Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction by promoting endothelial-to-mesenchymal transition

被引:22
|
作者
Chen, Jiahui [1 ]
Jia, Jianguo [1 ]
Ma, Leilei [1 ]
Li, Bingyu [1 ]
Qin, Qing [1 ]
Qian, Juying [1 ]
Ge, Junbo [1 ]
机构
[1] Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Dept Cardiol, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
cardiac fibrosis; EndMT; Nur77; NUCLEAR RECEPTOR NUR77; NF-KAPPA-B; EXPRESSION;
D O I
10.1002/jcp.29877
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. We demonstrated that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficiency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22 alpha, Snail, and decreased expression of PECAM-1 and eNOS compared with wild-type mice after MI. Then, we found overexpression Nur77 in human coronary artery endothelial cells significantly inhibited interleukin 1 beta and transforming growth factor beta 2-induced EndMT, as shown by a reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT by inhibiting the nuclear factor-kappa B-dependent pathway. In conclusion, Nur77 is involved in cardiac fibrosis by inhibiting EndMT and may be a promising target for therapy of cardiac fibrosis after MI.
引用
收藏
页码:495 / 506
页数:12
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