Cardiac CIP protein regulates dystrophic cardiomyopathy
Cardiac CIP protein regulates dystrophic cardiomyopathy
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心脏 CIP 蛋白调节营养不良性心肌病
DOI：
10.1016/j.ymthe.2021.08.022
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发表时间：
2022-02-02
影响因子：
12.4
通讯作者：
Wang, Da-Zhi
中科院分区：
文献类型：
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作者：
He, Xin;Liu, Jianming;Wang, Da-Zhi
心力衰竭是杜氏肌营养不良症（DMD）患者死亡的主要原因。在此之前，我们发现心脏和血管肌富含CIP蛋白在心脏功能中起重要作用。在这里，我们报告，CIP，横纹肌特异性蛋白，参与营养不良性心肌病的调节。使用人DMD的小鼠模型，我们发现CIP的缺失导致年轻的非综合征型mdx小鼠的扩张型心肌病和心力衰竭。相反，CIP的转基因过表达减少了老年综合征mdx小鼠的病理性营养不良性心肌病。全基因组转录组分析显示，涉及纤维发生和氧化应激的分子途径在CIP（CnA）中受到影响，以抑制CnA-活化T细胞核因子（NFAT）途径，这导致氧化应激途径的关键组分Nox 4的表达降低。Nox 4过表达加速mdx小鼠营养不良性心肌病的发展我们的研究表明CIP是营养不良性心肌病的修饰剂，是这种毁灭性疾病的潜在治疗靶点。
Heart failure is a leading cause of fatality in Duchenne muscular dystrophy (DMD) patients. Previously, we discovered that cardiac and skeletal-muscle-enriched CIP proteins play important roles in cardiac function. Here, we report that CIP, a striated muscle-specific protein, participates in the regulation of dystrophic cardiomyopathy. Using a mouse model of human DMD, we found that deletion of CIP leads to dilated cardiomyopathy and heart failure in young, non-syndromic mdx mice. Conversely, transgenic overexpression of CIP reduces pathological dystrophic cardiomyopathy in old, syndromic mdx mice. Genomewide transcriptome analyses reveal that molecular pathways involving fibrogenesis and oxidative stress are affected in CIP(CnA) to suppress the CnA-Nuclear Factor of Activated T cells (NFAT) pathway, which results in decreased expression of Nox4, a key component of the oxidative stress pathway. Overexpression of Nox4 accelerates the development of dystrophic cardiomyopathy in mdx mice. Our study indicates CIP is a modifier of dystrophic cardiomyopathy and a potential therapeutic target for this devastating disease.