The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure

Gabriele Giacomo Schiattarella; Giuliana Cerulo; Valeria De Pasquale; Pasquale Cocchiaro; Orlando Paciello; Luigi Avallone; Maria Paola Belfiore; Francesca Iacobellis; Daniele Di Napoli; Fabio Magliulo; Cinzia Perrino; Bruno Trimarco; Giovanni Esposito; Paola Di Natale; Luigi Michele Pavone

doi:10.1371/journal.pone.0131662

The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure

PLoS One. 2015 Jul 6;10(7):e0131662. doi: 10.1371/journal.pone.0131662. eCollection 2015.

Authors

Affiliations

¹ Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
² Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy.
³ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
⁴ Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy.
⁵ Radiology Department, Second University of Naples, Naples, Italy.
⁶ Biotechnology Centre, AORN Cardarelli, Naples, Italy.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylglucosaminidase / genetics
Animals
Disease Models, Animal*
Echocardiography
Heart Failure / complications*
Heart Failure / diagnostic imaging
Mice
Mice, Inbred C57BL
Mice, Knockout
Mucopolysaccharidosis III / complications
Mucopolysaccharidosis III / physiopathology*

Substances

alpha-N-acetyl-D-glucosaminidase
Acetylglucosaminidase

Grants and funding

This study was supported in part by grants from the Italian Ministry of Health–Young Researcher Grant (2009) and from the Italian Ministry of Health–FIRB 2012 Grant (Futuro in Ricerca) to C.P.