ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium.
ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium.
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DOI：
10.1161/atvbaha.111.238964
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Raffai RL
中科院分区：
文献类型：
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作者：
Gaudreault N;Kumar N;Posada JM;Stephens KB;Reyes de Mochel NS;Eberlé D;Olivas VR;Kim RY;Harms MJ;Johnson S;Messina LM;Rapp JH;Raffai RL
我们研究了apoE在降低血浆胆固醇能力之外的抗动脉粥样硬化特性。我们假设apoE通过减少循环单核细胞中的脂质积聚以及单核细胞和血管内皮的炎症状态来减少动脉粥样硬化。我们开发了具有和不具有血浆apoE的自发性高脂血症小鼠：将低密度脂蛋白受体缺陷的低形态apoE小鼠（Apoeh/hLdlr-/-）与Apoe-/-Ldlr-/-小鼠进行比较。尽管Apoeh/hLdlr-/-小鼠的血浆apoE是WT小鼠的4倍，但Apoeh/hLdlr-/-小鼠的血浆胆固醇与Apoe-/-Ldlr-/-小鼠相似，但在5月龄时动脉粥样硬化病变的发生率低4倍。Apoeh/hLdlr-/-小鼠的主动脉弓显示ICAM-1、PECAM-1和JAM-A的内皮表达降低。此外，Apoeh/hLdlr-/-小鼠具有较少的循环白细胞和促炎性Ly 6Chigh单核细胞。这些单核细胞具有降低的中性脂质含量和降低的ICAM-1、VLA-4和L-选择素的表面表达。Apoeh/hLdlr-/-小鼠显示富含apoA 1的HDL水平升高，这在促进细胞胆固醇流出方面是有效的。我们的研究结果表明，apoE通过增加血浆apoA 1-HDL来减少高脂血症患者的动脉粥样硬化，这可能有助于减少细胞内脂质积聚，从而激活循环白细胞和血管内皮细胞。
We investigated atheroprotective properties of apoE beyond its ability to lower plasma cholesterol. We hypothesized that apoE reduces atherosclerosis by decreasing lipid accumulation in circulating monocytes and the inflammatory state of monocytes and the vascular endothelium. We developed mice with spontaneous hyperlipidemia with and without plasma apoE: Hypomorphic apoE mice deficient in low-density lipoprotein receptor (Apoeh/hLdlr–/–) were compared to Apoe–/–Ldlr–/– mice. Despite 4-fold more plasma apoE than WT mice, Apoeh/hLdlr–/– mice displayed similar plasma cholesterol as Apoe–/–Ldlr–/– mice but developed 4-fold less atherosclerotic lesions by 5 months of age. The aortic arch of Apoeh/hLdlr–/– mice showed decreased endothelial expression of ICAM-1, PECAM-1, and JAM-A. In addition, Apoeh/hLdlr–/– mice had less circulating leukocytes and pro-inflammatory Ly6Chigh monocytes. These monocytes had decreased neutral lipid content and reduced surface expression of ICAM-1, VLA-4, and L-Selectin. Apoeh/hLdlr–/– mice displayed increased levels of apoA1-rich HDL that were potent in promoting cellular cholesterol efflux. Our findings suggest that apoE reduces atherosclerosis in the setting of hyperlipidemia by increasing plasma apoA1-HDL that likely contribute to reduce intracellular lipid accumulation and thereby the activation of circulating leukocytes and the vascular endothelium.