杜氏肌营养不良症(DMD)是一种由影响横纹肌的肌营养不良蛋白基因突变引起的神经肌肉疾病。由于骨骼肌治疗的进步,心肌病已成为死亡的主要原因。以前,尼可地尔,一种具有抗氧化和硝酸盐样特性的药物,改善年轻人的心脏损伤和改善心脏功能,受伤的mdx小鼠。尼可地尔通过刺激抗氧化活性和限制促氧化剂表达来减轻损伤。这里,我们检查了尼可地尔在老年mdx小鼠中是否具有类似的心脏保护作用。
尼可地尔(6mg/kg)的剂量超过15个月。与野生型(WT)小鼠相比,mdx小鼠在12个月时的超声心动图显示出一些功能缺陷,但不是在15个月。通过跑步机测定和存活,mdx小鼠的疾病表现很明显,但不是开放的领域和握力测定。mdx中SOD2和NOX4的心脏水平降低与WT.尼可地尔增加mdx的存活率,但不改变心脏功能,纤维化,膈肌功能或肌肉疲劳。
与我们之前的年轻工作相比,受伤的MDX小鼠,尼可地尔在15个月大的mdx小鼠中没有发挥心脏保护作用。与WT相比,老年mdx小鼠缺乏心脏病表现可以解释不一致的发现。而之前在年轻小鼠的亚急性损伤中观察到明显的心功能障碍。因此,我们无法得出长期尼可地尔对衰老mdx小鼠的任何心脏保护作用。
Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by dystrophin gene mutations affecting striated muscle. Due to advances in skeletal muscle treatment, cardiomyopathy has emerged as a leading cause of death. Previously, nicorandil, a drug with antioxidant and nitrate-like properties, ameliorated cardiac damage and improved cardiac function in young, injured
mdx mice. Nicorandil mitigated damage by stimulating antioxidant activity and limiting pro-oxidant expression. Here, we examined whether nicorandil was similarly cardioprotective in aged
mdx mice.
Nicorandil (6 mg/kg) was given over 15 months. Echocardiography of mdx mice showed some functional defects at 12 months compared to wild-type (WT) mice, but not at 15 months. Disease manifestation was evident in mdx mice via treadmill assays and survival, but not open field and grip strength assays. Cardiac levels of SOD2 and NOX4 were decreased in
mdx vs. WT. Nicorandil increased survival in
mdx but did not alter cardiac function, fibrosis, diaphragm function or muscle fatigue.
In contrast to our prior work in young, injured mdx mice, nicorandil did not exert cardioprotective effects in 15 month aged
mdx mice. Discordant findings may be explained by the lack of cardiac disease manifestation in aged mdx mice compared to WT, whereas significant cardiac dysfunction was previously seen with the sub-acute injury in young mice. Therefore, we are not able to conclude any cardioprotective effects with long-term nicorandil treatment in aging mdx mice.