Nur77 alleviates cardiac fibrosis by upregulating GSK-3β transcription during aging

Cardiac fibrosis is associated with aging, for which no targeted therapies are available. With aging, the levels of nerve growth factor-induced gene B (Nur77) are reduced during cardiac remodelling; however, its role in cardiac fibrosis in aging remains unclear. Here, we found that Nur77 knockout increased cardiac structure abnormalities, systolic and diastolic dysfunction, cardiac hypertrophy, and fibrotic marker expression in 15-month-old mice. Furthermore, Nur77 deficiency induced collagen type I (Col-1) and α-smooth muscle actin overproduction in transforming growth factor beta (TGF-β) treated H9c2 cells, whereas Nur77 overexpression attenuated this effect. Nur77 deficiency in vivo and in vitro downregulated glycogen synthase kinase (GSK)-3β expression and increased β-catenin activity, while its overexpression increased GSK-3β expression. GSK-3β knockdown counteracted the anti-fibrotic effect of Nur77 on TGF-β-treated H9c2 cells. Chromatin immunoprecipitation and luciferase reporter assay results suggested GSK-3β as the direct target of Nur77. Our findings suggest that Nur77 directly initiates GSK-3β transcription and age-related cardiac fibrosis partly through the GSK-3β/β-catenin pathway. This study proposes a novel mechanism for Nur77 regulating cardiac fibrosis and suggests Nur77 as a target for the prevention and treatment of aging-associated cardiac fibrosis and heart failure.