title: Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs.
abstract: Mucopolysaccharidosis VII (MPS VII) is due to the deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiovascular 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.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Bigg
authors.forename: Guilherme
authors.initials: G
authors.lastname: Baldo
authors.forename: Meg M
authors.initials: MM
authors.lastname: Sleeper
authors.forename: Patricia A
authors.initials: PA
authors.lastname: O'Donnell
authors.forename: Hanqing
authors.initials: H
authors.lastname: Bai
authors.forename: Venkata R P
authors.initials: VR
authors.lastname: Rokkam
authors.forename: Yuli
authors.initials: Y
authors.lastname: Liu
authors.forename: Susan
authors.initials: S
authors.lastname: Wu
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.forename: Margret L
authors.initials: ML
authors.lastname: Casal
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
mesh_terms: D000818:Animals; D002815:Chordae Tendineae / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004285:Dogs; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006349:Heart Valve Diseases / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008943:Mitral Valve / Q000378:metabolism / Q000473:pathology*; D016538:Mucopolysaccharidosis VII / Q000150:complications* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006025:Glycosaminoglycans; D003094:Collagen; D010447:Peptide Hydrolases
keywords: CT; Cathepsin; Ccl; Collagen; Cts; DTT; Dithiothreitol; Dog; ECM; EDTA; EM; ERT; GAG; GUSB; Glycosaminoglycan; HGF; HSCT; IDUA; IV; Il; Interleukin; Intravenous; Lysosomal storage disease; MMP; MPS; MR; MV; Mitral regurgitation; Mucopolysaccharidosis; NIH; National Institutes of Health; OMIM; Online Mendelian Inheritance in Man; Osm; RLU; RT; RV; SLRP; TNF; Tlr4; Toll-like receptor 4; Z-Phe-Arg-AMC; benzyloxycarbonyl-l-phenylalanyl-l-arginine-7-amido-4-methylcoumarin; chemokine (C–C motif) ligand; chordae tendineae; electron microscopy; enzyme replacement therapy; ethylenediaminetetraacetic acid; extracellular matrix; hematopoietic stem cell transplantation; hepatocyte growth factor; matrix metalloproteinase; mitral regurgitation; mitral valve; oncostatin M; red light units; retroviral vector; reverse-transcription; small leucine-rich proteoglycan; tumor necrosis factor-α; α-l-iduronidase; β-glucuronidase