Cardiac pathology in mucopolysaccharidosis I mice: Losartan modifies ERK1/2 activation during cardiac remodeling.

Autor: Gonzalez EA; Postgraduate Program in Genetic and Molecular Biology, UFRGS, Porto Alegre, Brazil.; Cells, Tissues, and Genes Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Tobar Leitão SA; Cardiovascular Research Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Postgraduate Program in Health Science: Cardiology and Cardiovascular Science, UFRGS, Porto Alegre, Brazil., Soares DDS; Cardiovascular Research Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Postgraduate Program in Health Science: Cardiology and Cardiovascular Science, UFRGS, Porto Alegre, Brazil., Tavares AMV; Cells, Tissues, and Genes Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Giugliani R; Postgraduate Program in Genetic and Molecular Biology, UFRGS, Porto Alegre, Brazil.; Cells, Tissues, and Genes Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Department of Genetics, UFRGS, Porto Alegre, Brazil., Baldo G; Postgraduate Program in Genetic and Molecular Biology, UFRGS, Porto Alegre, Brazil.; Cells, Tissues, and Genes Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Department of Genetics, UFRGS, Porto Alegre, Brazil., Matte U; Postgraduate Program in Genetic and Molecular Biology, UFRGS, Porto Alegre, Brazil.; Cells, Tissues, and Genes Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Department of Genetics, UFRGS, Porto Alegre, Brazil.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2021 May; Vol. 44 (3), pp. 740-750. Date of Electronic Publication: 2020 Nov 10.
DOI: 10.1002/jimd.12327
Abstrakt: 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.
(© 2020 SSIEM.)
Databáze: MEDLINE
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