Atherosclerosis, a chronic inflammatory disease of arteries, occurs
predominantly at regions of the arterial system that are exposed to disturbed
patterns of blood flow. Blood flow influences the atherosclerosis by exerting
shear stress on endothelial cells (ECs).
Although the signalling pathways that activate pro-inflammatory NF-κB
transcription factors are well defined, the regulation and physiological
significance of differential NF-κB subunit expression is poorly understood. In
this thesis, we demonstrate that RelA NF-κB sub-unit expression is positively
regulated in ECs via c-Jun N-terminal kinase (JNK) and the transcription
factor ATF2. This pathway promoted focal arterial inflammation as genetic
deletion of JNK1 reduced RelA expression and macrophage accumulation at
an athero-susceptible site. Furthermore, JNK signalling to RelA is controlled
by mechanical forces as en face immunostaining revealed that disturbed flow
patterns (generated by a constrictive cuff) elevated RelA expression in
murine carotid arteries via JNK1. Positron emission tomography and en face
staining revealed that disturbed flow enhanced 18F-fluorodeoxyglucose
uptake (a marker of inflammation) and accumulation of CD68-positive
inflammatory cells in arteries via JNK1. We conclude that disturbed flow
promotes arterial inflammation via a novel JNK-NF-κB cross-talk.
The duration of RelA nuclear localisation is an important determinant of the
magnitude and specificity of target gene expression. En face staining
revealed that RelA rapidly accumulated in the nucleus upon LPS stimulation
in ECs at both athero-protected and athero-susceptible sites. RelA was
exported from the nucleus to the cytoplasm in response to prolonged
stimulation in the athero-protected region but not in the athero-susceptible
region. The duration of RelA nuclear localisation was suppressed by histone
deacetylases which displayed higher activity at the protected site compared
to the susceptible site.
Overall, our findings reveal that ECs at athero-susceptible sites are primed
for inflammatory activation via complementary mechanisms that enhance
both the expression and the activity of NF-κB transcription factors.