LncRNA-ES3 inhibition by Bhlhe40 is involved in high glucose-induced calcification/senescence of vascular smooth muscle cells
LncRNA-ES3 inhibition by Bhlhe40 is involved in high glucose-induced calcification/senescence of vascular smooth muscle cells
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Bhlhe40 抑制 LncRNA-ES3 参与高糖诱导的血管平滑肌细胞钙化/衰老
DOI：
10.1111/nyas.14381
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发表时间：
2020-06-01
影响因子：
5.2
通讯作者：
Liu, You-Shuo
中科院分区：
文献类型：
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作者：
Zhong, Jia-Yu;Cui, Xing-Jun;Liu, You-Shuo
长链非编码RNA（lncRNAs）已作为参与多种生物过程的新型调控分子被深入研究。我们之前的研究表明，lncRNA - ES3与高糖诱导的人主动脉血管平滑肌细胞（HA - VSMCs）钙化/衰老相关。然而，lncRNA - ES3在血管钙化/衰老中的作用机制在很大程度上仍不明确。在此，我们报告称，在高糖处理的HA - VSMCs中，碱性螺旋 - 环 - 螺旋家族成员e40（Bhlhe40）的表达显著降低，而碱性亮氨酸拉链转录因子（BATF）的表达则升高。茜素红S染色以及衰老相关β - 半乳糖苷酶阳性细胞的检测结果证实，过表达Bhlhe40和抑制BATF可减轻HA - VSMCs的钙化/衰老。此外，我们发现Bhlhe40通过与lncRNA - ES3基因（LINC00458）的启动子区域结合，在HA - VSMCs中调控lncRNA - ES3。上调或抑制lncRNA - ES3的表达，分别会显著促进或减轻HA - VSMCs的钙化/衰老。另外，我们还发现lncRNA - ES3在这一过程中通过抑制miR - 95 - 5p、miR - 6776 - 5p、miR - 3620 - 5p和miR - 4747 - 5p的表达发挥作用。研究结果表明，lncRNA - ES3通过与Bhlhe40结合，引发多种微小RNA（miRNA）的基因沉默，从而导致血管平滑肌细胞钙化/衰老。我们的研究结果提示，以lncRNA - ES3为靶点的药物干预措施，可能对改善血管钙化/衰老具有治疗益处。
Long noncoding RNAs (lncRNAs) have been investigated as novel regulatory molecules involved in diverse biological processes. Our previous study demonstrated that lncRNA-ES3 is associated with the high glucose-induced calcification/senescence of human aortic vascular smooth muscle cells (HA-VSMCs). However, the mechanism of lncRNA-ES3 in vascular calcification/aging remained largely unknown. Here, we report that the expression of basic helix-loop-helix family member e40 (Bhlhe40) was decreased significantly in HA-VSMCs treated with high glucose, whereas the expression of basic leucine zipper transcription factor (BATF) was increased. Overexpression of Bhlhe40 and inhibition of BATF alleviated calcification/senescence of HA-VSMCs, as confirmed by Alizarin Red S staining and the presence of senescence-associated beta-galactosidase-positive cells. Moreover, we identified that Bhlhe40 regulates lncRNA-ES3 in HA-VSMCs by binding to the promoter region of the lncRNA-ES3 gene (LINC00458). Upregulation or inhibition of lncRNA-ES3 expression significantly promoted or reduced calcification/senescence of HA-VSMCs, respectively. Additionally, we identified that lncRNA-ES3 functions in this process by suppressing the expression of miR-95-5p, miR-6776-5p, miR-3620-5p, and miR-4747-5p. The results demonstrate that lncRNA-ES3 triggers gene silencing of multiple miRNAs by binding to Bhlhe40, leading to calcification/senescence of VSMCs. Our findings suggest that pharmacological interventions targeting lncRNA-ES3 may be therapeutically beneficial in ameliorating vascular calcification/aging.