Cargando…

Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice

Cerebral stroke remains one of the leading causes of death worldwide. Ischemic stroke caused by the sudden loss of blood flow in brain is the major type of cerebral stroke. In addition to necrotic cell death in the ischemic core region, neuronal apoptosis is usually observed in the ischemic penumbra...

Descripción completa

Detalles Bibliográficos
Autores principales: Hsu, Shu-Yuan, Chen, Chih-Hung, Mukda, Sujira, Leu, Steve
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944488/
https://www.ncbi.nlm.nih.gov/pubmed/35326115
http://dx.doi.org/10.3390/antiox11030466
_version_ 1784673726891032576
author Hsu, Shu-Yuan
Chen, Chih-Hung
Mukda, Sujira
Leu, Steve
author_facet Hsu, Shu-Yuan
Chen, Chih-Hung
Mukda, Sujira
Leu, Steve
author_sort Hsu, Shu-Yuan
collection PubMed
description Cerebral stroke remains one of the leading causes of death worldwide. Ischemic stroke caused by the sudden loss of blood flow in brain is the major type of cerebral stroke. In addition to necrotic cell death in the ischemic core region, neuronal apoptosis is usually observed in the ischemic penumbra. Pnn, a multi-functional protein, participates in cellular proliferation, migration, differentiation, apoptosis as well as cell–cell interaction through its abilities in regulating gene transcription and mRNA processing. Our recent studies have demonstrated that Pnn has a cell type-specific distribution manner in neural cells under ischemic injury and plays a protective role in astrocytes against ischemic stress. In this study, we generated an inducible neuron-specific Pnn deficiency mouse model to further investigate the physiological role of Pnn in neurons. To directly examine the role of neuronal Pnn in ischemic stress, four weeks after induction of Pnn deficiency in neurons, middle cerebral artery occlusion (MCAO) was applied to induce cerebral ischemia/reperfusion in mice. In the cerebrum and hippocampus with neuronal Pnn depletion, the expression of SRSF2, a mRNA splicing regulator, was increased, while the expression of SRSF1, a functional antagonist of SRSF2, was reduced. Expression levels of ROS generators (NOX-1 and NOX-2) and antioxidant proteins (GR, HO-1, NQO-1) were upregulated in brain tissue with loss of neuronal Pnn, echoing an increase in oxidized proteins in cortical and hippocampal neurons. Furthermore, the expression of DNA damage marker, p53bp1, was found in the choroid plexus of mice with neuronal Pnn depletion. In mice with MCAO, compared to wild type mice, both increased cerebral infarcted area and elevated expressions of proapoptotic proteins were found in mice with neuronal Pnn depletion. In conclusion, Pnn deficiency increases oxidative stress in neurons and exacerbates cerebral ischemia/reperfusion injury in mice.
format Online
Article
Text
id pubmed-8944488
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-89444882022-03-25 Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice Hsu, Shu-Yuan Chen, Chih-Hung Mukda, Sujira Leu, Steve Antioxidants (Basel) Article Cerebral stroke remains one of the leading causes of death worldwide. Ischemic stroke caused by the sudden loss of blood flow in brain is the major type of cerebral stroke. In addition to necrotic cell death in the ischemic core region, neuronal apoptosis is usually observed in the ischemic penumbra. Pnn, a multi-functional protein, participates in cellular proliferation, migration, differentiation, apoptosis as well as cell–cell interaction through its abilities in regulating gene transcription and mRNA processing. Our recent studies have demonstrated that Pnn has a cell type-specific distribution manner in neural cells under ischemic injury and plays a protective role in astrocytes against ischemic stress. In this study, we generated an inducible neuron-specific Pnn deficiency mouse model to further investigate the physiological role of Pnn in neurons. To directly examine the role of neuronal Pnn in ischemic stress, four weeks after induction of Pnn deficiency in neurons, middle cerebral artery occlusion (MCAO) was applied to induce cerebral ischemia/reperfusion in mice. In the cerebrum and hippocampus with neuronal Pnn depletion, the expression of SRSF2, a mRNA splicing regulator, was increased, while the expression of SRSF1, a functional antagonist of SRSF2, was reduced. Expression levels of ROS generators (NOX-1 and NOX-2) and antioxidant proteins (GR, HO-1, NQO-1) were upregulated in brain tissue with loss of neuronal Pnn, echoing an increase in oxidized proteins in cortical and hippocampal neurons. Furthermore, the expression of DNA damage marker, p53bp1, was found in the choroid plexus of mice with neuronal Pnn depletion. In mice with MCAO, compared to wild type mice, both increased cerebral infarcted area and elevated expressions of proapoptotic proteins were found in mice with neuronal Pnn depletion. In conclusion, Pnn deficiency increases oxidative stress in neurons and exacerbates cerebral ischemia/reperfusion injury in mice. MDPI 2022-02-26 /pmc/articles/PMC8944488/ /pubmed/35326115 http://dx.doi.org/10.3390/antiox11030466 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hsu, Shu-Yuan
Chen, Chih-Hung
Mukda, Sujira
Leu, Steve
Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice
title Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice
title_full Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice
title_fullStr Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice
title_full_unstemmed Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice
title_short Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice
title_sort neuronal pnn deficiency increases oxidative stress and exacerbates cerebral ischemia/reperfusion injury in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944488/
https://www.ncbi.nlm.nih.gov/pubmed/35326115
http://dx.doi.org/10.3390/antiox11030466
work_keys_str_mv AT hsushuyuan neuronalpnndeficiencyincreasesoxidativestressandexacerbatescerebralischemiareperfusioninjuryinmice
AT chenchihhung neuronalpnndeficiencyincreasesoxidativestressandexacerbatescerebralischemiareperfusioninjuryinmice
AT mukdasujira neuronalpnndeficiencyincreasesoxidativestressandexacerbatescerebralischemiareperfusioninjuryinmice
AT leusteve neuronalpnndeficiencyincreasesoxidativestressandexacerbatescerebralischemiareperfusioninjuryinmice