The transcription factor NF-ATc is essential for cardiac valve formation

Nature ◽  
10.1038/32426 ◽  
1998 ◽  
Vol 392 (6672) ◽  
pp. 186-190 ◽  
Author(s):  
Ann M. Ranger ◽  
Michael J. Grusby ◽  
Martin R. Hodge ◽  
Ellen M. Gravallese ◽  
Fabienne Charles de la Brousse ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cardiac Valve ◽  
Valve Formation

scholarly journals Protein Kinase D2 Controls Cardiac Valve Formation in Zebrafish by Regulating Histone Deacetylase 5 Activity

Circulation ◽  
2011 ◽  
Vol 124 (3) ◽  
pp. 324-334 ◽  
Author(s):  
Steffen Just ◽  
Ina M. Berger ◽  
Benjamin Meder ◽  
Johannes Backs ◽  
Andreas Keller ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase ◽  
Cardiac Valve ◽  
Valve Formation

Abstract MP235: PROX1 Contributes To Cardiac Valve Disease

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
YenChun Ho ◽  
Xin Geng ◽  
Rohan Varshney ◽  
Jang Kim ◽  
Sandeep Surbrahmanian ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heart Valves ◽  
Cardiac Valve ◽  
Valve Disease ◽  
Matrix Composition ◽  
Cardiac Valves ◽  
Aortic Valves ◽  
Mitral Valves ◽  
Valve Development ◽  
Cardiac Valve Disease

Background: Heart valves regulate the unidirectional forward flow and prevent retrograde backflow of blood during the cardiac cycle. Cardiac valve disease (CVD) is observed in approximately 2.5% of the general population and the incidence increases to ~10% in elderly people. Patients with severe CVD require surgery and effective pharmacological treatments are currently not available. PROX1 is a transcription factor that regulates the development of lymphatic, venous, and lymphovenous valves (vascular valves). We identified that PROX1 is also expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 regulates cardiac valve development and disease is not known. Method and Results: We have discovered that mice lacking Prox1 in their VECs ( Prox1 ΔVEC ) develop enlarged aortic and mitral valves in which the expression of proteoglycans is increased (control, N=10; Prox1 ΔVEC , N=9, p <0.05). Echocardiography revealed moderate to severe stenosis of aortic valves of Prox1 ΔVEC mice (control, N=5; Prox1 ΔVEC , N=9, p <0.05). PROX1 regulates the expression of the transcription factor FOXC2 in the vascular valves. Similarly, we have found that the expression of FOXC2 is downregulated in the VECs of Prox1 ΔVEC mice. Specific knockdown of FOXC2 in VECs results in the thickening of aortic valves (control, N=10; shFoxc2 ΔVEC , N=8, p <0.05). Furthermore, restoration of FOXC2 expression in VECs ( Foxc2 OE-VEC ) ameliorates the thickening of the aortic valves of Prox1 ΔVEC mice ( Prox1 ΔVEC , N=9; Foxc2 OE-VEC ; Prox1 ΔVEC , N=8, p <0.05). We have also determined that the expression of platelet-derived growth factor-B ( Pdgfb ) is increased in the valve tissue of Prox1 ΔVEC mice and in PROX1 deficient sheep mitral valve VECs (MVECs) (siCtrl , N=4; siProx1 , N=4, p <0.05). Additionally, hyperactivation of PDGF-B signaling in mice results in a phenotype that is similar to Prox1 ΔVEC mice (control , N=4; Pdgfb GOF , N=3, p <0.05). Conclusion: Together these data suggest that PROX1 maintains the extracellular matrix composition of cardiac valves by regulating the expressions of FOXC2 and PDGF-B in VECs.

Abstract 3407: The Transcriptional Mediator Complex Is Essential For Cardiac Valve Formation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Steffen Just ◽  
Ina Berger ◽  
Benjamin Meder ◽  
David Hassel ◽  
Alexander Hess ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Model Organism ◽  
Mutant Phenotype ◽  
Cardiac Valve ◽  
Mediator Complex ◽  
Zebrafish Embryos ◽  
Sequence Alignments ◽  
Human Cardiomyocytes ◽  
Ping Pong ◽  
Valve Formation

The genetic causes of congenital heart diseases especially cardiac valve disorders are mostly unknown. During the last decade, the zebrafish became an excellent and established model organism (1) to uncover these genetic defects and (2) to elucidate the underlying molecular pathomechanisms. We recently isolated the zebrafish mutation ping pong ( png m683 ) in a large-scale ENU-mutagenesis screen for recessive lethal mutations that perturb cardiac function. png mutant zebrafish embryos show pathologically developed cardiac valves. Due to malformation of the cardiac AV valves, png mutant zebrafish embryos exhibit vigorous regurgitation of blood between the atrium and the ventricle. Furthermore, as a result of the cardiac valve malformation and cardiac dysfunction png mutants die at day 6 post fertilization. Expression of several factors known to be crucial for the proper development and formation of the atrio-ventricluar canal (e.g. notch1b, bmp4 or versican) is significantly altered in png mutant zebrafish hearts. By a positional cloning approach we demonstrate that the ping pong phenotype is caused by a promotor mutation in a zebrafish gene encoding for a novel component of the “transcriptional mediator complex”. This mediator complex is a multi-protein complex that acts as a transcriptional coactivator and transduces informations from transcription factors to the RNA polymerase II. png is strongly expressed in zebrafish as well as human cardiomyocytes. Furthermore, sequence alignments demonstrate the evolutionary conservation of the ping pong gene product. Gene specific knock-down studies by means of modified antisense oligonucleotides reveal a phenocopy of the png mutant phenotype whereas injection of the gene-specific mRNA in png mutant embryos restores the mutant phenotype indicating that png is indeed responsible for the observed phenotype. The zebrafish evolved as an excellent model organism to study the molecular signalling pathways involved in cardiac valve formation. By detailed characterization of the zebrafish line ping pong we will obtain new insights into these molecular mechanisms especially the transcriptional control of valve formation and therefore the pathomechanisms of human cardiac valve disorders.

scholarly journals Thymosin Beta4 Regulates Cardiac Valve Formation Via Endothelial-Mesenchymal Transformation in Zebrafish Embryos

2014 ◽  
Vol 37 (4) ◽  
pp. 330-336 ◽  
Author(s):  
Sun-Hye Shin ◽  
Sangkyu Lee ◽  
Jong-Sup Bae ◽  
Jun-Goo Jee ◽  
Hee-Jae Cha ◽  
...  
Keyword(s):  
Cardiac Valve ◽  
Zebrafish Embryos ◽  
Mesenchymal Transformation ◽  
Valve Formation ◽  
Thymosin Beta4

scholarly journals Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation

2010 ◽  
Vol 120 (10) ◽  
pp. 3493-3507 ◽  
Author(s):  
Luis Luna-Zurita ◽  
Belén Prados ◽  
Joaquim Grego-Bessa ◽  
Guillermo Luxán ◽  
Gonzalo del Monte ◽  
...  
Keyword(s):  
Cardiac Valve ◽  
Cell Invasiveness ◽  
Valve Formation

scholarly journals PERK participates in cardiac valve development via fatty acid oxidation and endocardial-mesenchymal transformation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takashi Shimizu ◽  
Kazuaki Maruyama ◽  
Takeshi Kawamura ◽  
Yoshihiro Urade ◽  
Youichiro Wada
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Umbilical Vein ◽  
Conditional Knockout ◽  
Cardiac Valve ◽  
Acid Oxidation ◽  
Loss Of Function ◽  
Mesenchymal Transformation ◽  
Valve Formation

AbstractProtein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott–Rallison syndrome. This disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-β downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-β1 stimulation. As a result, PERK inhibition suppressed mitochondrial metabolic activity. Taken together, these results demonstrate that PERK signaling is required for cardiac valve formation via FAO and EndoMT.

scholarly journals Remodeling of the myocardium in early trabeculation and cardiac valve formation; a role for TGFβ2

2013 ◽  
Vol 57 (11-12) ◽  
pp. 853-863 ◽  
Author(s):  
Boudewijn P.T. Kruithof ◽  
Marianna Kruithof-De-Julio ◽  
Robert E. Poelmann ◽  
Adriana C. Gittenberger-De-Groot ◽  
Vinciane Gaussin ◽  
...  
Keyword(s):  
Cardiac Valve ◽  
Valve Formation

scholarly journals Activin receptor-like kinase 2 and Smad6 regulate epithelial–mesenchymal transformation during cardiac valve formation

2005 ◽  
Vol 280 (1) ◽  
pp. 201-210 ◽  
Author(s):  
Jay S. Desgrosellier ◽  
Nathan A. Mundell ◽  
Maureen A. McDonnell ◽  
Harold L. Moses ◽  
Joey V. Barnett
Keyword(s):  
Cardiac Valve ◽  
Activin Receptor ◽  
Receptor Like Kinase ◽  
Mesenchymal Transformation ◽  
Valve Formation
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