PMID- 30655286 OWN - NLM STAT- MEDLINE DCOM- 20190530 LR - 20210402 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 294 IP - 11 DP - 2019 Mar 15 TI - Long noncoding RNA ANRIL regulates endothelial cell activities associated with coronary artery disease by up-regulating CLIP1, EZR, and LYVE1 genes. PG - 3881-3898 LID - 10.1074/jbc.RA118.005050 [doi] AB - 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. CI - (c) 2019 Cho et al. FAU - Cho, Hyosuk AU - Cho H AD - From the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106. AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Shen, Gong-Qing AU - Shen GQ AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Wang, Xiaofeng AU - Wang X AD - Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195. FAU - Wang, Fan AU - Wang F AUID- ORCID: 0000-0001-9806-5037 AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Archacki, Stephen AU - Archacki S AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Li, Yabo AU - Li Y AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Yu, Gang AU - Yu G AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. AD - 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. FAU - Chakrabarti, Susmita AU - Chakrabarti S AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Chen, Qiuyun AU - Chen Q AD - the Departments of Cardiovascular and Metabolic Sciences and chenq3@ccf.org. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. FAU - Wang, Qing Kenneth AU - Wang QK AUID- ORCID: 0000-0002-2235-6572 AD - From the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, wangq2@ccf.org. AD - the Departments of Cardiovascular and Metabolic Sciences and. AD - the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and. AD - 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. LA - eng GR - R01 HL121358/HL/NHLBI NIH HHS/United States GR - R01 HL126729/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190117 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (CDKN2B antisense RNA, human) RN - 0 (Cytoskeletal Proteins) RN - 0 (LYVE1 protein, human) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Long Noncoding) RN - 0 (RNA, Small Interfering) RN - 0 (Vesicular Transport Proteins) RN - 0 (ezrin) RN - 148349-95-5 (cytoplasmic linker protein 170) SB - IM EIN - J Biol Chem. 2019 May 31;294(22):8715. PMID: 31152096 MH - Cell Movement MH - Cells, Cultured MH - Coronary Artery Disease/*metabolism/*pathology MH - Cytoskeletal Proteins/genetics/*metabolism MH - Endothelial Cells/*metabolism MH - Humans MH - Microtubule-Associated Proteins/genetics/*metabolism MH - Middle Aged MH - Neoplasm Proteins/genetics/*metabolism MH - RNA, Long Noncoding/antagonists & inhibitors/genetics/*metabolism MH - RNA, Small Interfering/pharmacology MH - Reverse Transcriptase Polymerase Chain Reaction MH - *Up-Regulation MH - Vesicular Transport Proteins/genetics/*metabolism PMC - PMC6422082 OTO - NOTNLM OT - ANRIL (CDKN2B-AS1) OT - CLIP1 (CLIP-170) OT - EZR (ezrin) OT - LYVE1 (LYVE-1) OT - cell adhesion OT - coronary artery disease OT - endothelial cell OT - gene regulation OT - long noncoding RNA (long ncRNA, lncRNA) OT - monocyte adhesion OT - transendothelial migration of monocytes (TEM) COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2019/01/19 06:00 MHDA- 2019/05/31 06:00 PMCR- 2020/03/15 CRDT- 2019/01/19 06:00 PHST- 2018/07/25 00:00 [received] PHST- 2019/01/11 00:00 [revised] PHST- 2019/01/19 06:00 [pubmed] PHST- 2019/05/31 06:00 [medline] PHST- 2019/01/19 06:00 [entrez] PHST- 2020/03/15 00:00 [pmc-release] AID - S0021-9258(20)41803-4 [pii] AID - RA118.005050 [pii] AID - 10.1074/jbc.RA118.005050 [doi] PST - ppublish SO - J Biol Chem. 2019 Mar 15;294(11):3881-3898. doi: 10.1074/jbc.RA118.005050. Epub 2019 Jan 17.