SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo
SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo
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DOI：
10.1161/atvbaha.118.311409
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发表时间：
2018-10-01
影响因子：
8.7
通讯作者：
Ono, Koh
中科院分区：
文献类型：
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作者：
Nishino, Tomohiro;Horie, Takahiro;Ono, Koh
目的动脉粥样硬化是由多种代谢和炎症紊乱引起的常见疾病。SREBF 2（固醇调节元件结合因子2）中的microRNA（miR）-33a是通过调节两个方面治疗动脉粥样硬化的有效靶点;然而，SREBF 1中miR-33 b的参与在很大程度上仍然未知。虽然它们的宿主基因差异可能导致miR-33 a/B的功能分歧，我们不能剖析miR-33 a/B在体内的作用，因为缺乏miR-33 B序列在小鼠，不像human.Approach和Results在这里，我们分析了动脉粥样硬化的发展使用miR-33 B敲入人源化小鼠载脂蛋白E缺陷的背景下。miR-33 b在人和小鼠的动脉粥样硬化条件下都是突出的。miR-33 b降低血清高密度脂蛋白胆固醇水平和全身胆固醇逆向转运。miR-33 b基因敲入的巨噬细胞通过调节脂筏表现出更低的胆固醇流出能力和更高的炎症状态。因此，miR-33 b促进易损动脉粥样硬化斑块形成。结论SREBF 1-miR-33 b轴在脂质代谢和巨噬细胞表型重塑中发挥重要作用，提示miR-33 b是治疗动脉粥样硬化的一个有希望的靶点。
Objective Atherosclerosis is a common disease caused by a variety of metabolic and inflammatory disturbances. MicroRNA (miR)-33a within SREBF2 (sterol regulatory element-binding factor 2) is a potent target for treatment of atherosclerosis through regulating both aspects; however, the involvement of miR-33b within SREBF1 remains largely unknown. Although their host genes difference could lead to functional divergence of miR-33a/b, we cannot dissect the roles of miR-33a/b in vivo because of lack of miR-33b sequences in mice, unlike human.Approach and Results Here, we analyzed the development of atherosclerosis using miR-33b knock-in humanized mice under apolipoprotein E-deficient background. MiR-33b is prominent both in human and mice on atheroprone condition. MiR-33b reduced serum high-density lipoprotein cholesterol levels and systemic reverse cholesterol transport. MiR-33b knock-in macrophages showed less cholesterol efflux capacity and higher inflammatory state via regulating lipid rafts. Thus, miR-33b promotes vulnerable atherosclerotic plaque formation. Furthermore, bone marrow transplantation experiments strengthen proatherogenic roles of macrophage miR-33b.Conclusions Our data demonstrated critical roles of SREBF1-miR-33b axis on both lipid profiles and macrophage phenotype remodeling and indicate that miR-33b is a promising target for treating atherosclerosis.