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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 myocardial inflammation and fibrosis in NAGLU-/- mice.Representative H&E staining for inflammatory infiltrate and Masson's trichrome staining for fibrosis in LV tissues from WT and NAGLU-/- mice (40x magnification). Arrow indicates inflammatory infiltrates within myocardial fibers and asterisk (*) indicates fibrosis within myocardial fibers. Scale bars: 20 μm.
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pone.0131662.g004: Histological analysis of myocardial inflammation and fibrosis in NAGLU-/- mice.Representative H&E staining for inflammatory infiltrate and Masson's trichrome staining for fibrosis in LV tissues from WT and NAGLU-/- mice (40x magnification). Arrow indicates inflammatory infiltrates within myocardial fibers and asterisk (*) indicates fibrosis within myocardial fibers. Scale bars: 20 μm.

Mentions: To investigate whether affected myocardium of NAGLU-/- mice presents increased inflammation and fibrosis, features often related to the cardiac failure, the presence of inflammatory infiltrates and fibrosis was evaluated respectively by H&E and Masson's trichrome staining (Fig 4). NAGLU-/- mice exhibited a significant recruitment of inflammatory cells within the myocardium labeled by the specific inflammatory markers CD3, CD4, CD8 and CD68 (S2 Fig). Moreover, the staining with CD68 confirmed the presence of vacuoles within the macrophages (arrows in S2 Fig), in accordance with literature data [11]. Concerning fibrosis of affected mice, collagen deposition was localized near the valves and at lower extent in the myocardium (S3 Fig). Many reports deal with an abnormal content or structure of collagen in cardiac tissues of MPS animal models and patients [2, 8, 25–26, 28–32]. Our results are consistent with previous findings showing myocardial fibrosis in the murine models of MPS I [28] and MPS II [29], and the deposition of large amounts of collagen in the valves and myocardium of patients affected by Hurler syndrome [30].


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 myocardial inflammation and fibrosis in NAGLU-/- mice.Representative H&E staining for inflammatory infiltrate and Masson's trichrome staining for fibrosis in LV tissues from WT and NAGLU-/- mice (40x magnification). Arrow indicates inflammatory infiltrates within myocardial fibers and asterisk (*) indicates fibrosis within myocardial fibers. Scale bars: 20 μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131662.g004: Histological analysis of myocardial inflammation and fibrosis in NAGLU-/- mice.Representative H&E staining for inflammatory infiltrate and Masson's trichrome staining for fibrosis in LV tissues from WT and NAGLU-/- mice (40x magnification). Arrow indicates inflammatory infiltrates within myocardial fibers and asterisk (*) indicates fibrosis within myocardial fibers. Scale bars: 20 μm.
Mentions: To investigate whether affected myocardium of NAGLU-/- mice presents increased inflammation and fibrosis, features often related to the cardiac failure, the presence of inflammatory infiltrates and fibrosis was evaluated respectively by H&E and Masson's trichrome staining (Fig 4). NAGLU-/- mice exhibited a significant recruitment of inflammatory cells within the myocardium labeled by the specific inflammatory markers CD3, CD4, CD8 and CD68 (S2 Fig). Moreover, the staining with CD68 confirmed the presence of vacuoles within the macrophages (arrows in S2 Fig), in accordance with literature data [11]. Concerning fibrosis of affected mice, collagen deposition was localized near the valves and at lower extent in the myocardium (S3 Fig). Many reports deal with an abnormal content or structure of collagen in cardiac tissues of MPS animal models and patients [2, 8, 25–26, 28–32]. Our results are consistent with previous findings showing myocardial fibrosis in the murine models of MPS I [28] and MPS II [29], and the deposition of large amounts of collagen in the valves and myocardium of patients affected by Hurler syndrome [30].

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