Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs

Abstract

Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiavascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact collagen in the MV at 6 months of age, when mitral regurgitation had developed. Electron microscopy demonstrated that collagen fibrils were of normal diameter, but failed to align into large parallel arrays. mRNA analysis demonstrated a modest reduction in the expression of genes that encode collagen or collagen-associated proteins such as the proteoglycan decorin which helps collagen fibrils assemble, and a marked increase for genes that encode proteases such as cathepsins. Indeed, enzyme activity for cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV collagen structure. This could be due to upregulation of enzymes that degrade collagen or collagen-associated proteins, to the accumulation of GAGs that compete with proteoglycans such as decorin for binding to collagen, or to other causes. Further delineation of the etiology of abnormal collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues.

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

“…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 ].…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…Neuropathology, skeletal and joint defects, and cardiac disorders are among the most prominent clinical manifestations of MPSs, which are refractory to the current therapies [106,108,109]. Although no studies are available in humans, investigations in animal models have shown a beneficial effect of CTS inhibition, especially in ameliorating cardiac disease in MPSs and other LSDs [161,162,171,173]. Since CTSs have also been shown to play a role in the onset and progression of neuropathology and skeletal disorders in MPSs, affected patients might gain benefits from treatments with CTS targeting-based drugs.…”

“…The in vivo treatment of MPS I mice with a CTSB inhibitor reduced aortic dilatation and heart valve thickening, and led to an improvement of cardiac function, suggesting that CTSB inhibition may have a potential benefit in the disease [161]. Elevated activity of CTSB was detected in the MPS VII dog model showing abnormalities in the collagen structure of mitral valve [162]. When affected dogs received an intravenous injection of a retroviral vector expressing canine β-glucuronidase (the deficient enzyme in MPS VII), a reduced CTSB activity was observed, which correlated with an improved signal for structurally intact-collagen.…”

Cardiovascular Histopathology of a 11-Year Old with Mucopolysaccharidosis VII Demonstrates Fibrosis, Macrophage Infiltration, and Arterial Luminal Stenosis

“…Elastin fragmentation (white arrowheads) was more notable in (e) the coronary artery than the (f) aorta. Macrophages, the CD68 (brown) staining cells marked with m, were also abundant within the lesions of (g) the coronary artery and (h) aorta but devoid of lipid-laden vacuoles (Vogler et al 1994;Metcalf et al 2010;Bigg et al 2013) 28 years (Gniadek et al 2015) 28 min (gest age unknown) (Irani et al 1983) Stillborn (32 weeks' gest) (Molyneux et al 1997) 6 days (33 weeks' gest) (Geipel et al 2002) Fetal Not applicable (no animal studies).…”

“…Even amongst MPSs, MPS VII is a rare condition, affecting 1 in every 345,000-2,000,000 live births (Muenzer 2011). Sudden death has been described in two older patients, and corresponding reports of cardiovascular histopathology are also minimal (Vogler et al 1994;Metcalf et al 2010;Bigg et al 2013;Gniadek et al 2015). We describe the cardiovascular histopathology findings in a 11-year-old boy with MPS VII who died after sustaining ventricular tachycardia during a dental procedure under anesthesia, and relate the findings to findings in animal models of MPS VII that may shed light upon pathogenesis of MPSassociated cardiovascular disease.…”