Sunitinib inhibits STAT3 phosphorylation in cardiac muscle and prevents cardiomyopathy in the mdx mouse model of Duchenne muscular dystrophy.
Sunitinib inhibits STAT3 phosphorylation in cardiac muscle and prevents cardiomyopathy in the mdx mouse model of Duchenne muscular dystrophy.
复制标题
舒尼替尼抑制心肌 STAT3 磷酸化并预防杜氏肌营养不良 mdx 小鼠模型中的心肌病。
DOI：
10.1093/hmg/ddac042
复制
发表时间：
2022
影响因子：
3.5
通讯作者：
Burkin,DeanJ
中科院分区：
文献类型：
--
作者：
Oliveira-Santos,Ariany;Dagda,Marisela;Burkin,DeanJ
杜氏肌营养不良症 (DMD) 是一种致命的 X 连锁遗传性疾病，影响全球大约五千分之一的男性新生儿。 DMD 是由肌营养不良蛋白基因突变引起的。肌营养不良蛋白通过将细胞骨架与细胞外基质连接起来，对于维持肌细胞膜的完整性和稳定性至关重要，从而保护肌纤维免受收缩引起的损伤。抗肌营养不良蛋白的缺失会导致机械引起的骨骼和心肌损伤。尽管 DMD 患者出生时这种疾病并不明显，但肌营养不良症会迅速进展，早在青少年时期就会导致呼吸和心肌衰竭。 DMD 患者的过早死亡是由于心律失常和左心室功能障碍所致。目前，DMD相关心力衰竭尚无有效治疗方法。最近，我们证明了美国食品和药物管理局批准的小分子舒尼替尼（一种多靶点酪氨酸激酶抑制剂）可以通过增加生肌能力、细胞膜完整性以及通过调节 STAT3 相关信号通路改善骨骼肌功能来减轻骨骼肌疾病。 STAT3 的慢性激活已被证明会促进心脏肥大和衰竭。在这项研究中，我们检查了长期舒尼替尼治疗对心脏病理和功能的影响。我们的结果表明，舒尼替尼治疗降低了 mdx 小鼠心肌中 STAT3 的磷酸化，改善了心电功能，增加了心输出量和每搏输出量，减少了心室肥大，减少了心肌细胞膜损伤、纤维化组织沉积，并略微减少了心脏炎症。总之，我们的研究支持舒尼替尼可以作为一种新的治疗方法来减缓 DMD 心肌病进展的观点。一句话总结在这项研究中，我们确定了舒尼替尼（美国食品和药物管理局批准的药物）是否可以在 DMD 动物模型中减少病理并改善心脏功能。
Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder affecting approximately 1 in 5000 male births worldwide. DMD is caused by mutations in the dystrophin gene. Dystrophin is essential for maintaining muscle cell membrane integrity and stability by linking the cytoskeleton to the extracellular matrix, which protects myofibers from contraction-induced damage. Loss of dystrophin leads to mechanically induced skeletal and cardiac muscle damage. Although the disease is not evident in DMD patients at birth, muscular dystrophy rapidly progresses and results in respiratory and cardiac muscle failure as early as the teenage years. Premature death in DMD patients is due to cardiac arrhythmias and left ventricular dysfunction. Currently, there is no effective treatment for DMD-related cardiac failure. Recently, we have shown that a Food and Drug Administration-approved small molecule, sunitinib, a multi-targeted tyrosine kinase inhibitor can mitigate skeletal muscle disease through an increase in myogenic capacity, cell membrane integrity, and improvement of skeletal muscle function via regulation of STAT3-related signaling pathway. Chronic activation of STAT3 has been shown to promote cardiac hypertrophy and failure. In this study, we examined the effects of long-term sunitinib treatment on cardiac pathology and function. Our results showed sunitinib treatment reduced STAT3 phosphorylation in the heart muscle ofmdxmice, improved cardiac electrical function, increased cardiac output and stroke volume, decreased ventricular hypertrophy, reduced cardiomyocytes membrane damage, fibrotic tissue deposition and slightly decreased cardiac inflammation. Together, our studies support the idea that sunitinib could serve as a novel treatment to slow cardiomyopathy progression in DMD.One Sentence SummaryIn this study, we determined if sunitinib, a Food and Drug Administration-approved drug, could reduce the pathology and improve cardiac function in an animal model for DMD.