Ischemic Preconditioning Protects Astrocytes against Oxygen Glucose Deprivation Via the Nuclear Erythroid 2-Related Fact
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ORIGINAL ARTICLE
Ischemic Preconditioning Protects Astrocytes against Oxygen Glucose Deprivation Via the Nuclear Erythroid 2-Related Factor 2 Pathway Srinivasan V. Narayanan 1,2,3,4 & Kunjan R. Dave 1,2,4 & Miguel A. Perez-Pinzon 1,2,4
Received: 11 August 2017 / Revised: 28 September 2017 / Accepted: 29 September 2017 # Springer Science+Business Media, LLC 2017
Abstract Induction of ischemic preconditioning (IPC) represents a potential therapy against cerebral ischemia by activation of adaptive pathways and modulation of mitochondria to induce ischemic tolerance to various cells and tissues. Mitochondrial dysfunction has been ascribed to contribute to numerous neurodegenerative conditions and cerebral ischemia. Nuclear erythroid 2related factor 2 (Nrf2) is a transcription factor that has traditionally been involved in upregulating cellular antioxidant systems to combat oxidative stress in the brain; however, the association of Nrf2 with mitochondria in the brain remains unclear. In the present study, we investigated the effects of Nrf2 on (i) IPC-induced protection of astrocytes; (ii) OXPHOS protein expression; and (iii) mitochondrial supercomplex formation. Oxygen-glucose deprivation (OGD) was used as an in vitro model of cerebral ischemia and IPC in cultured rodent astrocytes derived from WT C57Bl/6J and Nrf2−/− mice. OXPHOS proteins were probed via western
blotting, and supercomplexes were determined by blue native gel electrophoresis. IPC-induced cytoprotection in wild-type, but not Nrf2−/− mouse astrocyte cultures following a lethal duration of OGD. In addition, our results suggest that Nrf2 localizes to the outer membrane in non-synaptic brain mitochondria, and that a lack of Nrf2 in vivo produces altered supercomplex formation in mitochondria. Our findings support a role of Nrf2 in mediating IPCinduced protection in astrocytes, which can profoundly impact the ischemic tolerance of neurons. In addition, we provide novel evidence for the association of Nrf2 to brain mitochondria and supercomplex formation. These studies offer new targets and pathways of Nrf2, which may be heavily implicated following cerebral ischemia. Keywords Preconditioning . Nrf2 . Mitochondria . Reactive oxygen species
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12975-017-0574-y) contains supplementary material, which is available to authorized users. * Miguel A. Perez-Pinzon [email protected] 1
Cerebral Vascular Disease Research Laboratories, School of Medicine, University of Miami Miller, Miami, FL, USA
2
Neuroscience Program, Miller School of Medicine, University of Miami, Miami, FL, USA
3
School of Medicine MD/PhD Program, University of Miami, Miami, USA
4
Department of Neurology, D4-5, School of Medicine, University of Miami Miller, PO Box 016960, Miami, FL 33101, USA
A potential therapy that could mitigate the morbidity and mortality of cerebral ischemic injury may be conceptualized as ischemic preconditioning (IPC). Previous studies from our group and
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