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PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis

AIMS: Vascular injury leading to endothelial dysfunction is a characteristic feature of chronic renal disease, diabetes mellitus, and systemic inflammatory conditions, and predisposes to apoptosis and atherogenesis. Thus, endothelial dysfunction represents a potential therapeutic target for atherosc...

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Autores principales: Mylroie, Hayley, Dumont, Odile, Bauer, Andrea, Thornton, Clare C., Mackey, John, Calay, Damien, Hamdulay, Shahir S., Choo, Joan R., Boyle, Joseph J., Samarel, Allen M., Randi, Anna M., Evans, Paul C., Mason, Justin C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431664/
https://www.ncbi.nlm.nih.gov/pubmed/25883219
http://dx.doi.org/10.1093/cvr/cvv131
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author Mylroie, Hayley
Dumont, Odile
Bauer, Andrea
Thornton, Clare C.
Mackey, John
Calay, Damien
Hamdulay, Shahir S.
Choo, Joan R.
Boyle, Joseph J.
Samarel, Allen M.
Randi, Anna M.
Evans, Paul C.
Mason, Justin C.
author_facet Mylroie, Hayley
Dumont, Odile
Bauer, Andrea
Thornton, Clare C.
Mackey, John
Calay, Damien
Hamdulay, Shahir S.
Choo, Joan R.
Boyle, Joseph J.
Samarel, Allen M.
Randi, Anna M.
Evans, Paul C.
Mason, Justin C.
author_sort Mylroie, Hayley
collection PubMed
description AIMS: Vascular injury leading to endothelial dysfunction is a characteristic feature of chronic renal disease, diabetes mellitus, and systemic inflammatory conditions, and predisposes to apoptosis and atherogenesis. Thus, endothelial dysfunction represents a potential therapeutic target for atherosclerosis prevention. The observation that activity of either protein kinase C epsilon (PKCε) or haem oxygenase-1 (HO-1) enhances endothelial cell (EC) resistance to inflammation and apoptosis led us to test the hypothesis that HO-1 is a downstream target of PKCε. METHODS AND RESULTS: Expression of constitutively active PKCε in human EC significantly increased HO-1 mRNA and protein, whereas conversely aortas or cardiac EC from PKCε-deficient mice exhibited reduced HO-1 when compared with wild-type littermates. Angiotensin II activated PKCε and induced HO-1 via a PKCε-dependent pathway. PKCε activation significantly attenuated TNFα-induced intercellular adhesion molecule-1, and increased resistance to serum starvation-induced apoptosis. These responses were reversed by the HO antagonist zinc protoporphyrin IX. Phosphokinase antibody array analysis identified CREB1((Ser133)) phosphorylation as a PKCε signalling intermediary, and cAMP response element-binding protein 1 (CREB1) siRNA abrogated PKCε-induced HO-1 up-regulation. Likewise, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was identified as a PKCε target using nuclear translocation and DNA-binding assays, and Nrf2 siRNA prevented PKCε-mediated HO-1 induction. Moreover, depletion of CREB1 inhibited PKCε-induced Nrf2 DNA binding, suggestive of transcriptional co-operation between CREB1 and Nrf2. CONCLUSIONS: PKCε activity in the vascular endothelium regulates HO-1 via a pathway requiring CREB1 and Nrf2. Given the potent protective actions of HO-1, we propose that this mechanism is an important contributor to the emerging role of PKCε in the maintenance of endothelial homeostasis and resistance to injury.
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spelling pubmed-44316642015-05-27 PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis Mylroie, Hayley Dumont, Odile Bauer, Andrea Thornton, Clare C. Mackey, John Calay, Damien Hamdulay, Shahir S. Choo, Joan R. Boyle, Joseph J. Samarel, Allen M. Randi, Anna M. Evans, Paul C. Mason, Justin C. Cardiovasc Res Original Articles AIMS: Vascular injury leading to endothelial dysfunction is a characteristic feature of chronic renal disease, diabetes mellitus, and systemic inflammatory conditions, and predisposes to apoptosis and atherogenesis. Thus, endothelial dysfunction represents a potential therapeutic target for atherosclerosis prevention. The observation that activity of either protein kinase C epsilon (PKCε) or haem oxygenase-1 (HO-1) enhances endothelial cell (EC) resistance to inflammation and apoptosis led us to test the hypothesis that HO-1 is a downstream target of PKCε. METHODS AND RESULTS: Expression of constitutively active PKCε in human EC significantly increased HO-1 mRNA and protein, whereas conversely aortas or cardiac EC from PKCε-deficient mice exhibited reduced HO-1 when compared with wild-type littermates. Angiotensin II activated PKCε and induced HO-1 via a PKCε-dependent pathway. PKCε activation significantly attenuated TNFα-induced intercellular adhesion molecule-1, and increased resistance to serum starvation-induced apoptosis. These responses were reversed by the HO antagonist zinc protoporphyrin IX. Phosphokinase antibody array analysis identified CREB1((Ser133)) phosphorylation as a PKCε signalling intermediary, and cAMP response element-binding protein 1 (CREB1) siRNA abrogated PKCε-induced HO-1 up-regulation. Likewise, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was identified as a PKCε target using nuclear translocation and DNA-binding assays, and Nrf2 siRNA prevented PKCε-mediated HO-1 induction. Moreover, depletion of CREB1 inhibited PKCε-induced Nrf2 DNA binding, suggestive of transcriptional co-operation between CREB1 and Nrf2. CONCLUSIONS: PKCε activity in the vascular endothelium regulates HO-1 via a pathway requiring CREB1 and Nrf2. Given the potent protective actions of HO-1, we propose that this mechanism is an important contributor to the emerging role of PKCε in the maintenance of endothelial homeostasis and resistance to injury. Oxford University Press 2015-06-01 2015-04-16 /pmc/articles/PMC4431664/ /pubmed/25883219 http://dx.doi.org/10.1093/cvr/cvv131 Text en © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Mylroie, Hayley
Dumont, Odile
Bauer, Andrea
Thornton, Clare C.
Mackey, John
Calay, Damien
Hamdulay, Shahir S.
Choo, Joan R.
Boyle, Joseph J.
Samarel, Allen M.
Randi, Anna M.
Evans, Paul C.
Mason, Justin C.
PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
title PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
title_full PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
title_fullStr PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
title_full_unstemmed PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
title_short PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
title_sort pkcε-creb-nrf2 signalling induces ho-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431664/
https://www.ncbi.nlm.nih.gov/pubmed/25883219
http://dx.doi.org/10.1093/cvr/cvv131
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