title: RIP3 S-nitrosylation contributes to cerebral ischemic neuronal injury.
abstract: Cerebral ischemia-reperfusion is associated with NMDA receptor-mediated calcium influx which activates neuronal nitric oxide synthase (nNOS) and consequently induces NO production. NO S-nitrosylates cellular protein and aggravates neuronal injury. Receptor-interacting protein 3 (RIP3) is a sensor molecule regulating cell apoptosis and necrosis. However, the roles of RIP3 in cerebral ischemic injury remain elusive. In this study, we reported that RIP3 could be S-nitrosylated by the exogenous NO donor GSNO in HEK293 cells and the Cys(119) residue was the key nitrosylation site. In addition, we found that cerebral ischemia induced RIP3 S-nitrosylation at different time points of reperfusion, which was coupling with RIP3 phosphorylation (which is associated with its activation) and its interaction with receptor-interacting protein 1 (RIP1), and this process facilitated cerebral ischemic injury. Treatment with NMDA receptor antagonist MK801, or nNOS inhibitor 7NI, diminished RIP3 S-nitrosylation and reduced neuronal damage. Taken together, these data demonstrated that NMDAR-dependent RIP3 S-nitrosylation induced by ischemia facilitated its activation in the early stages of ischemia, blocking this process could reduce the ischemia neuronal injury.
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors: Wanying
authors: W
authors: Miao
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors: Zhongwei
authors: Z
authors: Qu
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors: Kejie
authors: K
authors: Shi
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors: Dengyue
authors: D
authors: Zhang
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors: Yanyan
authors: Y
authors: Zong
authors: Department of Physiology, College of Basic Medical Science, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
authors: Gongliang
authors: G
authors: Zhang
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China. Electronic address: gyzhang@xzmc.edu.cn.
authors: Guangyi
authors: G
authors: Zhang
authors: Center for Biochemistry and Molecular Biology; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China; Institute of Emergency Rescue Medicine, Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: hushuqun88@126.com.
authors: Shuqun
authors: S
authors: Hu
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D052248:Nitric Oxide Synthase Type I; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D005947:Glucose
keywords: Cerebral ischemia; Nitric oxide; OGD; RIP3; S-nitrosylation