Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil.
Postgraduation Program on Genetics and Molecular Biology, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
Interdiscip Sci. 2021 Mar;13(1):34-43. doi: 10.1007/s12539-020-00406-3. Epub 2021 Jan 21.
Mucopolysaccharidoses are caused by a deficiency of enzymes involved in the degradation of glycosaminoglycans. Heart diseases are a significant cause of morbidity and mortality in MPS patients, even in conditions in which enzyme replacement therapy is available. In this sense, cardiovascular manifestations, such as heart hypertrophy, cardiac function reduction, increased left ventricular chamber, and aortic dilatation, are among the most frequent. However, the downstream events which influence the heart dilatation process are unclear. Here, we employed systems biology tools together with transcriptomic data to investigate new elements that may be involved in aortic dilatation in Mucopolysaccharidoses syndrome. We identified candidate genes involved in biological processes related to inflammatory responses, deposition of collagen, and lipid accumulation in the cardiovascular system that may be involved in aortic dilatation in the Mucopolysaccharidoses I and VII. Furthermore, we investigated the molecular mechanisms of losartan treatment in Mucopolysaccharidoses I mice to underscore how this drug acts to prevent aortic dilation. Our data indicate that the association between the TGF-b signaling pathway, Fos, and Col1a1 proteins can play an essential role in aortic dilation's pathophysiology and its subsequent improvement by losartan treatment.
黏多糖贮积症是由于参与糖胺聚糖降解的酶缺乏引起的。心脏病是黏多糖贮积症患者发病率和死亡率的重要原因，即使在可提供酶替代疗法的情况下也是如此。在这种情况下，心血管表现，如心脏肥大、心脏功能降低、左心室腔增大和主动脉扩张等，是最常见的。然而，影响心脏扩张过程的下游事件尚不清楚。在这里，我们使用系统生物学工具和转录组数据来研究可能参与黏多糖贮积症综合征主动脉扩张的新元素。我们确定了与心血管系统炎症反应、胶原蛋白沉积和脂质积累相关的生物过程相关的候选基因，这些基因可能与黏多糖贮积症 I 和 VII 中的主动脉扩张有关。此外，我们研究了洛沙坦在黏多糖贮积症 I 小鼠中的治疗分子机制，以强调这种药物如何作用以预防主动脉扩张。我们的数据表明，TGF-b 信号通路、Fos 和 Col1a1 蛋白之间的关联可能在主动脉扩张的病理生理学及其随后通过洛沙坦治疗的改善中发挥重要作用。
