A miRNA-101-3p/Bim axis as a determinant of serum deprivation-induced endothelial cell apoptosis.
A miRNA-101-3p/Bim axis as a determinant of serum deprivation-induced endothelial cell apoptosis.
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DOI：
10.1038/cddis.2017.219
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发表时间：
2017-05-18
影响因子：
9
通讯作者：
Kim YM
中科院分区：
文献类型：
--
作者：
Kim JH;Lee DK;Kim J;Choi S;Park W;Ha KS;Kim TH;Choe J;Won MH;Kwon YG;Kim YM
血清剥夺或戒断诱导内皮细胞凋亡，导致与心血管疾病相关的内皮细胞功能障碍。然而，关于miRNA在血清剥夺诱导的细胞凋亡中的作用的信息仍然有限。我们发现，血清剥夺通过miRNA-101- 3 p下调增加caspase依赖性凋亡，而不改变其宿主基因RNA 3′-末端磷酸环化酶样1的表达，这与Dicer和Argonaute 2（Ago 2）的表达水平抑制高度相关，表明miR-101- 3 p在血清剥夺条件下转录后升高。miR-101- 3 p的下调通过靶向其3′-非翻译区（3′-UTR）引起Bim表达的升高。这导致通过与Bcl-2相互作用激活细胞凋亡的内在途径，降低线粒体膜电位，细胞色素c释放，线粒体活性氧（ROS）产生和caspase激活。这些事件被miR-101- 3 p模拟物和促凋亡Bim siRNA消除，这表明miR-101- 3 p/Bim轴在血清剥夺诱导的细胞凋亡中的决定性作用。由miR-101- 3 p介导的Bim表达诱导的细胞凋亡由caspase-3和-1介导，其分别由两种不同的内在机制激活，细胞色素c释放和ROS诱导的炎性小体激活。换句话说，抗氧化剂抑制由激活caspase-7的caspase-1介导的内皮细胞死亡，但不抑制caspase-3。这些发现提供了对miR-101- 3 p在通过激活两种不同的内在或线粒体凋亡途径触发的血清撤药诱导的凋亡中的新功能的机制性见解，暗示miR-101- 3 p作为限制与血管疾病相关的内皮细胞死亡的治疗靶点。
Serum deprivation or withdrawal induces apoptosis in endothelial cells, resulting in endothelial cell dysfunction that is associated with cardiovascular disease. However, there is still limited information on the role of miRNA in serum deprivation-induced apoptosis. Here we found that serum deprivation increased caspase-dependent apoptosis through miRNA-101-3p downregulation, without altering expression of its host gene RNA 3′-terminal phosphate cyclase-like 1, which was highly correlated with suppressed expression levels of Dicer and Argonaute 2 (Ago2), indicating that miR-101-3p is post-transcriptionally elevated in serum-deprived conditions. The decreased miR-101-3p caused elevated Bim expression by targeting its 3′-untranslated region (3′-UTR). This resulted in activation of the intrinsic pathway of apoptosis via interaction with Bcl-2, decreased mitochondrial membrane potential, cytochrome c release, mitochondrial reactive oxygen species (ROS) production, and caspase activation. These events were abrogated by miR-101-3p mimic and the proapoptotic Bim siRNA, which suggest a determinant role of the miR-101-3p/Bim axis in serum deprivation-induced apoptosis. The apoptosis induced by miR-101-3p-mediated Bim expression is mediated by both caspase-3 and -1, which are activated by two distinct intrinsic mechanisms, cytochrome c release and ROS-induced inflammasome activation, respectively. In other words, the antioxidant inhibited endothelial cell death mediated by caspase-1 that activated caspase-7, but not caspase-3. These findings provide mechanistic insight into a novel function of miR-101-3p in serum withdrawal-induced apoptosis triggered by activating two different intrinsic or mitochondrial apoptosis pathways, implicating miR-101-3p as a therapeutic target that limits endothelial cell death associated with vascular disorders.
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