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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

Echocardiographic and morphometric analysis of NAGLU-/- mice.A. Cumulative data of % fractional shortening (FS%) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). B. Representative M-mode echocardiographic tracings of WT and NAGLU-/- mice at 16 weeks and 32 weeks of age. C. Cumulative data of mitral annulus dimension (mm) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). D. Doppler analysis of mitral valve regurgitation of WT and NAGLU-/- mice at 32 weeks of age. E. Bar graphs showing mitral inflow E-wave to A-wave ratio in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). F. Bar graphs showing left ventricle weight to body weight ratio (LVW/BW) in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). G. Representative gross morphology of whole hearts from 32-week-old WT and NAGLU-/- mice.
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pone.0131662.g001: Echocardiographic and morphometric analysis of NAGLU-/- mice.A. Cumulative data of % fractional shortening (FS%) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). B. Representative M-mode echocardiographic tracings of WT and NAGLU-/- mice at 16 weeks and 32 weeks of age. C. Cumulative data of mitral annulus dimension (mm) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). D. Doppler analysis of mitral valve regurgitation of WT and NAGLU-/- mice at 32 weeks of age. E. Bar graphs showing mitral inflow E-wave to A-wave ratio in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). F. Bar graphs showing left ventricle weight to body weight ratio (LVW/BW) in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). G. Representative gross morphology of whole hearts from 32-week-old WT and NAGLU-/- mice.

Mentions: The progressive accumulation of undegraded GAGs in MPS results in multiple organ system dysfunctions that vary depending on the particular GAG deposited and the specific enzyme deficiency. Cardiac involvement has been reported in MPS diseases, although it has been better characterized for MPS I, II, and VI, and it significantly contributes to early mortality of these patients [2]. The cardiac causes of death include heart failure, sudden death from arrhythmias, pulmonary hypertension, and coronary occlusion [21–24]. In order to investigate cardiac involvement in MPS IIIB, we evaluated heart morphology and cardiac function in the murine model of MPS IIIB (NAGLU-/-) compared to wild-type (WT) mice starting from 16 to 32 weeks of age by serial echocardiograms over time. Interestingly, a decreased percentage of LV fractional shortening (FS%) was observed in NAGLU-/- mice compared to WT animals from 16 weeks to 32 weeks of age (Fig 1A and 1B). A significant reduction in LV FS% started from 24 weeks of age and was maintained up to 32 weeks of age.


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)

Echocardiographic and morphometric analysis of NAGLU-/- mice.A. Cumulative data of % fractional shortening (FS%) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). B. Representative M-mode echocardiographic tracings of WT and NAGLU-/- mice at 16 weeks and 32 weeks of age. C. Cumulative data of mitral annulus dimension (mm) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). D. Doppler analysis of mitral valve regurgitation of WT and NAGLU-/- mice at 32 weeks of age. E. Bar graphs showing mitral inflow E-wave to A-wave ratio in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). F. Bar graphs showing left ventricle weight to body weight ratio (LVW/BW) in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). G. Representative gross morphology of whole hearts from 32-week-old WT and NAGLU-/- mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131662.g001: Echocardiographic and morphometric analysis of NAGLU-/- mice.A. Cumulative data of % fractional shortening (FS%) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). B. Representative M-mode echocardiographic tracings of WT and NAGLU-/- mice at 16 weeks and 32 weeks of age. C. Cumulative data of mitral annulus dimension (mm) of WT and NAGLU-/- mice from 16 weeks to 32 weeks of age (*p<0.05). D. Doppler analysis of mitral valve regurgitation of WT and NAGLU-/- mice at 32 weeks of age. E. Bar graphs showing mitral inflow E-wave to A-wave ratio in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). F. Bar graphs showing left ventricle weight to body weight ratio (LVW/BW) in WT and NAGLU-/- mice at 32 weeks of age (*p<0.05). G. Representative gross morphology of whole hearts from 32-week-old WT and NAGLU-/- mice.
Mentions: The progressive accumulation of undegraded GAGs in MPS results in multiple organ system dysfunctions that vary depending on the particular GAG deposited and the specific enzyme deficiency. Cardiac involvement has been reported in MPS diseases, although it has been better characterized for MPS I, II, and VI, and it significantly contributes to early mortality of these patients [2]. The cardiac causes of death include heart failure, sudden death from arrhythmias, pulmonary hypertension, and coronary occlusion [21–24]. In order to investigate cardiac involvement in MPS IIIB, we evaluated heart morphology and cardiac function in the murine model of MPS IIIB (NAGLU-/-) compared to wild-type (WT) mice starting from 16 to 32 weeks of age by serial echocardiograms over time. Interestingly, a decreased percentage of LV fractional shortening (FS%) was observed in NAGLU-/- mice compared to WT animals from 16 weeks to 32 weeks of age (Fig 1A and 1B). A significant reduction in LV FS% started from 24 weeks of age and was maintained up to 32 weeks of age.

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