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.

中文翻译：

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粘多糖贮积症 I 型小鼠的心脏病理学：氯沙坦在心脏重塑过程中改变 ERK1/2 的激活

I型粘多糖贮积症 (MPS I) 是一种由IDUA突变引起的溶酶体贮积症编码α-L-艾杜糖苷酸酶的基因，该酶的缺乏导致糖胺聚糖的储存，具有多种临床表现。MPS I 患者死亡的主要原因之一是心脏并发症，例如心脏瓣膜增厚、传导异常、心肌功能障碍和心脏肥大。导致 MPS I 心脏功能障碍的机制尚不完全清楚。在之前的一项研究中，我们已经证明氯沙坦和普萘洛尔改善了 MPS I 小鼠的心脏功能。因此，我们旨在研究受这些药物影响的通路是否可以调节 MPS I 小鼠的心脏重塑过程。根据我们之前的观察，氯沙坦和普萘洛尔可以恢复心脏功能，而不会改变瓣膜厚度。MPS I 小鼠的 AKT 和 ERK1/2 激活减少，组织蛋白酶的活性增加，但没有观察到金属蛋白酶活性的改变。用氯沙坦治疗的动物显示组织蛋白酶活性降低并恢复 ERK1/2 激活。虽然氯沙坦和普萘洛尔都改善了心脏功能，但到目前为止还没有发现普萘洛尔的机制证据。我们的结果表明，氯沙坦或普萘洛尔可用于改善 MPS I 中的心脏病，并可作为治疗优化的辅助治疗候选药物。