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Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences

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Item Type:Article
Title:Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences
Creators Name:Tintu, A. and Rouwet, E. and Verlohren, S. and Brinkmann, J. and Ahmad, S. and Crispi, F. and van Bilsen, M. and Carmeliet, P. and Staff, A.C. and Tjwa, M. and Cetin, I. and Gratacos, E. and Hernandez-Andrade, E. and Hofstra, L. and Jacobs, M. and Lamers, W.H. and Morano, I. and Safak, E. and Ahmed, A. and le Noble, F.
Abstract:BACKGROUND: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. METHODS: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. PRINCIPAL FINDINGS: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. CONCLUSIONS/SIGNIFICANCE: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.
Keywords:Anoxia, Apoptosis, Dilated Cardiomyopathy, Echocardiography, Fetal Growth Retardation, Heart, Congenital Heart Defects, Muscle Proteins, Myocardial Contraction, Cardiac Myocytes, Protein Kinases, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Left Ventricular Function, Animals, Chickens
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:4
Number:4
Page Range:e5155
Date:9 April 2009
Official Publication:https://doi.org/10.1371/journal.pone.0005155
PubMed:View item in PubMed

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