Gender-related dimorphism in aortic insufficiency in murine mucopolysaccharidosis type I.

ABSTRACT

BACKGROUND AND AIM OF THE STUDY 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. CONCLUSION: 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.