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Antioxid Redox Signal. 2017 Dec 1;27(16):1297-1316. doi: 10.1089/ars.2016.6873. Epub 2017 Apr 18.

Nitration of TRPM2 as a Molecular Switch Induces Autophagy During Brain Pericyte Injury.

Author information

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.

KEYWORDS:

TRPM2; autophagy; brain; nitrosative stress; pericyte; protein nitration

PMID:
28292196
DOI:
10.1089/ars.2016.6873
[Indexed for MEDLINE]
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