TY - JOUR
T1 - MicroRNA-23 restricts cardiac valve formation by inhibiting Has2 and extracellular hyaluronic acid production
AU - Lagendijk, A.K.
AU - Goumans, M.J.
AU - Burkhard, S.B.
AU - Bakkers, J.
N1 - Reporting year: 2011
PY - 2011
Y1 - 2011
N2 - RATIONALE: Since their discovery almost 20 years ago, microRNAs have been shown to perform essential roles during tissue development and disease. Although roles for microRNAs in the myocardium during embryo development and cardiac disease have been demonstrated, very little is know about their role in the endocardium or during cardiac valve formation. OBJECTIVE: To study the role of microRNAs in cardiac valve formation. METHODS AND RESULTS: We show that zebrafish dicer mutant embryos, lacking mature miRNAs, form excessive endocardial cushions. By screening miRNAs expressed in the heart, we found that miR-23 is both necessary and sufficient for restricting the number of endocardial cells that differentiate into endocardial cushion cells. In addition, in mouse endothelial cells, miR-23 inhibited a transforming growth factor-beta-induced endothelial-to-mesenchymal transition. By in silico screening of expression data with predicted miR-23 target sites combined with in vivo testing, we identified hyaluronic acid synthase 2 (Has2), Icat, and Tmem2 as novel direct targets of miR-23. Finally, we demonstrate that the upregulation of Has2, an extracellular remodeling enzyme required for endocardial cushion and valve formation, is responsible for the excessive endocardial cushion cell differentiation in dicer mutants. CONCLUSIONS: MiR-23 in the embryonic heart is required to restrict endocardial cushion formation by inhibiting Has2 expression and extracellular hyaluronic acid production. [KEYWORDS: Animals, Animals, Genetically Modified, Cell Count, Cell Differentiation, Cells, Cultured, Endocardial Cushions/cytology/metabolism, Extracellular Fluid/ metabolism, Glucuronosyltransferase/antagonists & inhibitors/ biosynthesis, Heart Valves/ embryology/ metabolism, Hyaluronic Acid/antagonists & inhibitors/ biosynthesis, Mice, MicroRNAs/ physiology, Zebrafish, Zebrafish Proteins/antagonists & inhibitors/ biosynthesis]
AB - RATIONALE: Since their discovery almost 20 years ago, microRNAs have been shown to perform essential roles during tissue development and disease. Although roles for microRNAs in the myocardium during embryo development and cardiac disease have been demonstrated, very little is know about their role in the endocardium or during cardiac valve formation. OBJECTIVE: To study the role of microRNAs in cardiac valve formation. METHODS AND RESULTS: We show that zebrafish dicer mutant embryos, lacking mature miRNAs, form excessive endocardial cushions. By screening miRNAs expressed in the heart, we found that miR-23 is both necessary and sufficient for restricting the number of endocardial cells that differentiate into endocardial cushion cells. In addition, in mouse endothelial cells, miR-23 inhibited a transforming growth factor-beta-induced endothelial-to-mesenchymal transition. By in silico screening of expression data with predicted miR-23 target sites combined with in vivo testing, we identified hyaluronic acid synthase 2 (Has2), Icat, and Tmem2 as novel direct targets of miR-23. Finally, we demonstrate that the upregulation of Has2, an extracellular remodeling enzyme required for endocardial cushion and valve formation, is responsible for the excessive endocardial cushion cell differentiation in dicer mutants. CONCLUSIONS: MiR-23 in the embryonic heart is required to restrict endocardial cushion formation by inhibiting Has2 expression and extracellular hyaluronic acid production. [KEYWORDS: Animals, Animals, Genetically Modified, Cell Count, Cell Differentiation, Cells, Cultured, Endocardial Cushions/cytology/metabolism, Extracellular Fluid/ metabolism, Glucuronosyltransferase/antagonists & inhibitors/ biosynthesis, Heart Valves/ embryology/ metabolism, Hyaluronic Acid/antagonists & inhibitors/ biosynthesis, Mice, MicroRNAs/ physiology, Zebrafish, Zebrafish Proteins/antagonists & inhibitors/ biosynthesis]
U2 - 10.1161/CIRCRESAHA.111.247635
DO - 10.1161/CIRCRESAHA.111.247635
M3 - Article
SN - 0009-7330
VL - 109
SP - 649
EP - 657
JO - Circulation Research
JF - Circulation Research
IS - 6
ER -