Quan Jiang1, Yinping Gao1,2, Chengkun Wang1, Rongrong Tao1, Yan Wu3, Kaiyu Zhan3, Meihua Liao1, Nannan Lu1, Yingmei Lu2, Christopher S Wilcox4, Jianhong Luo3, Lin-Hua Jiang5,6, Wei Yang3, Feng Han1. 1. 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China . 2. 2 School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang, China . 3. 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China . 4. 4 Hypertension, Kidney, and Vascular Research Center, Georgetown University Medical Center , Washington, District of Columbia. 5. 5 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom . 6. 6 Sino-UK Joint Laboratory of Brain Function and Injury, and Department of Physiology and Neurobiology, Xinxiang Medical University , Henan, China .
Abstract
AIMS: 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.
AIMS: 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 Y1485STRPM2 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.
Entities:
Keywords:
TRPM2; autophagy; brain; nitrosative stress; pericyte; protein nitration
Authors: Shekoufeh Almasi; Barry E Kennedy; Mariam El-Aghil; Andra M Sterea; Shashi Gujar; Santiago Partida-Sánchez; Yassine El Hiani Journal: J Biol Chem Date: 2018-01-17 Impact factor: 5.157