Baldo Guilherme, Tavares Angela Maria Vicente, Gonzalez Esteban, Poletto Edina, Mayer Fabiana Quoos, Matte Ursula da Silveira, Giugliani Roberto
Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil; Post-Graduation Program in Genetics and Molecular Biology, UFRGS, RS, Brazil.
Gene Therapy Center-Hospital de Clinicas de Porto Alegre, RS, Brazil.
Cardiovasc Pathol. 2017 Mar-Apr;27:45-50. doi: 10.1016/j.carpath.2017.01.001. Epub 2017 Jan 6.
Mucopolysaccharidosis type I (MPS I) is a lysosomal disorder characterized by a deficiency of alpha-L-iduronidase and storage of undegraded glycosaminoglycans (GAGs). Clinical findings of the disease include heart failure, and patients often need valve replacement. It has been shown that, later in life, MPS I mice develop those abnormalities, but to date, there have not been studies on the progression and pathogenesis of the disease. Therefore, in the present study, we evaluated heart function in normal and MPS I male mice from 2 to 8 months of age. Echocardiographic analysis showed left ventricular enlargement with progressive reduction in ejection fraction, fractional area change, and left ventricular fractional shortening in the MPS I hearts at 6 and 8 months of age and a reduction in acceleration time/ejection time ratio of the pulmonary artery starting at 6 months of age, which suggests pulmonary vascular resistance. Histological and biochemical analysis confirmed progressive GAG storage from 2 months of age and onwards in the myocardium and heart valves, which had also increased in thickness. Additionally, macrophages were present in the MPS I heart tissue. Collagen content was reduced in the MPS I mouse valves. Cathepsin B, an enzyme that is known to be able to degrade collagen and is involved in heart dilatation, displayed a marked elevation in activity in the MPS I mice and could be responsible for the heart dilatation and valves alterations observed. Our results suggest that the MPS I mice have progressive heart failure and valve disease, which may be caused by cathepsin B overexpression.
I型黏多糖贮积症（MPS I）是一种溶酶体疾病，其特征是α-L-艾杜糖醛酸酶缺乏以及未降解的糖胺聚糖（GAGs）蓄积。该疾病的临床症状包括心力衰竭，患者常常需要进行瓣膜置换。研究表明，MPS I小鼠在生命后期会出现这些异常情况，但迄今为止，尚未有关于该疾病进展和发病机制的研究。因此，在本研究中，我们评估了2至8月龄正常和MPS I雄性小鼠的心脏功能。超声心动图分析显示，6个月和8月龄的MPS I小鼠心脏出现左心室扩大，射血分数、面积变化分数和左心室缩短分数逐渐降低，并且从6月龄开始肺动脉加速时间/射血时间比值降低，这提示肺血管阻力增加。组织学和生化分析证实，从2月龄起心肌和心脏瓣膜中GAG逐渐蓄积，且厚度也增加。此外，MPS I心脏组织中存在巨噬细胞。MPS I小鼠瓣膜中的胶原蛋白含量降低。组织蛋白酶B是一种已知能够降解胶原蛋白并参与心脏扩张的酶，其在MPS I小鼠中的活性显著升高，可能是观察到的心脏扩张和瓣膜改变的原因。我们的结果表明，MPS I小鼠患有进行性心力衰竭和瓣膜疾病，这可能是由组织蛋白酶B的过度表达引起的。
