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

Abstract

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.

Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes

“…While the role of Nur77 in epicardial cells was not studied here, it may also be of interest in relation to the fibrotic response and rupture after MI in Nur77-KO mice, since we have observed high Nur77 expression in epicardial cells upon MI in mice (data not shown). We furthermore cannot exclude the influence of proinflammatory macrophages and endothelial cells on myocardial thinning and rupture in our MI experiments with ApoE/Nur77-KO mice [24,34,36]. However, in the one-week model of ISO-induced cardiac hypertrophy, where monocyte infiltration, macrophage accumulation, and the expression of proinflammatory genes are not prominent, Nur77-KO mice also exhibit severe myocardial thinning, rupture and reduced scar density.…”

“…It has been shown that Nur77 deficiency in monocytes and macrophages promotes a proinflammatory phenotype, leading to impaired myocardial repair and larger scar size with reduced collagen density after MI [24,33]. Furthermore, Nur77 was shown to repress endothelial-to mesenchymal transition, leading to enhanced MI-induced fibrotic scar size in Nur77-KO mice [34]. Additionally, epicardial cells are thought to be involved in myocardial repair responses after MI by giving rise to cardiac myofibroblasts through epithelial-mesenchymal transition [7,35].…”

Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial‑mesenchymal transition in the valvular damage due to rheumatic heart disease

“…As early as 2003, Kuwahara et al (41) observed that the TGF-β signaling pathway is important in cardiac fibrosis and diastolic heart failure in rats and that altering the activity of this pathway inhibits the progression of cardiac fibrosis. Recent studies have shown that the EndMT is associated with heart failure (20,(42)(43)(44) and is also crucial in cardiac fibrosis following myocardial infarction (45). Cardiac function can be improved by inhibiting EndMT (46).…”

Application of vascular endothelial cells in stem cell medicine

“…Therefore, the process of myocardial fibrosis can be controlled by the regulation of EMT. Chen et al [ 78 ] found that NUR77, an orphan nuclear receptor, inhibits EMT and thus regulates myocardial fibrosis. Yin et al [ 79 ] found that Tongxinluo, a common drug used to treat cardiovascular disease, enhanced the expression of endothelial markers in VECs and inhibited EMT.…”