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Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression

NF-κB signaling is a key regulator of inflammation and atherosclerosis. NF-κB cooperates with bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, in endothelial inflammation. This study aimed to investigate whether BRD4 inhibition would prevent the proinflammatory re...

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Autores principales: Shahid, Sidra, Pantakani, Marlena, Binder, Lutz, Fischer, Andreas, Pantakani, Krishna, Asif, Abdul R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9692972/
https://www.ncbi.nlm.nih.gov/pubmed/36364277
http://dx.doi.org/10.3390/molecules27217453
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author Shahid, Sidra
Pantakani, Marlena
Binder, Lutz
Fischer, Andreas
Pantakani, Krishna
Asif, Abdul R.
author_facet Shahid, Sidra
Pantakani, Marlena
Binder, Lutz
Fischer, Andreas
Pantakani, Krishna
Asif, Abdul R.
author_sort Shahid, Sidra
collection PubMed
description NF-κB signaling is a key regulator of inflammation and atherosclerosis. NF-κB cooperates with bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, in endothelial inflammation. This study aimed to investigate whether BRD4 inhibition would prevent the proinflammatory response towards TNF-α in endothelial cells. We used TNF-α treatment of human umbilical cord-derived vascular endothelial cells to create an in vitro inflammatory model system. Two small molecule inhibitors of BRD4—namely, RVX208 (Apabetalone), which is in clinical trials for the treatment of atherosclerosis, and JQ1—were used to analyze the effect of BRD4 inhibition on endothelial inflammation and barrier integrity. BRD4 inhibition reduced the expression of proinflammatory markers such as SELE, VCAM-I, and IL6 in endothelial cells and prevented TNF-α-induced endothelial tight junction hyperpermeability. Endothelial inflammation was associated with increased expression of the heparin-binding growth factor midkine. BRD4 inhibition reduced midkine expression and normalized endothelial permeability upon TNF-α treatment. In conclusion, we identified that TNF-α increased midkine expression and compromised tight junction integrity in endothelial cells, which was preventable by pharmacological BRD4 inhibition.
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spelling pubmed-96929722022-11-26 Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression Shahid, Sidra Pantakani, Marlena Binder, Lutz Fischer, Andreas Pantakani, Krishna Asif, Abdul R. Molecules Article NF-κB signaling is a key regulator of inflammation and atherosclerosis. NF-κB cooperates with bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, in endothelial inflammation. This study aimed to investigate whether BRD4 inhibition would prevent the proinflammatory response towards TNF-α in endothelial cells. We used TNF-α treatment of human umbilical cord-derived vascular endothelial cells to create an in vitro inflammatory model system. Two small molecule inhibitors of BRD4—namely, RVX208 (Apabetalone), which is in clinical trials for the treatment of atherosclerosis, and JQ1—were used to analyze the effect of BRD4 inhibition on endothelial inflammation and barrier integrity. BRD4 inhibition reduced the expression of proinflammatory markers such as SELE, VCAM-I, and IL6 in endothelial cells and prevented TNF-α-induced endothelial tight junction hyperpermeability. Endothelial inflammation was associated with increased expression of the heparin-binding growth factor midkine. BRD4 inhibition reduced midkine expression and normalized endothelial permeability upon TNF-α treatment. In conclusion, we identified that TNF-α increased midkine expression and compromised tight junction integrity in endothelial cells, which was preventable by pharmacological BRD4 inhibition. MDPI 2022-11-02 /pmc/articles/PMC9692972/ /pubmed/36364277 http://dx.doi.org/10.3390/molecules27217453 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
Shahid, Sidra
Pantakani, Marlena
Binder, Lutz
Fischer, Andreas
Pantakani, Krishna
Asif, Abdul R.
Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression
title Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression
title_full Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression
title_fullStr Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression
title_full_unstemmed Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression
title_short Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer Integrity and Reduces Midkine Expression
title_sort small molecule brd4 inhibitors apabetalone and jq1 rescues endothelial cells dysfunction, protects monolayer integrity and reduces midkine expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9692972/
https://www.ncbi.nlm.nih.gov/pubmed/36364277
http://dx.doi.org/10.3390/molecules27217453
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