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

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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)