title: Progressive heart disease in mucopolysaccharidosis type I mice may be mediated by increased cathepsin B activity.
abstract: Mucopolysaccharidosis type I (MPS I) is a lysosomal disorder characterized by a deficiency of alpha-L-iduronidase and storage of undegraded glycosaminoglycans (GAGs). Clinical findings of the disease include heart failure, and patients often need valve replacement. It has been shown that, later in life, MPS I mice develop those abnormalities, but to date, there have not been studies on the progression and pathogenesis of the disease. Therefore, in the present study, we evaluated heart function in normal and MPS I male mice from 2 to 8 months of age. Echocardiographic analysis showed left ventricular enlargement with progressive reduction in ejection fraction, fractional area change, and left ventricular fractional shortening in the MPS I hearts at 6 and 8 months of age and a reduction in acceleration time/ejection time ratio of the pulmonary artery starting at 6 months of age, which suggests pulmonary vascular resistance. Histological and biochemical analysis confirmed progressive GAG storage from 2 months of age and onwards in the myocardium and heart valves, which had also increased in thickness. Additionally, macrophages were present in the MPS I heart tissue. Collagen content was reduced in the MPS I mouse valves. Cathepsin B, an enzyme that is known to be able to degrade collagen and is involved in heart dilatation, displayed a marked elevation in activity in the MPS I mice and could be responsible for the heart dilatation and valves alterations observed. Our results suggest that the MPS I mice have progressive heart failure and valve disease, which may be caused by cathepsin B overexpression.
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil; Post-Graduation Program in Genetics and Molecular Biology, UFRGS, RS, Brazil.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Baldo
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil.
authors.forename: Angela Maria Vicente
authors.initials: AM
authors.lastname: Tavares
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil.
authors.forename: Esteban
authors.initials: E
authors.lastname: Gonzalez
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil.
authors.forename: Edina
authors.initials: E
authors.lastname: Poletto
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil.
authors.forename: Fabiana Quoos
authors.initials: FQ
authors.lastname: Mayer
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil.
authors.forename: Ursula da Silveira
authors.initials: UD
authors.lastname: Matte
authors.affiliation: Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil; Post-Graduation Program in Genetics and Molecular Biology, UFRGS, RS, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002401:Cathepsin B; C533915:Ctsb protein, mouse
keywords: Cathepsin B; Glycosaminoglycan; Heart dilatation; Lysosomal storage disorder; Mucopolysaccharidosis type I