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-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.
Highlights
IntroductionIn early stages of the disease, endothelial cells get activated by circulating proinflammatory molecules such as cytokines (e.g. TNFα) or modified lipoproteins (e.g. oxidized LDL)
Inflammation plays a key role in the development and progression of atherosclerosis
Vasoconstriction with norepinephrine and endothelium-independent vasodilatation with sodium nitroprusside were normal (Figure 1B, C). eNOSderived nitric oxide (NO) plays an important role in vascular relaxation, and endothelial nitric oxide (NO) synthase (eNOS) activity is mainly regulated by Akt-dependent Ser1177 phosphorylation [21]
Summary
In early stages of the disease, endothelial cells get activated by circulating proinflammatory molecules such as cytokines (e.g. TNFα) or modified lipoproteins (e.g. oxidized LDL). Once activated, these cells express chemokines, cytokines, and adhesion molecules, which attract and recruit inflammatory cells such as macrophages and T cells [1, 2]. Hypertension, hypercholesterolemia, diabetes, and aging, which may all be associated with an excessive production of reactive oxygen species (ROS) and oxidant stress, may contribute to atherosclerosis by affecting endothelial function and inducing sustained endothelial activation [2,3,4,5]. NF-κB is of special interest in endothelial cells, since it drives the expression of important adhesion molecules, such as vascular cell www.impactaging.com
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