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J Biol Chem. 2019 Mar 15;294(11):3881-3898. doi: 10.1074/jbc.RA118.005050. Epub 2019 Jan 17.

Long noncoding RNA ANRIL regulates endothelial cell activities associated with coronary artery disease by up-regulating CLIP1, EZR, and LYVE1 genes.

Cho H1,2,3, Shen GQ2,3, Wang X4, Wang F2,3, Archacki S2,3, Li Y2,3, Yu G2,3,5, Chakrabarti S2,3, Chen Q6,3, Wang QK7,2,3,5.

Author information

1
From the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106.
2
the Departments of Cardiovascular and Metabolic Sciences and.
3
the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and.
4
Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
5
the Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan 430073, China.
6
the Departments of Cardiovascular and Metabolic Sciences and chenq3@ccf.org.
7
From the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, wangq2@ccf.org.

Abstract

Coronary artery disease (CAD) is the leading cause of death worldwide. Long noncoding RNAs (lncRNAs) are a class of noncoding transcripts of > 200 nucleotides and are increasingly recognized as playing functional roles in physiology and disease. ANRIL is an lncRNA gene mapped to the chromosome 9p21 genetic locus for CAD identified by the first series of genome-wide association studies (GWAS). However, ANRIL's role in CAD and the underlying molecular mechanism are unknown. Here, we show that the major ANRIL transcript in endothelial cells (ECs) is DQ485454 with a much higher expression level in ECs than in THP-1 monocytes. Of note, DQ485454 expression was down-regulated in CAD coronary arteries compared with non-CAD arteries. DQ485454 overexpression significantly reduced monocyte adhesion to ECs, transendothelial monocyte migration (TEM), and EC migration, which are critical cellular processes involved in CAD initiation, whereas siRNA-mediated ANRIL knockdown (KD) had the opposite effect. Microarray and follow-up quantitative RT-PCR analyses revealed that the ANRIL KD down-regulated expression of AHNAK2, CLIP1, CXCL11, ENC1, EZR, LYVE1, WASL, and TNFSF10 genes and up-regulated TMEM100 and TMEM106B genes. Mechanistic studies disclosed that overexpression of CLIP1, EZR, and LYVE1 reversed the effects of ANRIL KD on monocyte adhesion to ECs, TEM, and EC migration. These findings indicate that ANRIL regulates EC functions directly related to CAD, supporting the hypothesis that ANRIL is involved in CAD pathogenesis at the 9p21 genetic locus and identifying a molecular mechanism underlying lncRNA-mediated regulation of EC function and CAD development.

KEYWORDS:

ANRIL (CDKN2B-AS1); CLIP1 (CLIP-170); EZR (ezrin); LYVE1 (LYVE-1); cell adhesion; coronary artery disease; endothelial cell; gene regulation; long noncoding RNA (long ncRNA, lncRNA); monocyte adhesion; transendothelial migration of monocytes (TEM)

PMID:
30655286
PMCID:
PMC6422082
[Available on 2020-03-15]
DOI:
10.1074/jbc.RA118.005050
[Indexed for MEDLINE]

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