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

Schiattarella GG, Cerulo G, De Pasquale V, Cocchiaro P, Paciello O, Avallone L, Belfiore MP, Iacobellis F, Di Napoli D, Magliulo F, Perrino C, Trimarco B, Esposito G, Di Natale P, Pavone LM - PLoS ONE (2015)

Bottom Line: 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.Overall, our findings demonstrate that NAGLU(-/-) mice develop heart disease, valvular abnormalities and cardiac failure associated with an impaired lysosomal autophagic flux.

View Article: PubMed Central - PubMed

Affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, 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.

No MeSH data available.


Related in: MedlinePlus

Histological analysis of cardiac valves thickening.A. Representative images of haematoxylin and eosin (H&E) of aortic valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). B. Representative images of haematoxylin and eosin (H&E) of mitral valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). Scale bars: 20 μm.
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pone.0131662.g002: Histological analysis of cardiac valves thickening.A. Representative images of haematoxylin and eosin (H&E) of aortic valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). B. Representative images of haematoxylin and eosin (H&E) of mitral valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). Scale bars: 20 μm.

Mentions: The echocardiographic findings prompted us to carry out a histological analysis of cardiac valve structure. The analysis of both aortic and mitral valve morphology in NAGLU-/- and WT mice showed aortic and mitral valve defects in NAGLU-/- at 32 weeks of age (Fig 2). In particular, NAGLU-/- mice exhibited a significant aortic (Fig 2A) and mitral (Fig 2B) cuspid thickening as shown by H&E staining. Mitral and aortic valve thickening has been reported in canine MPS VII [26] as well as in a MPS I and VI mouse models [27–28]. Our results, in agreement with echocardiographic and Doppler analyses, indicate that the alterations in the valve morphology in NAGLU-/- mice are associated with a progressive reduction in cardiac function over time and that abnormal valve morphology and function produce both diastolic and systolic dysfunctions, suggesting that severe mitral regurgitation is the "primum movens" of cardiac dysfunction in MPS IIIB mice.


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

Schiattarella GG, Cerulo G, De Pasquale V, Cocchiaro P, Paciello O, Avallone L, Belfiore MP, Iacobellis F, Di Napoli D, Magliulo F, Perrino C, Trimarco B, Esposito G, Di Natale P, Pavone LM - PLoS ONE (2015)

Histological analysis of cardiac valves thickening.A. Representative images of haematoxylin and eosin (H&E) of aortic valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). B. Representative images of haematoxylin and eosin (H&E) of mitral valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). Scale bars: 20 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4493027&req=5

pone.0131662.g002: Histological analysis of cardiac valves thickening.A. Representative images of haematoxylin and eosin (H&E) of aortic valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). B. Representative images of haematoxylin and eosin (H&E) of mitral valve sections from WT and NAGLU-/- hearts at 32 weeks of age (20x magnification). Scale bars: 20 μm.
Mentions: The echocardiographic findings prompted us to carry out a histological analysis of cardiac valve structure. The analysis of both aortic and mitral valve morphology in NAGLU-/- and WT mice showed aortic and mitral valve defects in NAGLU-/- at 32 weeks of age (Fig 2). In particular, NAGLU-/- mice exhibited a significant aortic (Fig 2A) and mitral (Fig 2B) cuspid thickening as shown by H&E staining. Mitral and aortic valve thickening has been reported in canine MPS VII [26] as well as in a MPS I and VI mouse models [27–28]. Our results, in agreement with echocardiographic and Doppler analyses, indicate that the alterations in the valve morphology in NAGLU-/- mice are associated with a progressive reduction in cardiac function over time and that abnormal valve morphology and function produce both diastolic and systolic dysfunctions, suggesting that severe mitral regurgitation is the "primum movens" of cardiac dysfunction in MPS IIIB mice.

Bottom Line: 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.Overall, our findings demonstrate that NAGLU(-/-) mice develop heart disease, valvular abnormalities and cardiac failure associated with an impaired lysosomal autophagic flux.

View Article: PubMed Central - PubMed

Affiliation: Department of Advanced Biomedical Sciences, University of Naples Federico II, 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.

No MeSH data available.


Related in: MedlinePlus