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.
Highlights
Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) in various organs of affected patients [1]
As an impairment of autophagy was found in embryonic fibroblasts and brain tissues from MPS IIIA mice [12], in human skin fibroblasts from MPS VI patients and in the liver, spleen, and kidney tissues from MPS VI rats [13], we investigated the autophagic marker levels in the heart tissues of NAGLU-/- mice in order to verify whether abnormal autophagy might be involved in heart dysfunction in MPS IIIB
Cardiac involvement has been reported in MPS diseases, it has been better characterized for MPS I, II, and VI, and it significantly contributes to early mortality of these patients [2]
Summary
Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) in various organs of affected patients [1]. Deposition of GAGs in the heart of individuals with MPS causes cardiac dysfunctions [2]. Advances in MPS treatment, including enzyme replacement therapy [3], hematopoietic stem cell transplantation [4] and gene therapy [5], have significantly improved the outcome of these disorders, death from cardiac causes continues to be common among these patients. While cardiac involvement in patients with MPS I, II and VI has been well described [9], less is known about heart dysfunctions in MPS III
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