Hailong Fu1, Haitao Xu1, Huan Chen2, Yonghua Li1, Weiwei Li1, Qiufeng Zhu1, Qingqing Zhang1, Hongbin Yuan1, Fang Liu3, Quanxing Wang4, Mingyong Miao5, Xueyin Shi6. 1. Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China. 2. Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China. 3. National Key Laboratory of Medical Immunology and Department of Immunology, Second Military Medical University, Shanghai 200433, China. 4. National Key Laboratory of Medical Immunology and Department of Immunology, Second Military Medical University, Shanghai 200433, China. Electronic address: wangqx@immunol.org. 5. Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China. Electronic address: miaomy@163.com. 6. Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: shixueyin1128@163.com.
Abstract
BACKGROUND & AIMS: The mechanisms of glycogen synthase kinase-3 (GSK-3)-mediated cytoprotection during liver ischemia/reperfusion (I/R) remain controversial, particularly in older organs. This study explores the role and potential mechanisms of GSK-3 in young and aging livers. METHODS: A rodent partial warm I/R model was used to evaluate the therapeutic potential of GSK-3 modulation during hepatic I/R in young and aging Sprague-Dawley rats. RESULTS: GSK-3 inhibition through IPC or SB216763 (SB21) preconditioning protected young rats from I/R-induced liver injury. This protection was absent in old animals but could be restored by glucose infusion prior to the I/R insult. The protection conferred by GSK-3 inhibition depended on mitochondrial metabolism regulation. Indeed, the inhibition of GSK-3 suppressed mitochondrial permeability transition pore (MPTP) opening, triggering mitohormesis in young animals, whereas insufficient fuel suppressed mitochondrial metabolism and inactivated the GSK-3-related protection in old animals. SB21 and glucose reactivated the mitochondrial F0F1-ATPase and subsequent protective cascades in the senescent liver. These effects were antagonized by an ATPase inhibitor and by an MPTP opener. CONCLUSIONS: The protection conferred by GSK-3 inhibition during hepatic I/R insult is energy dependent, particularly in senescent livers. These findings demonstrate a key role for GSK-3-related mitochondrial energy homeostasis, which may shed new light on the clinical use of GSK-3 inhibitors to protect liver function in surgical settings, particularly for older patients.
BACKGROUND & AIMS: The mechanisms of glycogen synthase kinase-3 (GSK-3)-mediated cytoprotection during liver ischemia/reperfusion (I/R) remain controversial, particularly in older organs. This study explores the role and potential mechanisms of GSK-3 in young and aging livers. METHODS: A rodent partial warm I/R model was used to evaluate the therapeutic potential of GSK-3 modulation during hepatic I/R in young and aging Sprague-Dawley rats. RESULTS: GSK-3 inhibition through IPC or SB216763 (SB21) preconditioning protected young rats from I/R-induced liver injury. This protection was absent in old animals but could be restored by glucose infusion prior to the I/R insult. The protection conferred by GSK-3 inhibition depended on mitochondrial metabolism regulation. Indeed, the inhibition of GSK-3 suppressed mitochondrial permeability transition pore (MPTP) opening, triggering mitohormesis in young animals, whereas insufficient fuel suppressed mitochondrial metabolism and inactivated the GSK-3-related protection in old animals. SB21 and glucose reactivated the mitochondrial F0F1-ATPase and subsequent protective cascades in the senescent liver. These effects were antagonized by an ATPase inhibitor and by an MPTP opener. CONCLUSIONS: The protection conferred by GSK-3 inhibition during hepatic I/R insult is energy dependent, particularly in senescent livers. These findings demonstrate a key role for GSK-3-related mitochondrial energy homeostasis, which may shed new light on the clinical use of GSK-3 inhibitors to protect liver function in surgical settings, particularly for older patients.
Authors: Ming Ni; Haoming Zhou; Jing Zhang; Dan Jin; Tianfei Lu; Ronald W Busuttil; Jerzy W Kupiec-Weglinski; Xuehao Wang; Yuan Zhai Journal: J Immunol Date: 2020-07-17 Impact factor: 5.422
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Authors: Ahlam Alhusaini; Laila Fadda; Iman H Hasan; Hanaa M Ali; Naglaa F El Orabi; Amira M Badr; Enas Zakaria; Abeer M Alenazi; Ayman M Mahmoud Journal: Antioxidants (Basel) Date: 2019-11-24
Authors: Haoming Zhou; Han Wang; Ming Ni; Shi Yue; Yongxiang Xia; Ronald W Busuttil; Jerzy W Kupiec-Weglinski; Ling Lu; Xuehao Wang; Yuan Zhai Journal: J Hepatol Date: 2018-02-13 Impact factor: 30.083