Stuti Prakash1, Luis J J Borreguero1, Marc Sylva1, Lorena Flores Ruiz1, Fereshte Rezai1, Quinn D Gunst1, José-Luis de la Pompa1, Jan M Ruijter1, Maurice J B van den Hoff2. 1. From the Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands (S.P., M.S., F.R., Q.D.G., J.M.R., M.J.B.v.d.H.); Cardiovascular Imaging Laboratory, Centro Nacional de Investigación Cardiovascular, Madrid, Spain (L.J.J.B., L.F.R.); and Intercellular Signaling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigación Cardiovascular, Madrid, Spain (J.-L.d.l.P.). 2. From the Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands (S.P., M.S., F.R., Q.D.G., J.M.R., M.J.B.v.d.H.); Cardiovascular Imaging Laboratory, Centro Nacional de Investigación Cardiovascular, Madrid, Spain (L.J.J.B., L.F.R.); and Intercellular Signaling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigación Cardiovascular, Madrid, Spain (J.-L.d.l.P.). m.j.vandenhoff@amc.uva.nl.
Abstract
OBJECTIVE: Fstl1 (Follistatin-like 1) is a secreted protein that is expressed in the atrioventricular valves throughout embryonic development, postnatal maturation, and adulthood. In this study, we investigated the loss of Fstl1 in the endocardium/endothelium and their derived cells. APPROACH AND RESULTS: We conditionally ablated Fstl1 from the endocardial lineage using a transgenic Tie2-Cre mouse model. These mice showed a sustained Bmp and Tgfβ signaling after birth. This resulted in ongoing proliferation and endocardial-to-mesenchymal transition and ultimately in deformed nonfunctional mitral valves and a hypertrophic dilated heart. Echocardiographic and electrocardiographic analyses revealed that loss of Fstl1 leads to mitral regurgitation and left ventricular diastolic dysfunction. Cardiac function gradually deteriorated resulting in heart failure with preserved ejection fraction and death of the mice between 2 and 4 weeks after birth. CONCLUSIONS: We report on a mouse model in which deletion of Fstl1 from the endocardial/endothelial lineage results in deformed mitral valves, which cause regurgitation, heart failure, and early cardiac death. The findings provide a potential molecular target for the clinical research into myxomatous mitral valve disease.
OBJECTIVE:Fstl1 (Follistatin-like 1) is a secreted protein that is expressed in the atrioventricular valves throughout embryonic development, postnatal maturation, and adulthood. In this study, we investigated the loss of Fstl1 in the endocardium/endothelium and their derived cells. APPROACH AND RESULTS: We conditionally ablated Fstl1 from the endocardial lineage using a transgenic Tie2-Cre mouse model. These mice showed a sustained Bmp and Tgfβ signaling after birth. This resulted in ongoing proliferation and endocardial-to-mesenchymal transition and ultimately in deformed nonfunctional mitral valves and a hypertrophic dilated heart. Echocardiographic and electrocardiographic analyses revealed that loss of Fstl1 leads to mitral regurgitation and left ventricular diastolic dysfunction. Cardiac function gradually deteriorated resulting in heart failure with preserved ejection fraction and death of the mice between 2 and 4 weeks after birth. CONCLUSIONS: We report on a mouse model in which deletion of Fstl1 from the endocardial/endothelial lineage results in deformed mitral valves, which cause regurgitation, heart failure, and early cardiac death. The findings provide a potential molecular target for the clinical research into myxomatous mitral valve disease.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Stuti Prakash; Andrea Mattiotti; Marc Sylva; Barbara J M Mulder; Alex V Postma; Maurice J B van den Hoff Journal: Mol Genet Genomic Med Date: 2019-02-05 Impact factor: 2.183
Authors: Renélyn Wolters; Ray Deepe; Jenna Drummond; Andrew B Harvey; Emilye Hiriart; Marie M Lockhart; Maurice J B van den Hoff; Russell A Norris; Andy Wessels Journal: J Cardiovasc Dev Dis Date: 2021-05-12