Journal
JOURNAL OF INHERITED METABOLIC DISEASE
Volume 44, Issue 3, Pages 740-750Publisher
WILEY
DOI: 10.1002/jimd.12327
Keywords
AKT; cardiac disease; cardiac remodeling; ERK1; 2; losartan; mucopolysaccharidosis type I; propranolol
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul
- Hospital de Clinicas de Porto Alegre
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MPS I, caused by mutations in the IDUA gene, leads to heart complications in patients. Studies suggest that losartan and propranolol can improve cardiac function in MPS I mice, potentially serving as adjunctive treatment options.
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, that codifies the alpha-L-iduronidase enzyme, which deficiency leads to storage of glycosaminoglycans, with multiple clinical manifestations. One of the leading causes of death in MPS I patients are cardiac complications such as cardiac valve thickening, conduction abnormalities, myocardial dysfunction, and cardiac hypertrophy. The mechanism leading to cardiac dysfunction in MPS I is not entirely understood. In a previous study, we have demonstrated that losartan and propranolol improved the cardiac function in MPS I mice. Thus, we aimed to investigate whether the pathways influenced by these drugs may modulate the cardiac remodeling process in MPS I mice. According to our previous observation, losartan and propranolol restore the heart function, without altering valve thickness. MPS I mice presented reduced activation of AKT and ERK1/2, increased activity of cathepsins, but no alteration in metalloproteinase activity was observed. Animals treated with losartan showed a reduction in cathepsin activity and restored ERK1/2 activation. While both losartan and propranolol improved heart function, no mechanistic evidence was found for propranolol so far. Our results suggest that losartan or propranolol could be used to ameliorate the cardiac disease in MPS I and could be considered as adjuvant treatment candidates for therapy optimization.
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