title: Protein kinase Cε activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2- and NF-κB-dependent pathway to enhance vascular protection.
abstract: 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.
authors: Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors: Odile
authors: O
authors: Dumont
authors: Hayley
authors: H
authors: Mylroie
authors: Andrea
authors: A
authors: Bauer
authors: Damien
authors: D
authors: Calay
authors: Andrea
authors: A
authors: Sperone
authors: Clare
authors: C
authors: Thornton
authors: Shahir S
authors: SS
authors: Hamdulay
authors: Nadira
authors: N
authors: Ali
authors: Joseph J
authors: JJ
authors: Boyle
authors: Joan R
authors: JR
authors: Choo
authors: Allen M
authors: AM
authors: Samarel
authors: Dorian O
authors: DO
authors: Haskard
authors: Anna M
authors: AM
authors: Randi
authors: Paul C
authors: PC
authors: Evans
authors: Justin C
authors: JC
authors: Mason
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004789:Enzyme Activation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: C096816:BCL2-related protein A1; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D051744:Protein Kinase C-epsilon; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3