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. 2010 Sep;31(18):2301-9.
doi: 10.1093/eurheartj/ehq107. Epub 2010 Apr 23.

SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis

Sokrates Stein  1 , Christine Lohmann, Nicola Schäfer, Janin Hofmann, Lucia Rohrer, Christian Besler, Karin M Rothgiesser, Burkhard Becher, Michael O Hottiger, Jan Borén, Michael W McBurney, Ulf Landmesser, Thomas F Lüscher, Christian M Matter
Affiliations

SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis

Sokrates Stein et al. Eur Heart J. 2010 Sep.

Abstract

Aims: 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.

Methods and results: 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-κB signalling pathway.

Conclusion: 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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Figures

Figure 1
Figure 1
SIRT1 protects mice against atherosclerosis. (A) En face Oil red O (ORO) staining of thoraco-abdominal aortae and quantifications of plaque area. n = 9, ApoE−/− SIRT1+/+(▪); n = 11, ApoE−/− SIRT1+/−(□). (B) Representative images for Massons trichrome and Elastica van Gieson stainings from animals with comparable plaque sizes. Magnification: X 40. *P < 0.05.
Figure 2
Figure 2
SIRT1 deletion increases macrophage and T-cell accumulation in plaques. Immunohistochemistry with quantifications of Oil red O (ORO), CD68, and CD3 (arrows) on plaques from aortic sinus. Magnifications: Oil red O, CD68: ×40; CD3: ×400. n = 6 per genotype. *P < 0.05.
Figure 3
Figure 3
SIRT1 reduces foam cell formation. (A) Increased uptake of oxLDL in peritoneal thioglycolate-elicited macrophages from ApoE−/− SIRT1+/− compared with ApoE−/− SIRT1+/+ mice. oxLDL uptake is given as the ratio of the percentage of ORO-positive area divided by the percentage of total cell area in at least 150 cells per genotype. (B) siRNA-induced SIRT1 knockdown increases uptake of oxLDL in RAW 264.7 macrophages compared with scr-siRNA-treated cells. (C) siRNA-mediated SIRT1 silencing in 5 h TNFα-pretreated RAW 264.7 macrophages: left panel, expression of Lox-1; right panel, uptake of oxLDL in neutralizing anti-CD36 antibody-treated cells. *P < 0.05. ***P < 0.001. Magnifications: ×400.
Figure 4
Figure 4
SIRT1 function in macrophages is sufficient to decrease atherogenesis. Chimeric ApoE−/− mice that received ApoE−/− SIRT1+/− (n = 7) bone marrow cells develop more atherosclerosis than those which received ApoE−/− SIRT1+/+ (n = 5) bone marrow cells. *P < 0.05.
Figure 5
Figure 5
Deacetylation of RelA/p65 by SIRT1 diminishes Lox-1 expression. (A) Aortic Lox-1 expression is increased in ApoE−/− SIRT1+/− compared with ApoE−/− SIRT1+/+ mice. (B) Lox-1 expression is higher in 5 h TNFα-stimulated RAW 264.7 macrophages pretreated with 200 µM splitomicin (Splito) compared with untreated cells (nt). (C) Ectopic SIRT1 expression in SIRT1−/− MEF reduces Lox-1 expression. (D) In RelA/p65−/− MEF with reconstituted wt-RelA/p65, siRNA-mediated SIRT1 knockdown enhances Lox-1 expression upon 5 h TNFα stimulation, whereas no effect is observed in RelA/p65−/− MEF with a reconstituted mutated, non-acetylatable K310-RelA/p65. *P < 0.05; ***P < 0.001.
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