title: Nitration of TRPM2 as a Molecular Switch Induces Autophagy During Brain Pericyte Injury.
abstract: OBJECTIVE
  Dysfunction of neurovascular pericytes underlies breakdown of the blood-brain barrier, but the molecular mechanisms are largely unknown. In this study, we evaluated the role of the transient receptor potential melastatin-related 2 (TRPM2) channel and autophagy during brain pericyte injury both in vitro and in vivo.
  
  
  RESULTS
  A rapid induction in autophagy in human brain vascular pericytes, in the zinc oxide nanoparticles (ZnO-NP)-induced cell stress model, was paralleled with an increase in the expression of the TRPM2-S truncated isoform, which was abolished by treatment with a nitric oxide synthase inhibitor and a peroxynitrite scavenger. Furthermore, Y1485 in the C-terminus of the TRPM2 protein was identified as the tyrosine nitration substrate by mass spectrometry. Overexpression of the Y1485S TRPM2 mutant reduced LC3-II accumulation and pericyte injury induced by ZnO-NP. Consistently, LC3-II accumulation was reduced and pericytes were better preserved in intact brain microvessels of the TRPM2 knockout mice after ZnO-NP-induced vascular injury. Innovation and Conclusions: Our present study has revealed a novel mechanism of autophagy disturbance secondary to nitrosative stress-induced tyrosine nitration of TRPM2 during pericyte injury. Antioxid. Redox Signal. 27, 1297-1316.
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .
authors.forename: Quan
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .|2 School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang, China .
authors.forename: Yinping
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .
authors.forename: Chengkun
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .
authors.forename: Rongrong
authors.initials: R
authors.lastname: Tao
authors.affiliation: 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China .
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Zhan
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .
authors.forename: Meihua
authors.initials: M
authors.lastname: Liao
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .
authors.forename: Nannan
authors.initials: N
authors.lastname: Lu
authors.affiliation: 2 School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang, China .
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 4 Hypertension, Kidney, and Vascular Research Center, Georgetown University Medical Center , Washington, District of Columbia.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
authors.affiliation: 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China .
authors.forename: Jianhong
authors.initials: J
authors.lastname: Luo
authors.affiliation: 5 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom .|6 Sino-UK Joint Laboratory of Brain Function and Injury, and Department of Physiology and Neurobiology, Xinxiang Medical University , Henan, China .
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Jiang
authors.affiliation: 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China .
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .
authors.forename: Feng
authors.initials: F
authors.lastname: Han
mesh_terms: D000818:Animals; D001343:Autophagy; D001812:Blood-Brain Barrier; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry; D000073039:Nitrosative Stress; D020286:Pericytes; D050053:TRPM Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*; D015034:Zinc Oxide / Q000009:adverse effects*
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D014443:Tyrosine; D015034:Zinc Oxide
keywords: TRPM2; autophagy; brain; nitrosative stress; pericyte; protein nitration