Background: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.Methods: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.Results: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.Conclusions: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.

中文翻译：

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长链非编码 RNA MIAT 控制先进的动脉粥样硬化病变形成和斑块不稳定

背景：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剂。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。与非动脉粥样硬化对照动脉相比，lncRNA MIAT被鉴定为颈动脉斑块中上调最多的非编码 RNA 转录物，这通过定量实时聚合酶链反应和原位杂交证实。 结果：MIAT 的实验性敲低，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（SMCs）的增殖和迁移率，而且增加了它们的凋亡。MIAT通过 EGR1（早期生长反应 1）-ELK1（ETS 转录因子 ELK1）-ERK（细胞外信号调节激酶）途径机械调节 SMC 增殖。MIAT通过与KLF4的启动子区域结合并增强其转录，进一步参与了 SMC 表型向促炎巨噬细胞样细胞的转变。使用Miat ^–/–和Miat ^–/– ApoE ^–/–小鼠和尤卡坦LDLR 的研究^{- / -}微型猪，以及，确认这lncRNA在SMC的调节作用和去转和先进的粥样硬化病变formation.Conclusions：该lncRNA MIAT是在动脉粥样硬化先进细胞过程的一个新的调节控制增殖，凋亡，和 SMC 的表型转变，以及巨噬细胞的促炎特性。