SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice.
Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-kappaB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-kappaB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation.
Stein
Sokrates
S
Cardiovascular Research, Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, and Cardiovascular Center, Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland. sokrates@access.uzh.ch
Schäfer
Nicola
N
Breitenstein
Alexander
A
Besler
Christian
C
Winnik
Stephan
S
Lohmann
Christine
C
Heinrich
Kathrin
K
Brokopp
Chad E
CE
Handschin
Christoph
C
Landmesser
Ulf
U
Tanner
Felix C
FC
Lüscher
Thomas F
TF
Matter
Christian M
CM
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000378:metabolism*; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
D001057:Apolipoproteins E; D034741:RNA, Small Interfering; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1