Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding.
BACKGROUND
Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma.


RESULTS
Apoe(-/-) and Apoe(-/-)/IL-1R1(-/-) mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-)/IL-R1(-/-) mice had a reduced blood pressure and significantly less atheroma than Apoe(-/-) mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p < 0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress.


CONCLUSIONS
The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man.
Chamberlain
Janet
J
Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom. j.chamberlain@sheffield.ac.uk
Francis
Sheila
S
Brookes
Zoe
Z
Shaw
Gary
G
Graham
Delyth
D
Alp
Nicholas J
NJ
Dower
Steven
S
Crossman
David C
DC
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000503:physiopathology*; D001794:Blood Pressure; D004041:Dietary Fats / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology
D001057:Apolipoproteins E; D004041:Dietary Fats; D007375:Interleukin-1; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1