MicroRNA-19b/221/222 induces endothelial cell dysfunction via suppression of PGC-1α in the progression of atherosclerosis
MicroRNA-19b/221/222 induces endothelial cell dysfunction via suppression of PGC-1α in the progression of atherosclerosis
复制标题
MicroRNA-19b/221/222 通过抑制动脉粥样硬化进展中的 PGC-1α 诱导内皮细胞功能障碍。
DOI：
10.1016/j.atherosclerosis.2015.06.031
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发表时间：
2015-08-01
期刊：
影响因子：
5.3
通讯作者：
Jiang, Xiaohong
中科院分区：
文献类型：
--
作者：
Xue, Yunxing;Wei, Zhe;Jiang, Xiaohong
背景资料：过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）是细胞能量代谢的主要调节因子，与许多心血管疾病（包括动脉粥样硬化）相关。然而，PGC-1 α在动脉粥样硬化发病机制中的作用和潜在的调节机制尚未完全了解。在这里，我们确定了转录后调节PGC-1 α的生产和他们的角色在动脉粥样硬化的发病机制的microRNA。方法和结果：一个显着下调PGC-1 α蛋白在人类动脉粥样硬化血管样本中观察。通过基因芯片和生物信息学分析，发现PGC-1 α是miR-19 b-3 p、miR-221- 3 p和miR-222- 3 p的共同靶基因，主要定位于动脉粥样硬化血管内膜。通过炎性细胞因子TNF α和IFN γ对miR-19 b-3 p、miR-221- 3 p和miR-222- 3 p的体外诱导可能影响PGC-1 α蛋白的产生，并因此导致人主动脉内皮细胞（HAEC）中的线粒体功能障碍。miR-19 b3 p、miR-221- 3 p和miR-222- 3 p在HAECs中的过表达可引起细胞内ROS的积聚，进而导致细胞凋亡。结论：综上所述，这些结果表明PGC-1 α对动脉粥样硬化血管并发症具有保护作用。此外，miR-19 b/221/222对PGC-1 α的转录后调控机制也被揭示，这为一组microRNA通过调节线粒体功能调控内皮细胞凋亡提供了新的机制。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Background: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a master regulator of cellular energy metabolism that is associated with many cardiovascular diseases, including atherosclerosis. However, the role and underling regulatory mechanisms of PGC-1 alpha in the pathogenesis of atherosclerosis are not completely understood. Here, we identified the microRNAs that posttranscriptionally regulate PGC-1 alpha production and their roles in the pathogenesis of atherosclerosis.Methods and results: A significant down-regulation of PGC-1 alpha protein was observed in human atherosclerotic vessel samples. Using microarray and bioinformatics analyses, PGC-1 alpha was identified as a common target gene of miR-19b-3p, miR-221-3p and miR-222-3p, which are mainly located in the intima of atherosclerotic vessels. In vitro induction of miR-19b-3p, miR-221-3p and miR-222-3p by the inflammatory cytokines TNF alpha and IFN gamma may affect PGC-1 alpha protein production and consequently result in mitochondrial dysfunction in Human Aortic Endothelial Cells (HAECs). The overexpression of miR-19b3p, miR-221-3p and miR-222-3p in HAECs caused intracellular ROS accumulation, which led to cellular apoptosis.Conclusion: Taken together, these results demonstrate that PGC-1 alpha plays a protective role against the vascular complications of atherosclerosis. Moreover, the posttranscriptional regulation of PGC-1 alpha by miR-19b/221/222 was unveiled, which provides a novel mechanism in which a panel of microRNAs can modulate endothelial cell apoptosis via the regulation mitochondrial function. (C) 2015 Elsevier Ireland Ltd. All rights reserved.