Ribosomal Protein L13a Deficiency in Macrophages Promotes Atherosclerosis by Limiting Translation Control-Dependent Retardation of Inflammation
Ribosomal Protein L13a Deficiency in Macrophages Promotes Atherosclerosis by Limiting Translation Control-Dependent Retardation of Inflammation
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DOI：
10.1161/atvbaha.113.302573
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发表时间：
2014-03-01
影响因子：
8.7
通讯作者：
Mazumder, Barsanjit
中科院分区：
文献类型：
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作者：
Basu, Abhijit;Poddar, Darshana;Mazumder, Barsanjit
目的巨噬细胞未解决的炎症反应在动脉粥样硬化的发病机制中发挥着关键作用。之前我们发现核糖体蛋白 L13a 依赖性翻译沉默会抑制单核细胞和巨噬细胞中一组炎症蛋白的合成。我们还发现，在脂多糖诱导的内毒素血症小鼠模型中，巨噬细胞中 L13a 表达的基因消除显着损害了炎症的消退。然而，其在动脉粥样硬化发病机制中的作用尚不清楚。在这里，我们检查巨噬细胞中的L13a是否对高脂饮食引起的动脉粥样硬化具有保护作用。方法和结果我们将巨噬细胞特异性L13a敲除小鼠L13a Flox（+/+）Cre（+/+）培育到载脂蛋白E缺陷的背景上，并产生了实验性双敲除小鼠L13a Flox（+/+）Cre（+/+）载脂蛋白E缺陷(apoE(-/-))。使用载脂蛋白 E 缺陷背景的 L13a Flox(+/+) Cre(-/-) 小鼠作为对照。对照组和基因敲除小鼠接受高脂肪饮食 10 周。 enface对主动脉窦切片和整个主动脉的评估显示，基因敲除小鼠的动脉粥样硬化程度明显更高。基因敲除小鼠的动脉粥样硬化严重程度伴随着中层平滑肌细胞层变薄、内膜斑块区域巨噬细胞面积增大以及炎症细胞因子血浆水平升高。此外，从基因敲除小鼠中分离的巨噬细胞具有较高的多个靶mRNA多核糖体丰度，因此显示翻译控制缺陷。结论我们的数据表明，巨噬细胞中L13a的缺失增加了载脂蛋白E缺陷小鼠对动脉粥样硬化的易感性，揭示了L13a依赖性翻译控制作为对抗动脉粥样硬化的内源性保护机制的重要作用。
Objective Unresolved inflammatory response of macrophages plays a pivotal role in the pathogenesis of atherosclerosis. Previously we showed that ribosomal protein L13a-dependent translational silencing suppresses the synthesis of a cohort of inflammatory proteins in monocytes and macrophages. We also found that genetic abrogation of L13a expression in macrophages significantly compromised the resolution of inflammation in a mouse model of lipopolysaccharide-induced endotoxemia. However, its function in the pathogenesis of atherosclerosis is not known. Here, we examine whether L13a in macrophage has a protective role against high-fat diet-induced atherosclerosis.Approach and Results We bred the macrophage-specific L13a knockout mice L13a Flox(+/+) Cre(+/+) onto apolipoprotein E-deficient background and generated the experimental double knockout mice L13a Flox(+/+) Cre(+/+) apolipoprotein E deficient (apoE(-/-)). L13a Flox(+/+) Cre(-/-) mice on apolipoprotein E-deficient background were used as controls. Control and knockout mice were subjected to high-fat diet for 10 weeks. Evaluation of aortic sinus sections and entire aorta by en face showed significantly higher atherosclerosis in the knockout mice. Severity of atherosclerosis in knockout mice was accompanied by thinning of the smooth muscle cell layer in the media, larger macrophage area in the intimal plaque region and higher plasma levels of inflammatory cytokines. In addition, macrophages isolated from knockout mice had higher polyribosomal abundance of several target mRNAs, thus showing defect in translation control.Conclusions Our data demonstrate that loss of L13a in macrophages increases susceptibility to atherosclerosis in apolipoprotein E-deficient mice, revealing an important role of L13a-dependent translational control as an endogenous protection mechanism against atherosclerosis.