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Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog

Vascular endothelial cells (ECs) are important for maintaining vascular homeostasis. Dysfunction of ECs contributes to cardiovascular diseases, including atherosclerosis, and can impair the healing process during vascular injury. An important mediator of EC response to stress is the GTPase Rac1. Rac...

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Detalles Bibliográficos
Autores principales: Wall, S.B., Oh, J.-Y., Mitchell, L., Laube, A.H., Campbell, S.L., Renfrow, M.B., Landar, A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326178/
https://www.ncbi.nlm.nih.gov/pubmed/25677088
http://dx.doi.org/10.1016/j.redox.2015.01.016
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author Wall, S.B.
Oh, J.-Y.
Mitchell, L.
Laube, A.H.
Campbell, S.L.
Renfrow, M.B.
Landar, A.
author_facet Wall, S.B.
Oh, J.-Y.
Mitchell, L.
Laube, A.H.
Campbell, S.L.
Renfrow, M.B.
Landar, A.
author_sort Wall, S.B.
collection PubMed
description Vascular endothelial cells (ECs) are important for maintaining vascular homeostasis. Dysfunction of ECs contributes to cardiovascular diseases, including atherosclerosis, and can impair the healing process during vascular injury. An important mediator of EC response to stress is the GTPase Rac1. Rac1 responds to extracellular signals and is involved in cytoskeletal rearrangement, reactive oxygen species generation and cell cycle progression. Rac1 interacts with effector proteins to elicit EC spreading and formation of cell-to-cell junctions. Rac1 activity has recently been shown to be modulated by glutathiolation or S-nitrosation via an active site cysteine residue. However, it is not known whether other redox signaling compounds can modulate Rac1 activity. An important redox signaling mediator is the electrophilic lipid, 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)). This compound is a downstream product of cyclooxygenase and forms covalent adducts with specific cysteine residues, and induces cellular signaling in a pleiotropic manner. In this study, we demonstrate that a biotin-tagged analog of 15d-PGJ(2) (bt-15d-PGJ(2)) forms an adduct with Rac1 in vitro at the C157 residue, and an additional adduct was detected on the tryptic peptide associated with C178. Rac1 modification in addition to modulation of Rac1 activity by bt-15d-PGJ(2) was observed in cultured ECs. In addition, decreased EC migration and cell spreading were observed in response to the electrophile. These results demonstrate for the first time that Rac1 is a target for 15d-PGJ(2) in ECs, and suggest that Rac1 modification by electrophiles such as 15d-PGJ(2) may alter redox signaling and EC function.
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spelling pubmed-43261782015-02-14 Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog Wall, S.B. Oh, J.-Y. Mitchell, L. Laube, A.H. Campbell, S.L. Renfrow, M.B. Landar, A. Redox Biol Research Paper Vascular endothelial cells (ECs) are important for maintaining vascular homeostasis. Dysfunction of ECs contributes to cardiovascular diseases, including atherosclerosis, and can impair the healing process during vascular injury. An important mediator of EC response to stress is the GTPase Rac1. Rac1 responds to extracellular signals and is involved in cytoskeletal rearrangement, reactive oxygen species generation and cell cycle progression. Rac1 interacts with effector proteins to elicit EC spreading and formation of cell-to-cell junctions. Rac1 activity has recently been shown to be modulated by glutathiolation or S-nitrosation via an active site cysteine residue. However, it is not known whether other redox signaling compounds can modulate Rac1 activity. An important redox signaling mediator is the electrophilic lipid, 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)). This compound is a downstream product of cyclooxygenase and forms covalent adducts with specific cysteine residues, and induces cellular signaling in a pleiotropic manner. In this study, we demonstrate that a biotin-tagged analog of 15d-PGJ(2) (bt-15d-PGJ(2)) forms an adduct with Rac1 in vitro at the C157 residue, and an additional adduct was detected on the tryptic peptide associated with C178. Rac1 modification in addition to modulation of Rac1 activity by bt-15d-PGJ(2) was observed in cultured ECs. In addition, decreased EC migration and cell spreading were observed in response to the electrophile. These results demonstrate for the first time that Rac1 is a target for 15d-PGJ(2) in ECs, and suggest that Rac1 modification by electrophiles such as 15d-PGJ(2) may alter redox signaling and EC function. Elsevier 2015-02-03 /pmc/articles/PMC4326178/ /pubmed/25677088 http://dx.doi.org/10.1016/j.redox.2015.01.016 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Wall, S.B.
Oh, J.-Y.
Mitchell, L.
Laube, A.H.
Campbell, S.L.
Renfrow, M.B.
Landar, A.
Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog
title Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog
title_full Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog
title_fullStr Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog
title_full_unstemmed Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog
title_short Rac1 modification by an electrophilic 15-deoxy Δ(12,14)-prostaglandin J(2) analog
title_sort rac1 modification by an electrophilic 15-deoxy δ(12,14)-prostaglandin j(2) analog
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326178/
https://www.ncbi.nlm.nih.gov/pubmed/25677088
http://dx.doi.org/10.1016/j.redox.2015.01.016
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