The PGC-1α/NRF1/miR-378a axis protects vascular smooth muscle cells from FFA-induced proliferation, migration and inflammation in atherosclerosis
The PGC-1α/NRF1/miR-378a axis protects vascular smooth muscle cells from FFA-induced proliferation, migration and inflammation in atherosclerosis
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PGC-1α/NRF1/miR-378a 轴保护血管平滑肌细胞免受 FFA 诱导的动脉粥样硬化增殖、迁移和炎症的影响
DOI：
10.1016/j.atherosclerosis.2020.02.001
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发表时间：
2020-03-01
期刊：
影响因子：
5.3
通讯作者：
Wang, Dongjin
中科院分区：
文献类型：
--
作者：
Chong, Hoshun;Wei, Zhe;Wang, Dongjin
背景与目的：动脉粥样硬化（Atherosclerosis，AS）是心血管疾病的主要病因。PGC-1 α是细胞能量稳态的关键调节因子，但其在AS中的作用仍然存在争议。方法和结果：在我们的研究中，PGC-1 α被证明是显着降低在人类动脉粥样硬化血管的媒体。为了探索血管平滑肌细胞（VSMC）中miRNA是否可能受PGC-1 α调节，进行了微阵列分析。微阵列和Pearson相关分析显示，PGC-1 alpha和miR-378a在体内和体外均呈正相关。作为上游共激活因子，PGC-1 α被发现通过与VSMC中的转录因子NRF1结合来调节miR-378 a。因此，PGC-1 α表达的降低可能是AS中VSMCs中miR-378 a抑制的原因。此外，IGF1和TLR8这两个已知在致动脉粥样硬化血管中异常上调的基因被鉴定为miR-378a的直接靶点。miR-378a在体外可通过靶向IGF1和TLR8抑制游离脂肪酸（free fatty acid，FFA）诱导的VSMC增殖、迁移和炎症反应。结论：PGC-1 alpha/NRF1/miR-378a调控轴在AS的发生发展中具有保护作用，提示miR-378a可能是治疗AS的潜在靶点。
Background and aims: Atherosclerosis (AS) is the leading cause of cardiovascular diseases. PGC-1 alpha is a key regulator of cellular energy homeostasis, but its role in AS remains debatable.Methods and results: In our study, PGC-1 alpha was shown to be significantly decreased in the media of human atherosclerotic vessels. To explore whether miRNAs might be regulated by PGC-1 alpha in vascular smooth muscle cells (VSMCs), microarray analysis was performed. Microarray and Pearson's correlation analysis showed that PGC-1 alpha and miR-378a were positively correlated in vivo and in vitro. As an upstream co-activator, PGC-1 alpha was found to regulate miR-378a through binding to the transcriptional factor NRF1 in VSMCs. Therefore, the decreased expression of PGC-1 alpha might account for suppression of miR-378a in VSMCs in AS. Furthermore, IGF1 and TLR8, two genes known to be aberrantly up-regulated in atherogenic vessels, were identified as direct targets of miR-378a. In vitro up-regulation of miR-378a markedly inhibited free fatty acid (FFA)-induced VSMC proliferation, migration and inflammation through targeting IGF1 and TLR8.Conclusions: These findings highlight the protective role of the PGC-1 alpha/NRF1/miR-378a regulatory axis in AS progression and suggest miR-378a as potential therapeutic target for AS treatment.