Long noncoding RNA ZNF800 suppresses proliferation and migration of vascular smooth muscle cells by upregulating PTEN and inhibiting AKT/mTOR/HIF-1α signaling
Long noncoding RNA ZNF800 suppresses proliferation and migration of vascular smooth muscle cells by upregulating PTEN and inhibiting AKT/mTOR/HIF-1α signaling
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DOI：
10.1016/j.atherosclerosis.2020.09.007
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发表时间：
2020-11-01
期刊：
影响因子：
5.3
通讯作者：
Wang, Qian
中科院分区：
文献类型：
--
作者：
Lu, Yuan-Bin;Shi, Chao;Wang, Qian
背景和目标：长链非编码RNA（lncRNA）参与了许多生物学和疾病过程，但其参与动脉粥样硬化的确切机制尚不清楚。血管平滑肌细胞（VSMCs）的异常增殖和迁移是动脉粥样硬化病变发展的主要原因。本研究旨在研究lncRNA ZNF 800（一种以前未表征的lncRNA）对VSMC增殖和迁移的潜在影响。采用逆转录-定量PCR（RT-qPCR）检测lncRNA ZNF 800在动脉粥样硬化斑块组织中的表达，采用CCK 8法、transwell法、结果：lncRNA ZNF 800在动脉粥样硬化斑块组织中的表达量明显增加，并显著抑制VSMCs的增殖和迁移。LncRNA ZNF 800对10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）mRNA表达没有影响，但显著增加了PTEN蛋白水平。增强的lncRNA ZNF 800表达抑制AKT/mTOR/HIF-1 α信号通路的活性，下调血管内皮生长因子α（VEGF-α）和基质金属蛋白酶1（MMP 1）的表达，并抑制VSMC增殖和迁移。这些抑制作用的lncRNA ZNF 800被取消的敲除的PTEN。lncRNA ZNF 800对细胞增殖和迁移以及VSMC中VEGF-alpha和MMP 1表达的抑制作用因VSMC中HIF-1 alpha的敲低而加剧。结论：这些发现表明lncRNA ZNF 800通过AKT/mTOR/HIF-1 alpha信号传导机制与PTEN相互作用，抑制VSMC增殖和迁移。因此，它可能发挥关键的动脉粥样硬化保护作用，并代表了动脉粥样硬化相关疾病的潜在治疗靶点。
Background and aims: Long noncoding RNAs (lncRNAs) have recently been implicated in many biological and disease processes, but the exact mechanism of their involvement in atherosclerosis is unclear. The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic lesions. This study aimed to investigate the potential effects of lncRNA ZNF800, a previously uncharacterized lncRNA, on VSMC proliferation and migration.Methods: The expression of lncRNA ZNF800 in atherosclerotic plaque tissues was detected using reverse transcription-quantitative PCR (RT-qPCR), while the role and mechanism of lncRNA ZNF800 in proliferation and migration of VSMCs were investigated by CCK8 assay, transwell assay, scratch wound assay, RT-qPCR and Western blot.Results: We found that lncRNA ZNF800 was significantly more abundant in atherosclerotic plaque tissues, and substantially suppressed the proliferation and migration of VSMCs. LncRNA ZNF800 had no effect on phosphatase and tensin homolog deleted on chromosome 10 (PTEN) mRNA expression but dramatically increased the levels of PTEN protein. Enhanced lncRNA ZNF800 expression inhibited the activity of the AKT/mTOR/HIF-1 alpha signaling pathway, downregulated the expression of vascular endothelial growth factor alpha (VEGF-alpha) and matrix metalloproteinase 1 (MMP1), and suppressed VSMC proliferation and migration. These inhibitory effects of lncRNA ZNF800 were abolished by knockdown of PTEN. The inhibitory effects of lncRNA ZNF800 on cell proliferation and migration and the expression of VEGF-alpha and MMP1 were exacerbated by HIF-1 alpha knockdown in VSMCs.Conclusions: These findings demonstrated that lncRNA ZNF800 suppressed VSMC proliferation and migration by interacting with PTEN through a mechanism involving AKT/mTOR/HIF-1 alpha signaling. Therefore, it may play a key atheroprotective role and represent a potential therapeutic target for atherosclerosis-related diseases.