Arteriosclerosis, thrombosis, and vascular biology · 2017
Deletion of Fstl1 (Follistatin-Like 1) From the Endocardial/Endothelial Lineage Causes Mitral Valve Disease.
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Prakash Stuti, Borreguero Luis J J, Sylva Marc, Flores Ruiz Lorena, Rezai Fereshte, Gunst Quinn D, de la Pompa José-Luis, Ruijter Jan M, van den Hoff Maurice J B
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsBone Morphogenetic ProteinsCell LineageCell ProliferationDisease Models, AnimalDisease ProgressionEndocardiumEndothelial CellsEpithelial-Mesenchymal TransitionFollistatin-Related ProteinsGenetic Predisposition to DiseaseHeart Conduction SystemHeart FailureIntegrasesMice, KnockoutMitral ValveMitral Valve InsufficiencyMitral Valve ProlapsePhenotypeReceptor, TIE-2Signal TransductionTime FactorsTranscription FactorsTransforming Growth Factor betaVentricular Dysfunction, LeftVentricular Function, LeftVentricular Remodeling