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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

Biochemical evaluation of cardiac failure markers in NAGLU-/- mice.A. Representative immunoblot and densitometric analysis of CaMKII, Cx43, α-actinin and α-SMA protein levels in WT and NAGLU-/- heart samples at 32 weeks of age (*p<0.05). B. Real-time PCR analysis of ANP, BNP and Myh7 mRNA levels in WT and NAGLU-/- hearts at 32 weeks of age (*p<0.05).
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pone.0131662.g005: Biochemical evaluation of cardiac failure markers in NAGLU-/- mice.A. Representative immunoblot and densitometric analysis of CaMKII, Cx43, α-actinin and α-SMA protein levels in WT and NAGLU-/- heart samples at 32 weeks of age (*p<0.05). B. Real-time PCR analysis of ANP, BNP and Myh7 mRNA levels in WT and NAGLU-/- hearts at 32 weeks of age (*p<0.05).

Mentions: In order to confirm the ecocardiographic and histopathological data of the cardiac involvement in the MPS IIIB mouse model at the molecular level, biochemical analyses of LV samples from NAGLU-/- and WT mice were carried out. First, we found an enhanced expression of hypertrophy and fibrosis markers in heart tissues from NAGLU-/- mice compared to WT littermates, as demonstrated by increased myocardial protein levels of CaMKII [33], Cx43 [34], α-actinin [35] and α-SMA [18] (Fig 5A). Moreover, LV samples from NAGLU-/- mice were characterized by a significant increase in the mRNA levels of ANP, BNP and Myh7 (Fig 5B), hallmarks of cardiac dysfunctions and failure [36–37].


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)

Biochemical evaluation of cardiac failure markers in NAGLU-/- mice.A. Representative immunoblot and densitometric analysis of CaMKII, Cx43, α-actinin and α-SMA protein levels in WT and NAGLU-/- heart samples at 32 weeks of age (*p<0.05). B. Real-time PCR analysis of ANP, BNP and Myh7 mRNA levels in WT and NAGLU-/- hearts at 32 weeks of age (*p<0.05).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493027&req=5

pone.0131662.g005: Biochemical evaluation of cardiac failure markers in NAGLU-/- mice.A. Representative immunoblot and densitometric analysis of CaMKII, Cx43, α-actinin and α-SMA protein levels in WT and NAGLU-/- heart samples at 32 weeks of age (*p<0.05). B. Real-time PCR analysis of ANP, BNP and Myh7 mRNA levels in WT and NAGLU-/- hearts at 32 weeks of age (*p<0.05).
Mentions: In order to confirm the ecocardiographic and histopathological data of the cardiac involvement in the MPS IIIB mouse model at the molecular level, biochemical analyses of LV samples from NAGLU-/- and WT mice were carried out. First, we found an enhanced expression of hypertrophy and fibrosis markers in heart tissues from NAGLU-/- mice compared to WT littermates, as demonstrated by increased myocardial protein levels of CaMKII [33], Cx43 [34], α-actinin [35] and α-SMA [18] (Fig 5A). Moreover, LV samples from NAGLU-/- mice were characterized by a significant increase in the mRNA levels of ANP, BNP and Myh7 (Fig 5B), hallmarks of cardiac dysfunctions and failure [36–37].

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