disruption of astrocyte stat3 signaling decreases mitochondrial function and increases oxidative stress in vitro星形胶质细胞中断stat3信号增加线粒体功能和减少氧化应激在体外.pdfVIP

Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro 1 1 1 1 2 Theodore A. Sarafian *, Cindy Montes , Tetsuya Imura , Jingwei Qi , Giovanni Coppola , Daniel H. Geschwind2, Michael V. Sofroniew1 1 Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America, 2 Department of Neurology, The Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, California, United States of America Abstract Background: Astrocytes exert a wide variety of functions in health and disease and respond to a wide range of signaling pathways, including members of the Janus-kinase signal transducers and activators of transcription (Jak-STAT) family. We have recently shown that STAT3 is an important regulator of astrocyte reactivity after spinal cord injury in vivo [1]. Methodology/Principal Findings: Here, we used both a conditional gene deletion strategy that targets the deletion of STAT3 selectively to astrocytes (STAT3-CKO), and a pharmacological inhibitor of JAK-2, AG490, in cultured astrocytes in vitro, to investigate potential functions and molecules influenced by STAT3 signaling in relation to mitochondrial function and oxidative stress. Our findings show that the absence of STAT3 signaling in astrocytes leads to (i) increased production of superoxide anion and other reactive oxygen species and decreased level of glutathione, (ii) decreased mitochondrial membrane potential and decreased ATP production, and (iii) decreased rate of cell proliferation. Many of the differences observed in STAT3-CKO astrocytes were distinctly altered by exposur