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The murine model of mucopolysaccharidosis IIIB develops cardiopathies over time leading to heart failure

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Item Type:Article
Title:The murine model of mucopolysaccharidosis IIIB develops cardiopathies over time leading to heart failure
Creators Name:Schiattarella, G.G. and Cerulo, G. and De Pasquale, V. and Cocchiaro, P. and Paciello, O. and Avallone, L. and Belfiore, M.P. and Iacobellis, F. and Di Napoli, D. and Magliulo, F. and Perrino, C. and Trimarco, B. and Esposito, G. and Di Natale, P. and Pavone, L.M.
Abstract:Mucopolysaccharidosis (MPS) IIIB is a lysosomal disease due to the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The disease is characterized by mild somatic features and severe neurological disorders. Very little is known on the cardiac dysfunctions in MPS IIIB. In this study, we used the murine model of MPS IIIB (NAGLU knockout mice, NAGLU(-/-)) in order to investigate the cardiac involvement in the disease. Echocardiographic analysis showed a marked increase in left ventricular (LV) mass, reduced cardiac function and valvular defects in NAGLU(-/-) mice as compared to wild-type (WT) littermates. The NAGLU(-/-) mice exhibited a significant increase in aortic and mitral annulus dimension with a progressive elongation and thickening of anterior mitral valve leaflet. A severe mitral regurgitation with reduction in mitral inflow E-wave-to-A-wave ratio was observed in 32-week-old NAGLU(-/-) mice. Compared to WT mice, NAGLU(-/-) mice exhibited a significantly lower survival with increased mortality observed in particular after 25 weeks of age. Histopathological analysis revealed a significant increase of myocardial fiber vacuolization, accumulation of HS in the myocardial vacuoles, recruitment of inflammatory cells and collagen deposition within the myocardium, and an increase of LV fibrosis in NAGLU(-/-) mice compared to WT mice. Biochemical analysis of heart samples from affected mice showed increased expression levels of cardiac failure hallmarks such as calcium/calmodulin-dependent protein kinase II, connexin43, α-smooth muscle actin, α-actinin, atrial and brain natriuretic peptides, and myosin heavy polypeptide 7. Furthermore, heart samples from NAGLU(-/-) mice showed enhanced expression of the lysosome-associated membrane protein-2 (LAMP2), and the autophagic markers Beclin1 and LC3 isoform II (LC3-II). Overall, our findings demonstrate that NAGLU(-/-) mice develop heart disease, valvular abnormalities and cardiac failure associated with an impaired lysosomal autophagic flux.
Keywords:Acetylglucosaminidase, Animal Disease Models, Echocardiography, Heart Failure, Inbred C57BL Mice, Knockout Mice, Mucopolysaccharidosis III, Animals, Mice
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e0131662
Date:6 July 2015
Official Publication:https://doi.org/10.1371/journal.pone.0131662
PubMed:View item in PubMed

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