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Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.
Journal of Molecular and Cellular Cardiology ( IF 5 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.yjmcc.2020.01.002
Tasneem Arsiwala 1 , Jürgen Pahla 1 , Lambertus J van Tits 2 , Lavinia Bisceglie 3 , Daniel S Gaul 2 , Sarah Costantino 1 , Melroy X Miranda 2 , Kathrin Nussbaum 4 , Simona Stivala 5 , Przemyslaw Blyszczuk 2 , Julien Weber 2 , Anne Tailleux 6 , Sokrates Stein 2 , Francesco Paneni 2 , Jürg H Beer 5 , Melanie Greter 4 , Burkhard Becher 4 , Raul Mostoslavsky 7 , Urs Eriksson 1 , Bart Staels 6 , Johan Auwerx 8 , Michael O Hottiger 3 , Thomas F Lüscher 9 , Christian M Matter 2
Affiliation  

AIMS Sirtuin 6 (Sirt6) is a NAD+-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model. METHODS AND RESULTS Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe-/- mice fed a high-cholesterol diet for 12 weeks (n = 12-14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels. CONCLUSIONS Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.

中文翻译:

骨髓来源细胞中Sirt6缺失会增加动脉粥样硬化-巨噬细胞清除剂受体1的中心作用。

AIMS Sirtuin 6(Sirt6)是一种NAD +依赖性脱乙酰基酶,在DNA修复,炎症和脂质调节中起关键作用。无Sirt6小鼠表现出严重的代谢缺陷和加速衰老。通过清除剂受体形成巨噬细胞泡沫细胞是动脉粥样硬化形成的关键步骤。我们使用小鼠模型确定了骨髓限制性Sirt6缺失对泡沫细胞形成和动脉粥样硬化的影响。方法和结果喂食高胆固醇饮食12周的Apoe-/-小鼠的Apoe-/-小鼠骨髓来源的细胞中Sirt6缺失增加了主动脉斑块,脂质含量和巨噬细胞数量(n = 12-14,p <.001)。在RAW巨噬细胞中,Sirt6的过表达减少了氧化的低密度脂蛋白(oxLDL)的摄取,Sirt6的敲低增强了它的表达,并增加了巨噬细胞清道夫受体1(Msr1)的mRNA和蛋白质水平,而其他oxLDL摄取和外排转运蛋白的水平保持不变。同样,在人类原代巨噬细胞中,Sirt6敲低会增加MSR1蛋白水平和oxLDL摄取。Sirt6和Msr1的双重敲除消除了Sirt6单次敲除时oxLDL摄取的增加。从Sirt6缺陷骨髓移植小鼠的主动脉斑块中提取巨噬细胞的FACS分析显示,MSR1蛋白表达增加。RAW细胞中Sirt6和转录因子c-Myc的双重敲除消除了Msr1 mRNA和蛋白质水平的增加;c-Myc过表达增加Msr1 mRNA和蛋白质水平。结论骨髓来源的细胞中Sirt6的丢失是致动脉粥样硬化的。因此,鉴于人类和鼠类巨噬细胞中MSR1蛋白表达的c-Myc依赖性增加和oxLDL摄取增强,巨噬细胞起着重要作用。这些发现赋予巨噬细胞内源性SIRT6重要的抗动脉粥样硬化作用。
更新日期:2020-01-21
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