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

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.

The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls

“…Arteries normally contain all types of GAGs [17,18] that accumulate in each of these disorders. This conjecture is further supported by the histopathology observation of myointimal proliferation and fragmented elastin in coronary arteries or aortas of MPS IIIB, IIIC, IVA, and VII patients [9,19,20,21,22]. We are conducting ongoing carotid ultrasonography studies to confirm this hypothesis in MPS IVA patients.…”

Myocardial deformation in pediatric patients with mucopolysaccharidoses: A two‐dimensional speckle tracking echocardiography study

“…However, it is indeed possible that patients may not yet have developed sufficient coronary artery damage to alternate GLS. Conversely, alteration of circumferential midwall layer fibers and subepicardial radial fibers could be due to deposition of myocardial fibrosis, described even in early stages MPS experimental models . Although a preferential nonsubendocardial involvement was not observed previously in patients with MPS, it was found in other storage diseases, such as lysosomal disorders caused by α‐galactosidase deficiency .…”

“…Braunlin and coworkers observed a significant reduction in endocardial fractional shortening—despite a decrease of posterior wall thickness—in a series of five children with type I MPS after 7 years of ERT . The combination of glycosaminoglycan deposition with chronic inflammation, increased excretion of cytokines and production of reactive free radicals from oxidative stress could be responsible for irreversible myocardial changes. On the other hand, episodic cases of outcome improvement were demonstrated in ERT managed types I, II, and VI patients with MPS .…”

“…14,41 In the present study, MPS patients' GLS that refers to subendocardial fibers-more prone to ischemic damage 42 -was not significantly lower than in healthy 45 Braunlin and coworkers observed a significant reduction in endocardial fractional shortening-despite a decrease of posterior wall thickness-in a series of five children with type I MPS after 7 years of ERT. 46 The combination of glycosaminoglycan deposition with chronic inflammation, increased excretion of cytokines and production of reactive free radicals from oxidative stress 43 The main limitation of the present study is the poor sample size of MPS, which is however a rare disease. In particular, it is possible that this study did not achieve the power to detect beneficial effect of ERT due to small numbers of treated and untreated patients.…”

Therapeutic targeting of autophagy in cardiovascular disease

“…Perturbations in cardiac autophagy have been reported in a mouse model of MPS IIIB (Sanfilippo type B syndrome) that develops HF over time [59]. Defects in autophagosome-lysosome fusion have also been described in Danon syndrome [60], where mutations in the gene coding for LAMP2 disrupt intracellular catabolism and lead to accumulation of autophagic material in cardiomyocytes and skeletal muscle cells [61].…”