摘要

OBJECTIVE:Lamininα2-deficient congenital muscular dystrophy type 1A (MDC1A) is a cureless disease associated with severe disability and shortened lifespan. Previous studies have shown reduced fibrosis and restored skeletal muscle remodeling following treatment with losartan, an angiotensin II type I receptor blocker. We therefore evaluated the effect of losartan treatment in the dy(2J) /dy(2J) mouse model of MDC1A.
METHODS:Homozygous dy(2J) /dy(2J) and control mice were treated with losartan or placebo for 12 weeks from 6 weeks of age. Outcome measures included hindlimb and forelimb muscle strength by Grip Strength Meter and quantitative muscle fibrosis parameters. Losartan's effects on transforming growth factor β (TGF-β) and mitogen-activated protein kinase (MAPK) signaling pathways were evaluated with Western blotting, immunofluorescence, and cytokine measurements.
RESULTS:Losartan treatment was associated with significant impressive improvement in muscle strength and amelioration of fibrosis. Administration of losartan inhibited TGF-β signaling pathway, resulting in decreased serum TGF-β1 level and reduced downstream phosphorylated (P) Smad2/3 proteins. Moreover, losartan activated Smad7 protein, a key negative regulator of TGF-β signaling. In addition, losartan treatment inhibited the MAPK cascade as shown by decreased expression of P-p38 MAPK, P-c-jun-N-terminal kinase, and P-extracellular signal-regulated kinases 1 and 2 in the treated mice.
INTERPRETATION:Losartan, a commonly prescribed US Food and Drug Administration-approved medication for hypertension, demonstrated clinical improvement and amelioration of fibrosis in the dy(2J) /dy(2J) mouse model of MDC1A via TGF-β and MAPK signaling pathways. The results of this study support pursuing a clinical trial of losartan treatment in children with MDC1A.

译文

目的: 层粘连蛋白 α 2 缺陷型先天性肌营养不良 1A 型 (MDC1A) 是一种与严重残疾和寿命缩短相关的无生命疾病。先前的研究表明，使用血管紧张素 II ⅰ 型受体阻滞剂氯沙坦治疗后，纤维化减轻，骨骼肌重塑恢复。因此，我们在 MDC1A 的 dy (2J)/dy (2J) 小鼠模型中评价了氯沙坦治疗的效果。
方法: 从 6 周龄开始，用氯沙坦或安慰剂治疗纯合子 dy (2J)/dy (2J) 和对照组小鼠 12 周。结果测量包括通过握力计测量后肢和前肢肌肉力量和定量肌肉纤维化参数。用蛋白质印迹法、免疫荧光法和细胞因子法评估了氯沙坦对转化生长因子 β (TGF-β) 和丝裂原活化蛋白激酶 (MAPK) 信号通路的影响。
结果: 氯沙坦治疗显著改善肌肉力量和纤维化。服用氯沙坦可抑制 TGF-β 信号通路，导致血清 TGF-β 1 水平降低，下游磷酸化 (P) Smad2/3 蛋白减少。此外，氯沙坦激活了 TGF-β 信号传导的关键负调控因子-7 蛋白。此外，氯沙坦处理抑制 MAPK 级联反应，表现为 P-p38 MAPK 、 P-c-6月-N-末端激酶的表达减少, 以及治疗小鼠的 P-细胞外信号调节激酶 1 和 2。
解释: 氯沙坦，一种美国食品和药物管理局批准的治疗高血压的常用药物，证明了 dy (2J)/dy (2J) 纤维化的临床改善和改善通过 TGF-β 和 MAPK 信号通路建立 MDC1A 的小鼠模型。本研究的结果支持在 MDC1A 患儿中进行氯沙坦治疗的临床试验。