Vascular endothelial injury predisposes to endothelial dysfunction and atherogenesis. We have investigated the hypothesis that PKCϵ (protein kinase Cϵ) is an important upstream regulator of cytoprotective pathways in vascular ECs (endothelial cells). Depletion of PKCϵ in human ECs reduced expression of the cytoprotective genes A1, A20 and Bcl-2. Conversely, constitutively active PKCϵ expressed in human ECs increased mRNA and protein levels of these cytoprotective genes, with up-regulation dependent upon ERK1/2 (extracellular-signal-regulated kinase 1/2) activation. Furthermore, inhibition of NF-κB (nuclear factor κB) by the pharmacological antagonist BAY 11-7085 or an IκB (inhibitor of NF-κB) SuperRepressor prevented cytoprotective gene induction. Activation of PKCϵ enhanced p65 NF-κB DNA binding and elevated NF-κB transcriptional activity. Importantly, although NF-κB activation by PKCϵ induced cytoprotective genes, it did not up-regulate pro-inflammatory NF-κB targets [E-selectin, VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1)]. Indeed, PKCϵ exhibited cytoprotective and anti-inflammatory actions, including inhibition of TNFα (tumour necrosis factor α)-induced JNK (c-Jun N-terminal kinase) phosphorylation and ICAM-1 up-regulation, a response attenuated by depletion of A20. Thus we conclude that PKCϵ plays an essential role in endothelial homoeostasis, acting as an upstream co-ordinator of gene expression through activation of ERK1/2, inhibition of JNK and diversion of the NF-κB pathway to cytoprotective gene induction, and propose that PKCϵ represents a novel therapeutic target for endothelial dysfunction.
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October 2012
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Research Article|
September 26 2012
Protein kinase Cϵ activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2- and NF-κB-dependent pathway to enhance vascular protection
Odile Dumont;
Odile Dumont
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Hayley Mylroie;
Hayley Mylroie
1
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Andrea Bauer;
Andrea Bauer
1
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Damien Calay;
Damien Calay
1
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Andrea Sperone;
Andrea Sperone
1
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Clare Thornton;
Clare Thornton
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Shahir S. Hamdulay;
Shahir S. Hamdulay
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Nadira Ali;
Nadira Ali
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Joseph J. Boyle;
Joseph J. Boyle
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Joan R. Choo;
Joan R. Choo
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Allen M. Samarel;
Allen M. Samarel
†The Cardiovascular Institute, Loyola University, Chicago Stritch School of Medicine, Maywood, IL, U.S.A.
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Dorian O. Haskard;
Dorian O. Haskard
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Anna M. Randi;
Anna M. Randi
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Paul C. Evans;
Paul C. Evans
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
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Justin C. Mason
Justin C. Mason
2
*Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, U.K.
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 10 2012
Revision Received:
July 30 2012
Accepted:
July 31 2012
Accepted Manuscript online:
July 31 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 447 (2): 193–204.
Article history
Received:
April 10 2012
Revision Received:
July 30 2012
Accepted:
July 31 2012
Accepted Manuscript online:
July 31 2012
Citation
Odile Dumont, Hayley Mylroie, Andrea Bauer, Damien Calay, Andrea Sperone, Clare Thornton, Shahir S. Hamdulay, Nadira Ali, Joseph J. Boyle, Joan R. Choo, Allen M. Samarel, Dorian O. Haskard, Anna M. Randi, Paul C. Evans, Justin C. Mason; Protein kinase Cϵ activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2- and NF-κB-dependent pathway to enhance vascular protection. Biochem J 15 October 2012; 447 (2): 193–204. doi: https://doi.org/10.1042/BJ20120574
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