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.