Long Noncoding RNA <i>MIAT</i> Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization.

Abstract

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 (<i>MIAT</i>) 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 <i>MIAT</i> 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 <i>MIAT</i>, 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. <i>MIAT</i> mechanistically regulated SMC proliferation through the EGR1 (Early Growth Response 1)-ELK1 (ETS Transcription Factor ELK1)-ERK (Extracellular Signal-Regulated Kinase) pathway. <i>MIAT</i> is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of <i>KLF4</i> and enhancing its transcription. Studies using <i>Miat</i>^-/- and <i>Miat</i>^-/-<i>ApoE</i>^-/- mice, and Yucatan <i>LDLR</i>^-/- mini-pigs, as well, confirmed the regulatory role of this lncRNA in SMC de- and transdifferentiation and advanced atherosclerotic lesion formation. The lncRNA <i>MIAT</i> 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.