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

STAT3（信号换能器和转录激活器3）将应激信号从质膜传导到细胞核，导致基因转录发生变化。STAT3除了在心肌细胞肥大和凋亡中发挥作用外，还参与缺血预处理（IP）减少梗死面积（is）。虽然详细的信号转导级联和IP的末端执行器仍有待阐明，但已提出通过糖原合成酶3 β (GSK3)的磷酸化延迟线粒体通透性过渡孔（MPTP）开放参与IP的心脏保护。在初步实验中，我们现在表明STAT3存在于心肌细胞线粒体中。由于GSK3也位于线粒体中，可能是STAT3的下游靶点，我们将进一步分析这两种线粒体蛋白是否相互作用，以及STAT3是否通过修饰GSK3的磷酸化影响MPTP的开放。此外，还将研究线粒体STAT3的输入及其确切的亚线粒体定位。虽然STAT3有助于IP的心脏保护，但STAT3是否也参与缺血后适应（iPoco）的is减少尚不清楚，iPoco是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在心肌细胞特异性缺失STAT3的小鼠中降低IS的潜力。由于初步数据表明心肌STAT3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适应的重要性。(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)