RESEARCH PAPER

AGING, Vol 2, No 6 , pp 353-360
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SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice

Sokrates Stein1, Nicola Schäfer1, Alexander Breitenstein1, Christian Besler1, Stephan Winnik1, Christine Lohmann1, Kathrin Heinrich1, Chad E. Brokopp1, Christoph Handschin2, Ulf Landmesser1, Felix C. Tanner1, Thomas F. Lüscher1, and Christian M. Matter1
1 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
2 Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Key words:
SIRT1, atherosclerosis, endothelium, inflammation
Received:
06/23/10; accepted: 06/26/10; published on line: 06/28/10
E-mail:

Abstract

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-κB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-κB 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.