SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.
OBJECTIVE
Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis.


RESULTS
Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-κB signalling pathway.


CONCLUSIONS
Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation.
Stein
Sokrates
S
Cardiovascular Research, Institute of Physiology, Zurich University and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Lohmann
Christine
C
Schäfer
Nicola
N
Hofmann
Janin
J
Rohrer
Lucia
L
Besler
Christian
C
Rothgiesser
Karin M
KM
Becher
Burkhard
B
Hottiger
Michael O
MO
Borén
Jan
J
McBurney
Michael W
MW
Landmesser
Ulf
U
Lüscher
Thomas F
TF
Matter
Christian M
CM
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005487:Foam Cells / Q000473:pathology*; D017353:Gene Deletion; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051127:Scavenger Receptors, Class E / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000502:physiology*
D008074:Lipoproteins; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C447939:SIRT1 protein, human; D056564:Sirtuin 1