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

J Cell Physiol. 2021 Jan;236(1):495-506. doi: 10.1002/jcp.29877. Epub 2020 Jun 15.


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, SM22α, 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 1β and transforming growth factor β2-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-κB-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.

Keywords: EndMT; Nur77; cardiac fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Coronary Vessels / metabolism
  • Coronary Vessels / pathology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelium / metabolism
  • Endothelium / pathology
  • Epithelial-Mesenchymal Transition / physiology*
  • Fibrosis / metabolism*
  • Fibrosis / pathology
  • Heart / physiology
  • Humans
  • Interleukin-1beta / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / metabolism*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / deficiency*
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / metabolism


  • Interleukin-1beta
  • NF-kappa B
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Transforming Growth Factor beta