title: LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity.
abstract: BACKGROUND
  Long noncoding RNAs (lncRNAs) have recently been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown.
  
  
  RESULTS
  We identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically downregulated in atherosclerotic plaques of ApoE(-/-) mice, an animal model for atherosclerosis. Through loss- and gain-of-function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in patients with coronary artery disease.
  
  
  CONCLUSIONS
  Our studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders.
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.|Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Gengze
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Zhan-Peng
authors.initials: ZP
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hefei
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yukai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zaicheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Duofen
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Heath, Boston, MA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Heath, Boston, MA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D058426:Neointima / Q000235:genetics* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D062085:RNA, Long Noncoding; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2 protein; RNA, long noncoding; apoptosis; atherosclerosis; cell proliferation; tumor suppressor protein p53