Zhen Liu1, Kai Hu2, Yue-Sheng Chen3, Ying-Jie Huang1, Qian Hu1, Wei Zeng1, Yue Cao1, Qin Xiao1, Xue-Kang Zhang4. 1. Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi Province, People's Republic of China. 2. Department of Anesthesiology, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, 330008, Jiangxi Province, People's Republic of China. 3. Department of Anesthesiology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China. 4. Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi Province, People's Republic of China. xuekangzhang71@gmail.com.
Abstract
BACKGROUND: Intestinal ischemia-reperfusion (I/R) causes severe injury to the intestine, leading to systemic inflammation and multiple organ failure. Autophagy is a stress-response mechanism that can protect against I/R injury by removing damaged organelles and toxic protein aggregates. Recent evidence has identified JAK-STAT signaling pathway as a new regulator of autophagy process, however, their regulatory relationship in intestinal I/R remains unknown. METHODS AND RESULTS: We systematically analyzed intestinal transcriptome data and found that JAK-STAT pathway was largely activated in response to I/R with most significant upregulation observed for JAK2 and STAT3. ChIP-Seq and luciferase assays in an in vitro oxygen-glucose deprivation and reoxygenation model revealed that activated JAK2/STAT3 signaling directly inhibited the transcription of autophagy regulator Beclin-1, leading to the suppression of autophagy and the activation of intestinal cell death. These findings were further confirmed in an in vivo mouse model, in which, intestinal I/R injury was associated with the activation of JAK2/STAT3 pathway and the deactivation of Beclin-1-mediated autophagy, while inhibiting JAK2/STAT3 with AG490 reactivated autophagy and improved survival after intestinal I/R injury. CONCLUSIONS: JAK2/STAT3 signaling suppresses autophagy process during intestinal I/R, while inhibiting JAK-STAT can be protective against intestinal I/R injury by activating autophagy. These findings expand our knowledge on intestinal I/R injury and provide therapeutic targets for clinical treatment.
BACKGROUND: Intestinal ischemia-reperfusion (I/R) causes severe injury to the intestine, leading to systemic inflammation and multiple organ failure. Autophagy is a stress-response mechanism that can protect against I/R injury by removing damaged organelles and toxic protein aggregates. Recent evidence has identified JAK-STAT signaling pathway as a new regulator of autophagy process, however, their regulatory relationship in intestinal I/R remains unknown. METHODS AND RESULTS: We systematically analyzed intestinal transcriptome data and found that JAK-STAT pathway was largely activated in response to I/R with most significant upregulation observed for JAK2 and STAT3. ChIP-Seq and luciferase assays in an in vitro oxygen-glucose deprivation and reoxygenation model revealed that activated JAK2/STAT3 signaling directly inhibited the transcription of autophagy regulator Beclin-1, leading to the suppression of autophagy and the activation of intestinal cell death. These findings were further confirmed in an in vivo mouse model, in which, intestinal I/R injury was associated with the activation of JAK2/STAT3 pathway and the deactivation of Beclin-1-mediated autophagy, while inhibiting JAK2/STAT3 with AG490 reactivated autophagy and improved survival after intestinal I/R injury. CONCLUSIONS: JAK2/STAT3 signaling suppresses autophagy process during intestinal I/R, while inhibiting JAK-STAT can be protective against intestinal I/R injury by activating autophagy. These findings expand our knowledge on intestinal I/R injury and provide therapeutic targets for clinical treatment.
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