Auraptene Enhances Junction Assembly in Cerebrovascular Endothelial Cells by Promoting Resilience to Mitochondrial Stress through Activation of Antioxidant Enzymes and mtUPR.

Min Joung Lee,Eunji Namgung,Xianshu Ju,Woosuk Chung,Hyoeun Kang,Jianchen Cui,Dahyun Go,Jiebo Zhu,Hyeongseok Kim,Yunseon Jang,Jun Young Heo,Yu Lim Lee,Changjun Seo

doi:10.3390/antiox10030475

Abstract

Junctional proteins in cerebrovascular endothelial cells are essential for maintaining the barrier function of the blood-brain barrier (BBB), thus protecting the brain from the infiltration of pathogens. The present study showed that the potential therapeutic natural compound auraptene (AUR) enhances junction assembly in cerebrovascular endothelial cells by inducing antioxidant enzymes and the mitochondrial unfolded protein response (mtUPR). Treatment of mouse cerebrovascular endothelial cells with AUR enhanced the expression of junctional proteins, such as occludin, zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin), by increasing the levels of mRNA encoding antioxidant enzymes. AUR treatment also resulted in the depolarization of mitochondrial membrane potential and activation of mtUPR. The ability of AUR to protect against ischemic conditions was further assessed using cells deprived of oxygen and glucose. Pretreatment of these cells with AUR protected against damage to junctional proteins, including occludin, claudin-5, ZO-1 and VE-cadherin, accompanied by a stress resilience response regulated by levels of ATF5, LONP1 and HSP60 mRNAs. Collectively, these results indicate that AUR promotes resilience against oxidative stress and improves junction assembly, suggesting that AUR may help maintain intact barriers in cerebrovascular endothelial cells.

Highlights

AUR pretreatment protected junctional protein disruption after oxygen-glucose deprivation, an in vitro condition similar to stroke. These findings suggest that AUR treatment can strengthen junctional proteins in cerebrovascular endothelial cells by inducing resilience to stress resulting from the induction of mitochondrial unfolded protein response (mtUPR)
Because AUR induced antioxidant enzymes in response to a neurotoxic model of Parkinson’s disease [21,24], we investigated the effect of AUR on junction assembly of endothelial cells required for blood-brain barrier (BBB) maintenance
Oxygen-Glucose Deprivation (OGD) increased the levels of CLPP and CHOP mRNAs, but this increase was abrogated by AUR pretreatment. These findings suggest that AUR induction of mild mitochondrial stress, resulting in mitochondrial membrane depolarization, leads to the induction of mtUPR expression and that the latter can contribute to resilience to oxidative stress in bEnd.3 cells

Summary

Introduction

The blood-brain barrier (BBB) is a selectively permeable barrier that divides the central nervous system (CNS) from the peripheral circulation, preventing infectious substances and immune cells from entering the CNS [1]. Endothelial cells of the BBB interact with junctional proteins, such as occludin, claudin-5, zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin), forming a barrier that prevents pathogens from crossing into the brain [2,3]. Loss of junctional proteins during pathological conditions, such as neurodegenerative diseases and multiple sclerosis, increases BBB permeability, allowing the infiltration of immune cells and resulting in brain damage [4,5,6].

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Conclusion