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• W2742090168 abstract "The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus. The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus. New sequencing technologies, combined with bioinformatics and computational tools, have allowed the scientific community to appreciate the great complexity of the transcriptome.1Ozsolak F. Milos P.M. RNA sequencing: advances, challenges and opportunities.Nat. Rev. Genet. 2011; 12: 87-98Crossref PubMed Scopus (1132) Google Scholar In particular, the discovery of various types of non-protein coding RNAs (ncRNAs) and their different functions in regulating developmental and disease processes is expanding our knowledge of molecular biology and could significantly advance therapeutic options for many patients, including those suffering from cardiovascular disease. Thousands of ncRNAs have been described and classified into two large groups: small ncRNAs, which are up to 200 nucleotides long, and long non-coding RNAs (lncRNAs), which are longer than 200 nucleotides. lncRNAs are a heterogeneous group of transcripts exerting major regulatory roles in gene expression, and their importance in cardiovascular disease has been reinforced.2Devaux Y. Zangrando J. Schroen B. Creemers E.E. Pedrazzini T. Chang C.P. Dorn 2nd, G.W. Thum T. Heymans S. Cardiolinc networkLong noncoding RNAs in cardiac development and ageing.Nat. Rev. Cardiol. 2015; 12: 415-425Crossref PubMed Google Scholar, 3Bär C. Chatterjee S. Thum T. Long noncoding RNAs in cardiovascular pathology, diagnosis, and therapy.Circulation. 2016; 134: 1484-1499Crossref PubMed Scopus (87) Google Scholar The dynamic expression and specific profiles of lncRNAs in different pathophysiological states suggest their functional relevance and potential to be used as non-invasive markers of disease and therapeutic targets.4Devaux Y. Transcriptome of blood cells as a reservoir of cardiovascular biomarkers.Biochim. Biophys. Acta. 2017; 1864: 209-216Crossref PubMed Scopus (1) Google Scholar, 5Boon R.A. Jaé N. Holdt L. Dimmeler S. Long noncoding RNAs: From clinical genetics to therapeutic targets?.J. Am. Coll. Cardiol. 2016; 67: 1214-1226Crossref PubMed Scopus (145) Google Scholar However, establishing the biological actions of each lncRNA is proving more complex than investigating microRNAs (miRNAs, the most popular class of small ncRNAs within the biomedical community). This is due to lncRNAs’ multiple modalities of action and their low conservation among vertebrates.6Johnsson P. Lipovich L. Grandér D. Morris K.V. Evolutionary conservation of long non-coding RNAs; sequence, structure, function.Biochim. Biophys. Acta. 2014; 1840: 1063-1071Crossref PubMed Scopus (309) Google Scholar Therefore, a large gap remains between the number of lncRNAs identified, and then listed in databases, and their functional characterization and implications in pathophysiological situations. A list of databases and their major characteristics, such as number of lncRNAs, species, and association with function and other genes, is given in Table 1.Table 1List of Available Databases on lncRNAsDatabaseWhatSpeciesNo. of lncRNAsLast UpdateAssociation with FunctionAssociation with Protein-Coding RNAsAssociation with miRNAsReferenceANGIOGENESin silico screening of protein-coding genes and lncRNAs in ECshuman, mouse, zebrafish24,382 (15,149 in human)2016X164Müller R. Weirick T. John D. Militello G. Chen W. Dimmeler S. Uchida S. ANGIOGENES: knowledge database for protein-coding and noncoding RNA genes in endothelial cells.Sci. Rep. 2016; 6: 32475Crossref PubMed Scopus (1) Google ScholarChIPBasetranscriptional regulation of lncRNA from ChIP-seq data1010,200 ChIP-seq datasets2016X165Zhou K.R. Liu S. Sun W.J. Zheng L.L. Zhou H. Yang J.H. Qu L.H. ChIPBase v2.0: decoding transcriptional regulatory networks of non-coding RNAs and protein-coding genes from ChIP-seq data.Nucleic Acids Res. 2017; 45: D43-D50Crossref PubMed Scopus (70) Google Scholar, 166Yang J.H. Li J.H. Jiang S. Zhou H. Qu L.H. ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-seq data.Nucleic Acids Res. 2013; 41: D177-D187Crossref PubMed Scopus (0) Google ScholardeepBaseidentification, annotation, and function prediction of lncRNAs from RNA-seq data14191,5472016X167Zheng L.L. Li J.H. Wu J. Sun W.J. Liu S. Wang Z.L. Zhou H. Yang J.H. Qu L.H. deepBase v2.0: identification, expression, evolution and function of small RNAs, lncRNAs and circular RNAs from deep-sequencing data.Nucleic Acids Res. 2016; 44: D196-D202Crossref PubMed Scopus (50) Google Scholar, 168Yang J.H. Shao P. Zhou H. Chen Y.Q. Qu L.H. deepBase: a database for deeply annotating and mining deep sequencing data.Nucleic Acids Res. 2010; 38: D123-D130Crossref PubMed Scopus (97) Google ScholarGENCODEmanually curated human and mouse lncRNA reference based on ENCODE projecthuman, mouse42,3022016169Mudge J.M. Harrow J. Creating reference gene annotation for the mouse C57BL6/J genome assembly.Mamm. Genome. 2015; 26: 366-378Crossref PubMed Scopus (105) Google Scholar, 170Harrow J. Frankish A. Gonzalez J.M. Tapanari E. Diekhans M. Kokocinski F. Aken B.L. Barrell D. Zadissa A. Searle S. et al.GENCODE: the reference human genome annotation for the ENCODE Project.Genome Res. 2012; 22: 1760-1774Crossref PubMed Scopus (2166) Google ScholarLincSNPannotated disease-associated SNPs in human lncRNAshuman244,5452016X171Ning S. Yue M. Wang P. Liu Y. Zhi H. Zhang Y. Zhang J. Gao Y. Guo M. Zhou D. et al.LincSNP 2.0: an updated database for linking disease-associated SNPs to human long non-coding RNAs and their TFBSs.Nucleic Acids Res. 2017; 45: D74-D78Crossref PubMed Scopus (0) Google ScholarLNCipediaannotated lncRNA sequences, structures, protein coding potential, and miRNA binding siteshuman118,7772016XX172Volders P.J. Verheggen K. Menschaert G. Vandepoele K. Martens L. Vandesompele J. Mestdagh P. An update on LNCipedia: a database for annotated human lncRNA sequences.Nucleic Acids Res. 2015; 43: D174-D180Crossref PubMed Scopus (207) Google Scholar, 173Volders P.J. Helsens K. Wang X. Menten B. Martens L. Gevaert K. Vandesompele J. Mestdagh P. LNCipedia: a database for annotated human lncRNA transcript sequences and structures.Nucleic Acids Res. 2013; 41: D246-D251Crossref PubMed Scopus (315) Google ScholarlncRNAdbcurated reference database of functionally annotated eukaryotic lncRNAs71295 (183 in human)2015X174Quek X.C. Thomson D.W. Maag J.L. Bartonicek N. Signal B. Clark M.B. Gloss B.S. Dinger M.E. lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs.Nucleic Acids Res. 2015; 43: D168-D173Crossref PubMed Google Scholar, 175Amaral P.P. Clark M.B. Gascoigne D.K. Dinger M.E. Mattick J.S. lncRNAdb: a reference database for long noncoding RNAs.Nucleic Acids Res. 2011; 39: D146-D151Crossref PubMed Scopus (398) Google ScholarLncRNADiseaseexperimentally supported and predicted associations between lncRNAs and diseaseshuman1,5642015X176Chen G. Wang Z. Wang D. Qiu C. Liu M. Chen X. Zhang Q. Yan G. Cui Q. LncRNADisease: a database for long-non-coding RNA-associated diseases.Nucleic Acids Res. 2013; 41: D983-D986Crossref PubMed Scopus (504) Google ScholarlncRNomeannotated human lncRNAshuman17,5472013XXX177Bhartiya D. Pal K. Ghosh S. Kapoor S. Jalali S. Panwar B. Jain S. Sati S. Sengupta S. Sachidanandan C. et al.lncRNome: a comprehensive knowledgebase of human long noncoding RNAs.Database (Oxford). 2013; 2013: bat034Crossref PubMed Scopus (0) Google ScholarNONCODEintegrated annotation of ncRNAs, especially lncRNAs16487,164 (167,150 in human)2016XX178Zhao Y. Li H. Fang S. Kang Y. Wu W. Hao Y. Li Z. Bu D. Sun N. Zhang M.Q. Chen R. NONCODE 2016: an informative and valuable data source of long non-coding RNAs.Nucleic Acids Res. 2016; 44: D203-D208Crossref PubMed Google ScholarChIP-seq, chromatin immunoprecipitation sequencing. Open table in a new tab ChIP-seq, chromatin immunoprecipitation sequencing. So far, it has been demonstrated that lncRNAs can regulate gene expression through functional mechanisms including epigenetic, transcriptional, and post-transcriptional, either activating or suppressing gene expression. lncRNAs can also mediate signaling, such as phosphorylation, and trafficking of proteins.7Willingham A.T. Orth A.P. Batalov S. Peters E.C. Wen B.G. Aza-Blanc P. Hogenesch J.B. Schultz P.G. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT.Science. 2005; 309: 1570-1573Crossref PubMed Scopus (529) Google Scholar, 8Wang P. Xue Y. Han Y. Lin L. Wu C. Xu S. Jiang Z. Xu J. Liu Q. Cao X. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation.Science. 2014; 344: 310-313Crossref PubMed Scopus (505) Google Scholar One way to classify lncRNAs is according to their mechanism of action: signal, decoy, guide, scaffold,9Wang K.C. Chang H.Y. Molecular mechanisms of long noncoding RNAs.Mol. Cell. 2011; 43: 904-914Abstract Full Text Full Text PDF PubMed Scopus (2095) Google Scholar enhancer, or sponge lncRNAs (particularly circular lncRNAs [circRNAs]) (Figure 1).10Ørom U.A. Derrien T. Beringer M. Gumireddy K. Gardini A. Bussotti G. Lai F. Zytnicki M. Notredame C. Huang Q. et al.Long noncoding RNAs with enhancer-like function in human cells.Cell. 2010; 143: 46-58Abstract Full Text Full Text PDF PubMed Scopus (1214) Google Scholar, 11Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen B. Damgaard C.K. Kjems J. Natural RNA circles function as efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref PubMed Scopus (2515) Google Scholar In this review, we do not address in detail the lncRNAs mechanisms of action but instead refer to reviews on the subject.2Devaux Y. Zangrando J. Schroen B. Creemers E.E. Pedrazzini T. Chang C.P. Dorn 2nd, G.W. Thum T. Heymans S. Cardiolinc networkLong noncoding RNAs in cardiac development and ageing.Nat. Rev. Cardiol. 2015; 12: 415-425Crossref PubMed Google Scholar, 12Quinn J.J. Chang H.Y. Unique features of long non-coding RNA biogenesis and function.Nat. Rev. Genet. 2016; 17: 47-62Crossref PubMed Scopus (988) Google Scholar, 13Zhang K. Shi Z.M. Chang Y.N. Hu Z.M. Qi H.X. Hong W. The ways of action of long non-coding RNAs in cytoplasm and nucleus.Gene. 2014; 547: 1-9Crossref PubMed Scopus (84) Google Scholar, 14Rashid F. Shah A. Shan G. Long non-coding RNAs in the cytoplasm.Genomics Proteomics Bioinformatics. 2016; 14: 73-80Crossref PubMed Scopus (115) Google Scholar A growing number of lncRNAs are implicated in cardiovascular development and disease, although it is not clearly understood how they participate in pathological processes. Their potential as therapeutic targets has often been raised, and there are a few examples of in vivo modulation of lncRNAs. However, modulating lncRNAs has been a challenging task to date.15Viereck J. Kumarswamy R. Foinquinos A. Xiao K. Avramopoulos P. Kunz M. Dittrich M. Maetzig T. Zimmer K. Remke J. et al.Long noncoding RNA Chast promotes cardiac remodeling.Sci. Transl. Med. 2016; 8: 326ra22Crossref PubMed Scopus (143) Google Scholar, 16Meng L. Ward A.J. Chun S. Bennett C.F. Beaudet A.L. Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA.Nature. 2015; 518: 409-412Crossref PubMed Scopus (188) Google Scholar, 17Michalik K.M. You X. Manavski Y. Doddaballapur A. Zörnig M. Braun T. John D. Ponomareva Y. Chen W. Uchida S. et al.Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth.Circ. Res. 2014; 114: 1389-1397Crossref PubMed Scopus (483) Google Scholar, 18Krieg A.M. Targeting LDL cholesterol with LNA.Mol. Ther. Nucleic Acids. 2012; 1: e6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19Wheeler T.M. Leger A.J. Pandey S.K. MacLeod A.R. Nakamori M. Cheng S.H. Wentworth B.M. Bennett C.F. Thornton C.A. Targeting nuclear RNA for in vivo correction of myotonic dystrophy.Nature. 2012; 488: 111-115Crossref PubMed Scopus (290) Google Scholar Here, we summarize the current understanding of lncRNA function in cardiovascular pathophysiology and discuss its potential for therapy. Transcriptomics profiling and loss-of-function approaches in progenitor and embryonic stem cells (ESCs) have demonstrated the importance of lncRNAs for cardiac development and cell differentiation. More than 1,000 lncRNAs were reported as being dynamically regulated during differentiation,20Guttman M. Donaghey J. Carey B.W. Garber M. Grenier J.K. Munson G. Young G. Lucas A.B. Ach R. Bruhn L. et al.lincRNAs act in the circuitry controlling pluripotency and differentiation.Nature. 2011; 477: 295-300Crossref PubMed Scopus (1306) Google Scholar, 21Ounzain S. Pezzuto I. Micheletti R. Burdet F. Sheta R. Nemir M. Gonzales C. Sarre A. Alexanian M. Blow M.J. et al.Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease.J. Mol. Cell. Cardiol. 2014; 76: 55-70Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar and further transcriptome analyses of embryonic and adult-stage murine hearts identified several lncRNAs specific to tissue and developmental stage.22Matkovich S.J. Edwards J.R. Grossenheider T.C. de Guzman Strong C. Dorn 2nd, G.W. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs.Proc. Natl. Acad. Sci. USA. 2014; 111: 12264-12269Crossref PubMed Scopus (88) Google Scholar, 23Werber M. Wittler L. Timmermann B. Grote P. Herrmann B.G. The tissue-specific transcriptomic landscape of the mid-gestational mouse embryo.Development. 2014; 141: 2325-2330Crossref PubMed Google Scholar Among biologically validated lncRNAs, several have been associated with cardiac development (Table 2). For example, Braveheart (Bvht) has a critical role in cardiac lineage commitment in mouse. It is abundantly expressed in embryonic stem cells and regulates the transition from nascent mesoderm to cardiac progenitor.24Xue Z. Hennelly S. Doyle B. Gulati A.A. Novikova I.V. Sanbonmatsu K.Y. Boyer L.A. A G-rich motif in the lncRNA Braveheart interacts with a zinc-finger transcription factor to specify the cardiovascular lineage.Mol. Cell. 2016; 64: 37-50Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Bvht, by modulating the core cardiovascular gene network and mediating the epigenetic regulation of cardiac fate, is necessary to maintain cardiac commitment.25Klattenhoff C.A. Scheuermann J.C. Surface L.E. Bradley R.K. Fields P.A. Steinhauser M.L. Ding H. Butty V.L. Torrey L. Haas S. et al.Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.Cell. 2013; 152: 570-583Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar Conversely, the lateral mesoderm-specific lncRNA Fendrr (fetal-lethal non-coding developmental regulatory RNA) controls mesodermal differentiation, as well as heart and body wall development, by binding to the histone-remodeling polycomb repressive complex PRC2 and TrxG/MLL to modulate chromatin status.26Grote P. Wittler L. Hendrix D. Koch F. Währisch S. Beisaw A. Macura K. Bläss G. Kellis M. Werber M. Herrmann B.G. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse.Dev. Cell. 2013; 24: 206-214Abstract Full Text Full Text PDF PubMed Scopus (532) Google ScholarTable 2lcnRNAs Associated with Cardiovascular BiologylncRNAExpressionBiological ContextActionGenomic LocalizationOrganismReferenceDifferentiation and Cardiac DevelopmentBvhtembryonic stem cellscardiomyocyte differentiationsignalintergenicmouse24Xue Z. Hennelly S. Doyle B. Gulati A.A. Novikova I.V. Sanbonmatsu K.Y. Boyer L.A. A G-rich motif in the lncRNA Braveheart interacts with a zinc-finger transcription factor to specify the cardiovascular lineage.Mol. Cell. 2016; 64: 37-50Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 25Klattenhoff C.A. Scheuermann J.C. Surface L.E. Bradley R.K. Fields P.A. Steinhauser M.L. Ding H. Butty V.L. Torrey L. Haas S. et al.Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.Cell. 2013; 152: 570-583Abstract Full Text Full Text PDF PubMed Scopus (553) Google ScholarFendrrlateral plate mesodermdevelopment of heart and body wallsignalintergenichuman, mouse, rat26Grote P. Wittler L. Hendrix D. Koch F. Währisch S. Beisaw A. Macura K. Bläss G. Kellis M. Werber M. Herrmann B.G. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse.Dev. Cell. 2013; 24: 206-214Abstract Full Text Full Text PDF PubMed Scopus (532) Google ScholarNovlnc6embryonic stem cells (particularly left ventricle), cardiomyocytescardiac differentiation and maturationdecoyhuman, mouse27Ounzain S. Micheletti R. Beckmann T. Schroen B. Alexanian M. Pezzuto I. Crippa S. Nemir M. Sarre A. Johnson R. et al.Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.Eur. Heart J. 2015; 36 (353–68a)Crossref PubMed Scopus (57) Google ScholarCARMENcardiac precursor cellcardiomyocyte differentiation of cardiac precursor cellsenhancerintergenichuman, mouse, rat28Ounzain S. Micheletti R. Arnan C. Plaisance I. Cecchi D. Schroen B. Reverter F. Alexanian M. Gonzales C. Ng S.Y. et al.CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.J. Mol. Cell. Cardiol. 2015; 89: 98-112Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholarn411949embryonic heartcardiac developmentunknownantisensemouse22Matkovich S.J. Edwards J.R. Grossenheider T.C. de Guzman Strong C. Dorn 2nd, G.W. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs.Proc. Natl. Acad. Sci. USA. 2014; 111: 12264-12269Crossref PubMed Scopus (88) Google Scholarn413445embryonic heartcardiac developmentunknownintronicmouse22Matkovich S.J. Edwards J.R. Grossenheider T.C. de Guzman Strong C. Dorn 2nd, G.W. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs.Proc. Natl. Acad. Sci. USA. 2014; 111: 12264-12269Crossref PubMed Scopus (88) Google ScholarContractile FunctionKCNQ1OT1cardiac developmentsignalantisensehuman, mouse30Korostowski L. Sedlak N. Engel N. The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart.PLoS Genet. 2012; 8: e1002956Crossref PubMed Scopus (89) Google Scholarβ-RNAadult ventriclescontractile phenotype, pressure overloadunknownantisenserat33Haddad F. Bodell P.W. Qin A.X. Giger J.M. Baldwin K.M. Role of antisense RNA in coordinating cardiac myosin heavy chain gene switching.J. Biol. Chem. 2003; 278: 37132-37138Crossref PubMed Scopus (77) Google ScholarVascular DevelopmentSENCRsmooth muscle cellsmaintenance of smooth muscle cells’ differentiated statedecoyantisensehuman37Bell R.D. Long X. Lin M. Bergmann J.H. Nanda V. Cowan S.L. Zhou Q. Han Y. Spector D.L. Zheng D. Miano J.M. Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA.Arterioscler. Thromb. Vasc. Biol. 2014; 34: 1249-1259Crossref PubMed Scopus (159) Google Scholar, 38Boulberdaa M. Scott E. Ballantyne M. Garcia R. Descamps B. Angelini G.D. Brittan M. Hunter A. McBride M. McClure J. et al.A role for the long noncoding RNA SENCR in commitment and function of endothelial cells.Mol. Ther. 2016; 24: 978-990Abstract Full Text Full Text PDF PubMed Scopus (71) Google ScholarSMILRVSMCsproliferation of smooth muscle cellsproposed scaffold or enhancerintergenichuman39Ballantyne M.D. Pinel K. Dakin R. Vesey A.T. Diver L. Mackenzie R. Garcia R. Welsh P. Sattar N. Hamilton G. et al.Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation.Circulation. 2016; 133: 2050-2065Crossref PubMed Scopus (91) Google ScholarMALAT1ECsproliferation of ECs and vascularizationdecoyintergenichuman, mouse17Michalik K.M. You X. Manavski Y. Doddaballapur A. Zörnig M. Braun T. John D. Ponomareva Y. Chen W. Uchida S. et al.Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth.Circ. Res. 2014; 114: 1389-1397Crossref PubMed Scopus (483) Google ScholarPUNISHERECsidentity of ECsguideantisensehuman, mouse, zebrafish42Kurian L. Aguirre A. Sancho-Martinez I. Benner C. Hishida T. Nguyen T.B. Reddy P. Nivet E. Krause M.N. Nelles D.A. et al.Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development.Circulation. 2015; 131: 1278-1290Crossref PubMed Scopus (105) Google Scholar Open table in a new tab Numerous enhancer-associated lncRNAs have been implicated in cardiogenic differentiation,21Ounzain S. Pezzuto I. Micheletti R. Burdet F. Sheta R. Nemir M. Gonzales C. Sarre A. Alexanian M. Blow M.J. et al.Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease.J. Mol. Cell. Cardiol. 2014; 76: 55-70Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 27Ounzain S. Micheletti R. Beckmann T. Schroen B. Alexanian M. Pezzuto I. Crippa S. Nemir M. Sarre A. Johnson R. et al.Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.Eur. Heart J. 2015; 36 (353–68a)Crossref PubMed Scopus (57) Google Scholar among which the enhancer lncRNA Novlnc6 modulates expression of MKX2.5, a transcription factor critical for cardiac differentiation and maturation.27Ounzain S. Micheletti R. Beckmann T. Schroen B. Alexanian M. Pezzuto I. Crippa S. Nemir M. Sarre A. Johnson R. et al.Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.Eur. Heart J. 2015; 36 (353–68a)Crossref PubMed Scopus (57) Google Scholar CARMEN (cardiac mesoderm enhancer-associated non-coding RNA) is also responsible for cardiogenic specification and differentiation in precursor cells, possibly by regulating PRC2.28Ounzain S. Micheletti R. Arnan C. Plaisance I. Cecchi D. Schroen B. Reverter F. Alexanian M. Gonzales C. Ng S.Y. et al.CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.J. Mol. Cell. Cardiol. 2015; 89: 98-112Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Furthermore, several lncRNAs regulate specific mRNA abundance during heart development, although as yet there is no clear understanding of their role during cardiogenic differentiation. For example, n411949 regulates Mccc1 mRNA, which metabolizes leucine, and n413445 modulates ReIb, which is involved in the nuclear factor κB (NF-κB) pathway.22Matkovich S.J. Edwards J.R. Grossenheider T.C. de Guzman Strong C. Dorn 2nd, G.W. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs.Proc. Natl. Acad. Sci. USA. 2014; 111: 12264-12269Crossref PubMed Scopus (88) Google Scholar Overall, fetal gene program reactivation constitutes a hallmark in multiple cardiovascular diseases. Although a moderate number of dynamically regulated lncRNAs in embryonic cells are equally regulated in the hypertrophic heart,22Matkovich S.J. Edwards J.R. Grossenheider T.C. de Guzman Strong C. Dorn 2nd, G.W. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs.Proc. Natl. Acad. Sci. USA. 2014; 111: 12264-12269Crossref PubMed Scopus (88) Google Scholar some lncRNAs associated with cardiac pathologies may also be implicated in cardiac development.27Ounzain S. Micheletti R. Beckmann T. Schroen B. Alexanian M. Pezzuto I. Crippa S. Nemir M. Sarre A. Johnson R. et al.Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.Eur. Heart J. 2015; 36 (353–68a)Crossref PubMed Scopus (57) Google Scholar As for cell proliferation, a study identified eight lncRNAs putatively implicated in the proliferative capacity of cardiac cells in fetal heart29Wang J. Geng Z. Weng J. Shen L. Li M. Cai X. Sun C. Chu M. Microarray analysis reveals a potential role of lncRNAs expression in cardiac cell proliferation.BMC Dev. Biol. 2016; 16: 41Crossref PubMed Scopus (0) Google Scholar that require further investigation. Cardiomyocyte repolarization during the final stage of the action potential needs potassium fluxes mediated by the Kv7.1 channels. In late embryogenesis, lncRNA Kcnq1ot1 (potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1) regulates the expression of the transcript Kcnq1, which encodes the potassium channel Kv7.1.30Korostowski L. Sedlak N. Engel N. The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart.PLoS Genet. 2012; 8: e1002956Crossref PubMed Scopus (89) Google Scholar Such regulation fulfills the requirement for increased cardiac contractile activity in this late developmental stage. Dysregulation of KCNQ1OT1 expression has been associated with left ventricular (LV) dysfunction after myocardial infarction (MI),31Vausort M. Wagner D.R. Devaux Y. Long noncoding RNAs in patients with acute myocardial infarction.Circ. Res. 2014; 115: 668-677Crossref PubMed Google Scholar thereby potentially linking this lncRNA to cardiac contractility and arrhythmia in a clinical setting. A switch in myosin heavy chain (MHC) isoforms accompanies the acquisition of the adult cardiac contractile phenotype. The expression of α-MHC in adult left and right ventricles is associated with higher filament sliding velocity, while the slower β-MHC confers higher force at lower energy cost.32VanBuren P. Harris D.E. Alpert N.R. Warshaw D.M. Cardiac V1 and V3 myosins differ in their hydrolytic and mechanical activities in vitro.Circ. Res. 1995; 77: 439-444Crossref PubMed Google Scholar In rodent models (which mainly express the α-MHC isoform in the normal adult stage), the intergenic region between the two genes has been shown to regulate the transition from β- to α-MHC during cardiac development through co-transcription of an antisense RNA, called β-RNA, targeting and inhibiting the myosin heavy chain 7 (MYH7) transcript (encoding the β-MHC isoform).33Haddad F. Bodell P.W. Qin A.X. Giger J.M. Baldwin K.M. Role of antisense RNA in coordinating cardiac myosin heavy chain gene switching.J. Biol. Chem. 2003; 278: 37132-37138Crossref PubMed Scopus (77) Google Scholar, 34Reiser P.J. Portman M.A. Ning X.H. Schomisch Moravec C. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles.Am. J. Physiol. Heart Circ. Physiol. 2001; 280: H1814-H1820Crossref PubMed Google Scholar This mechanism is responsive to thyroid status and further implicated in the response to pressure overload.35Haddad F. Qin A.X. Bodell P.W. Jiang W. Giger J.M. Baldwin K.M. Intergenic transcription and developmental regulation of cardiac myosin heavy chain genes.Am. J. Physiol. Heart Circ. Physiol. 2008; 294: H29-H40Crossref PubMed Scopus (0) Google Scholar, 36Haddad F. Qin A.X. Bodell P.W. Zhang L.Y. Guo H. Giger J.M. Baldwin K.M. Regulation of antisense RNA expression during cardiac MHC gene switching in response to pressure overload.Am. J. Physiol. Heart Circ. Physiol. 2006; 290: H2351-H2361Crossref PubMed Scopus (0) Google Scholar Growing evidence describes lncRNAs as key molecular players of vascular and endothelial cell (EC) biology. SENCR (smooth muscle and EC-enriched migration/differentiation-associated lncRNA) was among the first lncRNAs to be identified in human vascular smooth muscle cells (VSMCs) and ECs, being involved in their differentiation.37Bell R.D. Long X. Lin M. Bergmann J.H. Nanda V. Cowan S.L. Zhou Q. Han Y. Spector D.L. Zheng D. Miano J.M. 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• W2742090168 date "2017-09-01" @default.
• W2742090168 modified "2023-10-16" @default.
• W2742090168 title "The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease" @default.
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