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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. [ABSTRACT FROM AUTHOR]

Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male Balb/c mice were divided into three groups, sedentary, swimming twice a day without overload (T2), and swimming three times a day with a 2% body weight overload (T3), totaling 6 wk of training. Both training groups developed similar cardiac hypertrophy, but only T3 mice improved their oxidative capacity. We observed that T2 had increased levels of MASR, which was followed by the activation of its main downstream protein AKT; meanwhile, AT1R and its main downstream protein ERK remained unchanged. Furthermore, no change was observed regarding the levels of angiotensin peptides, in either group. In addition, we observed no change in the ratio of expression of the myosin heavy chain β-isoform to that of the α-isoform. Fibrosis was not observed in any of the groups. In conclusion, our results suggest that increasing exercise volume and intensity did not induce a pathological hypertrophy phenotype, but instead improved the oxidative capacity, and this process might have the participation of the RAS alternative axis. [ABSTRACT FROM AUTHOR]