BACKGROUND Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM. METHODS We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm; P<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6]; P=0.004) as assessed by echocardiography. RESULTS Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca2+-responsiveness (pCa50=6.15±0.11 [n=13] versus 6.24±0.06 [n=14]; P=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180G mice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis. CONCLUSIONS This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca2+-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.

中文翻译：

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鞘氨醇-1-磷酸受体调节剂FTY720可改善与肥厚型心肌病相关的Tm-E180G小鼠模型的舒张功能障碍，并部分逆转心房重构。

背景技术肥厚型心肌病（HCM）是一种遗传性心血管疾病，主要涉及肌节蛋白的突变。HCM患者存在肥大，舒张功能障碍和纤维化，但尚无特效治疗方法。鞘氨醇-1-磷酸受体调节剂FTY720 /芬戈莫德被批准用于治疗多发性硬化症。我们假设FTY720对鞘氨醇-1-磷酸受体的调节在与肌节相连的HCM中具有治疗作用。方法我们用FTY720或赋形剂处理了原肌球蛋白（Tm-E180G）和非转基因同窝动物中具有HCM连锁突变的小鼠6周。与媒介物治疗相比，经FTY720治疗的Tm-E180G小鼠的左心房大小显着减少（1.99±0.19 [n = 7]对2.70±0.44 [n = 6] mm； P <0。001）和通过超声心动图评估舒张功能的改善（E / A比：2.69±0.38 [n = 7]与5.34±1.19 [n = 6]； P = 0.004）。结果压力-容积关系显示出舒张末期压力-容积关系，松弛动力学，预负荷可招募的冲程功和射血分数的显着改善。洗涤剂提取的纤维束显示出肌丝Ca2 +反应性显着降低（pCa50 = 6.15±0.11 [n = 13]与6.24±0.06 [n = 14]； P = 0.041）。我们将这些改善归因于FTY720治疗的Tm-E180G小鼠中心脏肌球蛋白结合蛋白C的S-谷胱甘肽酰化的下调以及NADPH氧化酶的下调而纤维化没有改变，从而减轻了氧化应激。结论这是第一个证明S1PR的调节可导致HCM的肌丝Ca2 +响应性降低和舒张功能改善。我们将这些变化与通过下调NOX2降低肌丝蛋白的氧化修饰有关。我们的数据支持以下假设，即鞘脂信号的修饰可能是HCM中的一种新型治疗方法。