SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice
Sokrates Stein1, Nicola Schäfer, Alexander Breitenstein
1Cardiovascular 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
Aging
|July 8, 2010
Summary
Reduced SIRT1 (silent mating type information regulation 2 homolog 1) activity worsens endothelial activation in atherosclerosis by increasing superoxide production and inflammatory signaling, but does not impact vasodilation.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Atherosclerosis Research
Background:
- Reactive oxygen species (ROS) drive atherosclerosis via endothelial dysfunction and inflammation.
- SIRT1 (class III histone deacetylase) activation improves endothelial function by stimulating eNOS.
- The impact of SIRT1 loss-of-function on endothelial cells in atherosclerosis is unknown.
Purpose of the Study:
- To investigate the endothelial effects of reduced endogenous SIRT1 in hypercholesterolemic ApoE-/- mice.
- To characterize the role of SIRT1 in endothelial activation and function during atherosclerosis progression.
Main Methods:
- Utilized 20-week-old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice.
- Assessed endothelial relaxation and eNOS phosphorylation.
- Measured endothelial superoxide production, NF-kappaB signaling, and adhesion molecule expression (ICAM-1, VCAM-1).
- Administered lipopolysaccharide to assess NF-kappaB pathway response.
Main Results:
- No significant difference in endothelial relaxation or eNOS (Ser1177) phosphorylation between groups.
- SIRT1 significantly prevented endothelial superoxide production.
- SIRT1 inhibited NF-kappaB signaling and reduced expression of adhesion molecules.
- SIRT1+/- mice exhibited more pronounced endothelial ICAM-1 and VCAM-1 expression upon LPS challenge.
Conclusions:
- Endogenous SIRT1 mitigates endothelial activation in hypercholesterolemic ApoE-/- mice.
- SIRT1 plays a protective role against endothelial inflammation and superoxide production.
- SIRT1 loss-of-function does not impair endothelium-dependent vasodilation in this model.
