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Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology
Author(s) -
Osborn Mark J.,
Webber Beau R.,
McElmurry Ronald T.,
Rudser Kyle D.,
DeFeo Anthony P.,
Muradian Michael,
Petryk Anna,
Hallgrimsson Benedikt,
Blazar Bruce R.,
Tolar Jakub,
Braunlin Elizabeth A.
Publication year - 2017
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-016-9988-z
Subject(s) - mucopolysaccharidosis type i , losartan , craniofacial , medicine , mucopolysaccharidosis i , endocrinology , angiotensin ii , mucopolysaccharidosis , pathology , enzyme replacement therapy , receptor , disease , psychiatry
Mucopolysaccharidosis type I (MPS IH) is a lysosomal storage disease (LSD) caused by inactivating mutations to the alpha‐ L ‐iduronidase (IDUA) gene. Treatment focuses on IDUA enzyme replacement and currently employed methods can be non‐uniform in their efficacy particularly for the cardiac and craniofacial pathology. Therefore, we undertook efforts to better define the pathological cascade accounting for treatment refractory manifestations and demonstrate a role for the renin angiotensin system (RAS) using the IDUA −/− mouse model. Perturbation of the RAS in the aorta was more profound in male animals suggesting a causative role in the observed gender dimorphism and angiotensin receptor blockade (ARB) resulted in improved cardiac function. Further, we show the ability of losartan to prevent shortening of the snout, a common craniofacial anomaly in IDUA −/− mice. These data show a key role for the RAS in MPS associated pathology and support the inclusion of losartan as an augmentation to current therapies.