Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China.
Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China.
J Atheroscler Thromb. 2018 Mar 1;25(3):244-253. doi: 10.5551/jat.40212. Epub 2017 Sep 1.
Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages.
ApoE KO male mice on a C57BL/6 background were fed a high-fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels.
Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir.
These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease.
动脉粥样硬化是心血管疾病（如心肌梗死和中风）的最常见原因。先前的研究表明，微小 RNA（miR）-134 通过血管生成素样 4（ANGPTL4）/脂质脂蛋白（LPL）信号通路促进 THP-1 巨噬细胞中的脂质积累和促炎细胞因子分泌。
apoE KO 雄性小鼠以 C57BL/6 为背景，从 8 到 16 周龄喂食高脂肪/高胆固醇西方饮食。将小鼠分为四组，分别在开始西方饮食后每两周通过尾静脉注射 miR-134 激动剂、miR-134 拮抗剂或相应的对照物之一。8 周后，我们测量主动脉粥样硬化、LPL 活性、ANGPTL4 和 LPL 的 mRNA 和蛋白水平、LPL/低密度脂蛋白受体相关蛋白 1 复合物形成、促炎细胞因子分泌和脂质水平。
尽管有此发现，但 miR-134 对体内动脉粥样硬化的影响仍有待确定。使用载脂蛋白 E 敲除的公认的小鼠动脉粥样硬化模型，我们发现系统递送 miR-134 激动剂显著增强了动脉粥样硬化病变的大小，同时促炎细胞因子分泌和腹腔巨噬细胞脂质含量显著增加。此外，miR-134 的过表达降低了主动脉组织和腹腔巨噬细胞中 ANGPTL4 的表达，但增加了 LPL 的表达和活性，同时在腹腔巨噬细胞中增加了 LPL/低密度脂蛋白受体相关蛋白 1 复合物的形成。然而，miR-134 拮抗剂则观察到相反的效果。
这些发现表明，miR-134 通过 ANGPTL4/LPL 通路促进脂质积累和促炎细胞因子分泌，从而加速动脉粥样硬化形成。因此，靶向 miR-134 可能为预防和治疗动脉粥样硬化性心血管疾病提供一种有前途的策略。
