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Protein kinase Cε activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2- and NF-κB-dependent pathway to enhance vascular protection.
Dumont, Odile; Mylroie, Hayley; Bauer, Andrea; Calay, Damien; Sperone, Andrea; Thornton, Clare; Hamdulay, Shahir S; Ali, Nadira; Boyle, Joseph J; Choo, Joan R; Samarel, Allen M; Haskard, Dorian O; Randi, Anna M; Evans, Paul C; Mason, Justin C.
Afiliación
  • Dumont O; Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK.
Biochem J ; 447(2): 193-204, 2012 Oct 15.
Article en En | MEDLINE | ID: mdl-22849349
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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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: FN-kappa B / Proteína Quinasa 1 Activada por Mitógenos / Proteína Quinasa 3 Activada por Mitógenos / Proteína Quinasa C-epsilon Límite: Animals / Humans Idioma: En Revista: Biochem J Año: 2012 Tipo del documento: Article
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: FN-kappa B / Proteína Quinasa 1 Activada por Mitógenos / Proteína Quinasa 3 Activada por Mitógenos / Proteína Quinasa C-epsilon Límite: Animals / Humans Idioma: En Revista: Biochem J Año: 2012 Tipo del documento: Article