title: The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure.
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.
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: Gabriele Giacomo
authors.initials: GG
authors.lastname: Schiattarella
authors.affiliation: 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.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cerulo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: De Pasquale
authors.affiliation: 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.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Cocchiaro
authors.affiliation: Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy.
authors.forename: Orlando
authors.initials: O
authors.lastname: Paciello
authors.affiliation: Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Avallone
authors.affiliation: Radiology Department, Second University of Naples, Naples, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Belfiore
authors.affiliation: Radiology Department, Second University of Naples, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Iacobellis
authors.affiliation: Biotechnology Centre, AORN Cardarelli, Naples, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Napoli
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Magliulo
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Perrino
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Natale
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Luigi Michele
authors.initials: LM
authors.lastname: Pavone
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D006333:Heart Failure / Q000150:complications* / Q000000981:diagnostic imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000150:complications / Q000503:physiopathology*
chemical_list: C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase