title: Gender-related dimorphism in aortic insufficiency in murine mucopolysaccharidosis type I.
abstract: OBJECTIVE
  Hurler syndrome (mucopolysaccharidosis type I/H; MPS I/H) is a lethal heritable enzymopathy that leads to an accumulation of glycosaminoglycans (GAGs) and dysfunction of multiple organs of the body, including the heart. As gender-related differences are common in heart disease and a murine model for mucopolysaccharidosis type I (MPSI) has been used for the preclinical evaluation of strategies to correct heart valve disease in Hurler syndrome, the study aim was to determine the impact of gender on heart disease in the murine MPSI model.
  
  
  METHODS
  Murine hearts were examined by high-resolution ultrasound biomicroscopy, the tissue and urinary contents of GAGs were measured, and the quantitative reverse transcribed ribonucleic acid polymerase chain reaction for metalloproteinase (MMP) -9 and -12 determined.
  
  
  RESULTS
  In MPSI mice, aortic insufficiency (AI) in conjunction with depressed myocardial function was observed significantly more often in males than females. Neither the total body GAG burden nor myocardial GAG content was responsible for this difference. In contrast, in the aorta the expression of extracellular matrix tissue MMP-12, but not MMP-9, was significantly elevated in males with AI when compared to females with AI.
  
  
  CONCLUSIONS
  Gender-related dimorphism occurs in cardiac valvular disease in MPSI mice. Male MPSI mice showed an increased incidence of AI associated with an increase in the MMP-12 content of the aortic arch. The evaluation of findings in relation to gender is important in the experimental treatment of murine models of disease, so that gender-related variations in genetic penetrance are not mistaken for disease correction.
authors.affiliation: Divisions of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. tolar003@umn.edu
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Braunlin
authors.forename: Megan
authors.initials: M
authors.lastname: Riddle
authors.forename: Brandon
authors.initials: B
authors.lastname: Peacock
authors.forename: Ron T
authors.initials: RT
authors.lastname: McElmurry
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Orchard
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D001022:Aortic Valve Insufficiency / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D033401:Microscopy, Acoustic; D008059:Mucopolysaccharidosis I / Q000453:epidemiology* / Q000503:physiopathology; D012737:Sex Factors; D018487:Ventricular Dysfunction, Left / Q000453:epidemiology
chemical_list: D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12