title: Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA. osbor026@umn.edu.|Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. osbor026@umn.edu.|Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA. osbor026@umn.edu.|Asan-Minnesota Institute for Innovating Transplantation, Seoul, Republic of Korea. osbor026@umn.edu.|School of Public Health, University of Minnesota, Minneapolis, MN, USA. osbor026@umn.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Osborn
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.
authors.forename: Beau R
authors.initials: BR
authors.lastname: Webber
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.
authors.forename: Ronald T
authors.initials: RT
authors.lastname: McElmurry
authors.affiliation: Department of Cell Biology and Anatomy and the Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Rudser
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: DeFeo
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Muradian
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Petryk
authors.affiliation: Department of Cell Biology and Anatomy and the Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Hallgrimsson
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA.|Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.|Asan-Minnesota Institute for Innovating Transplantation, Seoul, Republic of Korea.|School of Public Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware ST SE, MMC 366, Minneapolis, MN, 55455, USA. braun002@umn.edu.|Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA. braun002@umn.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Braunlin
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D019465:Craniofacial Abnormalities / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006331:Heart Diseases / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D007068:Iduronidase / Q000235:genetics; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D011945:Receptors, Angiotensin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D007068:Iduronidase; D019808:Losartan