s cardioprotection, it remains unknown whether or not STAT3 is also involved in IS reduction by ischemic postconditioning (iPoco), a clinically feasible method to reduce myocardial ischemia/reperfusion injury. Therefore, the potential of iPoco to reduce IS in mice with a cardiomyocyte-specific deletion of STAT3 will be investigated. Since preliminary data demonstrate a reduced myocardial STAT3 expression also with age, the importance of ischemic postconditioning will be assessed in in situ hearts of aged mice. (1596 character)