Twist1 promotes heart valve cell proliferation and extracellular matrix gene expression during development in vivo and is expressed in human diseased aortic valves

• Published in: Developmental biology Vol. 347; no. 1; pp. 167 - 179
• Main Authors: Chakraborty, Santanu, Wirrig, Elaine E., Hinton, Robert B., Merrill, Walter H., Spicer, Douglas B., Yutzey, Katherine E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2010
• Subjects: Animals; Animals, Newborn; Aortic valve disease; Base Sequence; bHLH transcription factor; Biomarkers - metabolism; Calcinosis - complications; Calcinosis - genetics; Calcinosis - pathology; Cardiomyopathies - complications; Cardiomyopathies - genetics; Cardiomyopathies - pathology; Cell Proliferation; Collagen Type II - genetics; Collagen Type II - metabolism; Extracellular matrix; Extracellular Matrix - enzymology; Extracellular Matrix - genetics; Gene Expression Regulation, Developmental; Heart valve development; Heart Valve Diseases - complications; Heart Valve Diseases - genetics; Heart Valve Diseases - pathology; Heart Valves - abnormalities; Heart Valves - embryology; Heart Valves - metabolism; Heart Valves - pathology; Humans; Introns - genetics; Mice; Molecular Sequence Data; Morphogenesis - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Binding; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, TIE-2; Regulatory Sequences, Nucleic Acid - genetics; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Twist1; Cell proliferation; Heart valve development; Extracellular matrix; Aortic valve disease; bHLH transcription factor; Twist1
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2010.08.021

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.