First Author | Dumont O | Year | 2012 |
Journal | Biochem J | Volume | 447 |
Issue | 2 | Pages | 193-204 |
PubMed ID | 22849349 | Mgi Jnum | J:191320 |
Mgi Id | MGI:5461443 | Doi | 10.1042/BJ20120574 |
Citation | Dumont O, et al. (2012) Protein kinase Cepsilon activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2- and NF-kappaB-dependent pathway to enhance vascular protection. Biochem J 447(2):193-204 |
abstractText | Vascular endothelial injury predisposes to endothelial dysfunction and atherogenesis. We have investigated the hypothesis that PKCepsilon (protein kinase Cepsilon) is an important upstream regulator of cytoprotective pathways in vascular ECs (endothelial cells). Depletion of PKCepsilon in human ECs reduced expression of the cytoprotective genes A1, A20 and Bcl-2. Conversely, constitutively active PKCepsilon 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-kappaB (nuclear factor kappaB) by the pharmacological antagonist BAY 11-7085 or an IkappaB (inhibitor of NF-kappaB) SuperRepressor prevented cytoprotective gene induction. Activation of PKCepsilon enhanced p65 NF-kappaB DNA binding and elevated NF-kappaB transcriptional activity. Importantly, although NF-kappaB activation by PKCepsilon induced cytoprotective genes, it did not up-regulate pro-inflammatory NF-kappaB targets [E-selectin, VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1)]. Indeed, PKCepsilon exhibited cytoprotective and anti-inflammatory actions, including inhibition of TNFalpha (tumour necrosis factor alpha)-induced JNK (c-Jun N-terminal kinase) phosphorylation and ICAM-1 up-regulation, a response attenuated by depletion of A20. Thus we conclude that PKCepsilon 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-kappaB pathway to cytoprotective gene induction, and propose that PKCepsilon represents a novel therapeutic target for endothelial dysfunction. |