下调和上调
杜氏肌营养不良
医学
心肌病
心脏纤维化
纤维化
心肌纤维化
心功能曲线
肌营养不良蛋白
肌营养不良
威尔姆斯瘤
癌症研究
内科学
mdx鼠标
心力衰竭
病理
内分泌学
生物
基因
生物化学
作者
Zhan Guo,Mengyuan Geng,Yuting Huang,Gang Hou,Renwei Jing,Caorui Lin,Xiaoning Zhang,Miaomiao Zhang,Guanwei Fan,Rui Wang,HaiFang Yin
标识
DOI:10.1038/s41418-022-00979-0
摘要
Cardiomyopathy is a primary cause of mortality in Duchenne muscular dystrophy (DMD) patients. Mechanistic understanding of cardiac fibrosis holds the key to effective DMD cardiomyopathy treatments. Here we demonstrate that upregulation of Wilms' tumor 1 (Wt1) gene in epicardial cells increased cardiac fibrosis and impaired cardiac function in 8-month old mdx mice lacking the RNA component of telomerase (mdx/mTR-/-). Levels of phosphorylated IƙBα and p65 significantly rose in mdx/mTR-/- dystrophic hearts and Wt1 expression declined in the epicardium of mdx/mTR-/- mice when nuclear factor κB (NF-κB) and inflammation were inhibited by metformin. This demonstrates that Wt1 expression in epicardial cells is dependent on inflammation-triggered NF-κB activation. Metformin effectively prevented cardiac fibrosis and improved cardiac function in mdx/mTR-/- mice. Our study demonstrates that upregulation of Wt1 in epicardial cells contributes to fibrosis in dystrophic hearts and metformin-mediated inhibition of NF-κB can ameliorate the pathology, and thus showing clinical potential for dystrophic cardiomyopathy. Translational Perspective: Cardiomyopathy is a major cause of mortality in Duchenne muscular dystrophy (DMD) patients. Promising exon-skipping treatments are moving to the clinic, but getting sufficient dystrophin expression in the heart has proven challenging. The present study shows that Wilms' Tumor 1 (Wt1) upregulation in epicardial cells is primarily responsible for cardiac fibrosis and dysfunction of dystrophic mice and likely of DMD patients. Metformin effectively prevents cardiac fibrosis and improves cardiac function in dystrophic mice, thus representing a treatment option for DMD patients on top of existing therapies.
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