MiR-216a: a link between endothelial dysfunction and autophagy.
MiR-216a: a link between endothelial dysfunction and autophagy.
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DOI：
10.1038/cddis.2013.556
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发表时间：
2014-01-30
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
内皮功能障碍和自噬活性受损在心血管功能障碍和动脉粥样硬化等衰老相关疾病中起着至关重要的作用。我们已经确定miR-216 a是一种在内皮衰老过程中诱导的microRNA，根据计算分析，其靶点包括两个自噬相关基因Beclin 1（BECN 1）和ATG 5。因此，我们评估了miR-216 a作为参与内皮老化过程中自噬功能丧失的分子组分的作用。miR-216 a和自噬基因之间的负相关性在人脐静脉内皮细胞（HUVECs）老化和人动脉粥样硬化和心力衰竭的体内模型中是保守的。荧光素酶实验表明BECN 1而不是ATG 5是miR-216 a的直接靶点。转染HUVEC以调节miR-216 a表达，并用100 μg/ml氧化低密度脂蛋白（ox-LDL）刺激以诱导应激修复自噬过程。我们发现，在年轻的HUVECs中，miR-216 a过表达抑制了BECN 1和ATG 5的表达，并通过微管相关蛋白1轻链3（LC 3B）分析和细胞荧光分析评估了ox-LDL诱导的自噬。此外，miR-216 a刺激HUVECs中ox-LDL积累和单核细胞粘附。相反，在老年HUVEC中抑制miR-216 a拯救了诱导保护性自噬的能力，以响应ox-LDL刺激。总之，mir-216 a通过调节细胞内BECN 1水平来控制ox-LDL诱导的HUVEC自噬，并且可能在心血管疾病和动脉粥样硬化的发病机制中具有相关作用。
Endothelial dysfunction and impaired autophagic activity have a crucial role in aging-related diseases such as cardiovascular dysfunction and atherosclerosis. We have identified miR-216a as a microRNA that is induced during endothelial aging and, according to the computational analysis, among its targets includes two autophagy-related genes, Beclin1 (BECN1) and ATG5. Therefore, we have evaluated the role of miR-216a as a molecular component involved in the loss of autophagic function during endothelial aging. The inverse correlation between miR-216a and autophagic genes was conserved during human umbilical vein endothelial cells (HUVECs) aging and in vivo models of human atherosclerosis and heart failure. Luciferase experiments indicated BECN1, but not ATG5 as a direct target of miR-216a. HUVECs were transfected in order to modulate miR-216a expression and stimulated with 100 μg/ml oxidized low-density lipoprotein (ox-LDL) to induce a stress repairing autophagic process. We found that in young HUVECs, miR-216a overexpression repressed BECN1 and ATG5 expression and the ox-LDL induced autophagy, as evaluated by microtubule-associated protein 1 light chain 3 (LC3B) analysis and cytofluorimetric assay. Moreover, miR-216a stimulated ox-LDL accumulation and monocyte adhesion in HUVECs. Conversely, inhibition of miR-216a in old HUVECs rescued the ability to induce a protective autophagy in response to ox-LDL stimulus. In conclusion, mir-216a controls ox-LDL induced autophagy in HUVECs by regulating intracellular levels of BECN1 and may have a relevant role in the pathogenesis of cardiovascular disorders and atherosclerosis.
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