Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress

The brain endothelium is an integral element of the blood-brain barrier (BBB). Dysfunction of this formation due to increased generation of reactive oxygen species (ROS) progresses the establishment of neurological disorders including stroke and traumatic brain injury. Heat shock protein 90 inhibito...

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Main Authors: Mohammad A. Uddin, Mohammad S. Akhter, Khadeja-Tul Kubra, Kathryn E. Whitaker, Summer L. Shipley, Landon M. Smith, Nektarios Barabutis
Format: Article
Language:English
Published: Elsevier 2021-03-01
Series:Brain Disorders
Subjects:
P53
Online Access:http://www.sciencedirect.com/science/article/pii/S2666459320300019
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spelling doaj-30eb902d1d804648841d900fd6a6a4502021-09-03T04:47:04ZengElsevierBrain Disorders2666-45932021-03-011100001Hsp90 inhibition protects the brain microvascular endothelium against oxidative stressMohammad A. Uddin0Mohammad S. Akhter1Khadeja-Tul Kubra2Kathryn E. Whitaker3Summer L. Shipley4Landon M. Smith5Nektarios Barabutis6School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USASchool of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USASchool of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USASchool of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USASchool of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USASchool of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USACorresponding author.; School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USAThe brain endothelium is an integral element of the blood-brain barrier (BBB). Dysfunction of this formation due to increased generation of reactive oxygen species (ROS) progresses the establishment of neurological disorders including stroke and traumatic brain injury. Heat shock protein 90 inhibitors are anti-inflammatory agents, and their activities are mediated, at least in part, by P53. This is a tumor suppressor protein which regulates the opposing activities of Rac1 and RhoA in the cellular cytoskeleton. In the present study we investigated the role of Hsp90 inhibitors in the H2O2-induced brain endothelium breakdown, by employing human cerebral microvascular endothelial cells (hCMEC/D3). Our findings suggest that H2O2 downregulates P53 by enhancing the P53 suppressor mouse double minute 2 homolog (MDM2), as well as by increasing the apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref1). The H2O2 – triggered violation of the brain endothelium barrier was reflected in measurements of transendothelial resistance, and the increased expression of the key cytoskeletal modulators cofilin and myosin light chain 2 (MLC2). Treatment of the hCMEC/D3 cells with Hsp90 inhibitors counteracted those events, and reduced the generation of the hydrogen peroxide – induced reactive oxygen species. Hence, our study suggests that Hsp90 inhibition supports the BBB integrity, and may represent a promising therapeutic approach for disorders associated with brain endothelium breakdown; including COVID-19.http://www.sciencedirect.com/science/article/pii/S2666459320300019InflammationReactive oxygen speciesOxidative damageP53Heat shock protein 90 inhibitors
collection DOAJ
language English
format Article
sources DOAJ
author Mohammad A. Uddin
Mohammad S. Akhter
Khadeja-Tul Kubra
Kathryn E. Whitaker
Summer L. Shipley
Landon M. Smith
Nektarios Barabutis
spellingShingle Mohammad A. Uddin
Mohammad S. Akhter
Khadeja-Tul Kubra
Kathryn E. Whitaker
Summer L. Shipley
Landon M. Smith
Nektarios Barabutis
Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
Brain Disorders
Inflammation
Reactive oxygen species
Oxidative damage
P53
Heat shock protein 90 inhibitors
author_facet Mohammad A. Uddin
Mohammad S. Akhter
Khadeja-Tul Kubra
Kathryn E. Whitaker
Summer L. Shipley
Landon M. Smith
Nektarios Barabutis
author_sort Mohammad A. Uddin
title Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
title_short Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
title_full Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
title_fullStr Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
title_full_unstemmed Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
title_sort hsp90 inhibition protects the brain microvascular endothelium against oxidative stress
publisher Elsevier
series Brain Disorders
issn 2666-4593
publishDate 2021-03-01
description The brain endothelium is an integral element of the blood-brain barrier (BBB). Dysfunction of this formation due to increased generation of reactive oxygen species (ROS) progresses the establishment of neurological disorders including stroke and traumatic brain injury. Heat shock protein 90 inhibitors are anti-inflammatory agents, and their activities are mediated, at least in part, by P53. This is a tumor suppressor protein which regulates the opposing activities of Rac1 and RhoA in the cellular cytoskeleton. In the present study we investigated the role of Hsp90 inhibitors in the H2O2-induced brain endothelium breakdown, by employing human cerebral microvascular endothelial cells (hCMEC/D3). Our findings suggest that H2O2 downregulates P53 by enhancing the P53 suppressor mouse double minute 2 homolog (MDM2), as well as by increasing the apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref1). The H2O2 – triggered violation of the brain endothelium barrier was reflected in measurements of transendothelial resistance, and the increased expression of the key cytoskeletal modulators cofilin and myosin light chain 2 (MLC2). Treatment of the hCMEC/D3 cells with Hsp90 inhibitors counteracted those events, and reduced the generation of the hydrogen peroxide – induced reactive oxygen species. Hence, our study suggests that Hsp90 inhibition supports the BBB integrity, and may represent a promising therapeutic approach for disorders associated with brain endothelium breakdown; including COVID-19.
topic Inflammation
Reactive oxygen species
Oxidative damage
P53
Heat shock protein 90 inhibitors
url http://www.sciencedirect.com/science/article/pii/S2666459320300019
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