title: Twist1 promotes heart valve cell proliferation and extracellular matrix gene expression during development in vivo and is expressed in human diseased aortic valves.
abstract: During embryogenesis the heart valves develop from undifferentiated mesenchymal endocardial cushions (EC), and activated interstitial cells of adult diseased valves share characteristics of embryonic valve progenitors. Twist1, a class II basic-helix-loop-helix (bHLH) transcription factor, is expressed during early EC development and is down-regulated later during valve remodeling. The requirements for Twist1 down-regulation in the remodeling valves and the consequences of prolonged Twist1 activity were examined in transgenic mice with persistent expression of Twist1 in developing and mature valves. Persistent Twist1 expression in the remodeling valves leads to increased valve cell proliferation, increased expression of Tbx20, and increased extracellular matrix (ECM) gene expression, characteristic of early valve progenitors. Among the ECM genes predominant in the EC, Col2a1 was identified as a direct transcriptional target of Twist1. Increased Twist1 expression also leads to dysregulation of fibrillar collagen and periostin expression, as well as enlarged hypercellular valve leaflets prior to birth. In human diseased aortic valves, increased Twist1 expression and cell proliferation are observed adjacent to nodules of calcification. Overall, these data implicate Twist1 as a critical regulator of valve development and suggest that Twist1 influences ECM production and cell proliferation during disease.
authors.affiliation: The Heart Institute, Cincinnati Children's Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Santanu
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Wirrig
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hinton
authors.forename: Walter H
authors.initials: WH
authors.lastname: Merrill
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Spicer
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002114:Calcinosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006349:Heart Valve Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; C103173:TWIST1 protein, human; C486013:Tbx20 protein, mouse; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
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