Journal
EUROPEAN HEART JOURNAL
Volume 31, Issue 18, Pages 2301-2309Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehq107
Keywords
SIRT1; Macrophage foam cell; Atherogenesis
Categories
Funding
- Swiss National Science Foundation [31-114094/1, 3100-068118]
- MERCATOR Foundation Switzerland
- University of Zurich
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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. 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-kappa B signalling pathway. 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.
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