Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology

作者：O**orn 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^*

来源：Journal of Inherited Metabolic Disease, 2017, 40(2): 281-289.

DOI：10.1007/s10545-016-9988-z

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.

• 出版日期2017-3