Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization.
Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization.
复制标题
长非编码RNA MIAT控制晚期动脉粥样硬化病变的形成和斑块的失稳。
DOI：
10.1161/circulationaha.120.052023
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发表时间：
2021-11-09
期刊：
影响因子：
37.8
通讯作者：
Maegdefessel L
中科院分区：
文献类型：
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作者：
Fasolo F;Jin H;Winski G;Chernogubova E;Pauli J;Winter H;Li DY;Glukha N;Bauer S;Metschl S;Wu Z;Koschinsky ML;Reilly M;Pelisek J;Kempf W;Eckstein HH;Soehnlein O;Matic L;Hedin U;Bäcklund A;Bergmark C;Paloschi V;Maegdefessel L
补充数字内容可在文本中找到。长链非编码RNA（lncRNA）是参与血管组织稳态和疾病发展的生物过程的重要调节因子。本研究评估了lncRNA心肌梗死相关转录物（MIAT）对动脉粥样硬化和颈动脉疾病的功能贡献。我们分析了来自Karolinska Endarterectomies生物样本库的晚期颈动脉粥样硬化病变患者的RNA转录表达差异。与非动脉粥样硬化对照动脉相比，lncRNA MIAT被确定为颈动脉斑块中上调最多的非编码RNA转录本，这是通过定量实时聚合酶链反应和原位杂交证实的。实验敲低MIAT，使用位点特异性反义寡核苷酸（LNA GapmeRs）不仅显着降低了培养的人颈动脉平滑肌细胞（SMC）的增殖和迁移率，但也增加了他们的凋亡。MIAT通过EGR 1（早期生长反应1）-ELK 1（ETS转录因子ELK 1）-ERK（细胞外信号调节激酶）途径机械调节SMC增殖。MIAT通过与KLF 4的启动子区结合并增强其转录，进一步参与SMC向促炎性巨噬细胞样细胞的表型转变。使用Miat-/-和Miat-/-ApoE-/-小鼠以及尤卡坦LDLR-/-小型猪的研究也证实了这种lncRNA在SMC去分化和转分化以及晚期动脉粥样硬化病变形成中的调节作用。lncRNA MIAT是晚期动脉粥样硬化中细胞过程的新型调节剂，其控制SMC的增殖、凋亡和表型转变，以及巨噬细胞的促炎特性。
Supplemental Digital Content is available in the text. Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The present study assessed the functional contribution of the lncRNA myocardial infarction-associated transcript (MIAT) to atherosclerosis and carotid artery disease. We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies. The lncRNA MIAT was identified as the most upregulated noncoding RNA transcript in carotid plaques compared with nonatherosclerotic control arteries, which was confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. Experimental knockdown of MIAT, using site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs) but also increased their apoptosis. MIAT mechanistically regulated SMC proliferation through the EGR1 (Early Growth Response 1)-ELK1 (ETS Transcription Factor ELK1)-ERK (Extracellular Signal-Regulated Kinase) pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat–/– and Miat–/–ApoE–/– mice, and Yucatan LDLR–/– mini-pigs, as well, confirmed the regulatory role of this lncRNA in SMC de- and transdifferentiation and advanced atherosclerotic lesion formation. The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs, and the proinflammatory properties of macrophages, as well.