Abstract：
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.
摘要：
心脏纤维化与衰老有关,没有针对性的治疗方法。随着年龄的增长，在心脏重塑过程中，神经生长因子诱导的基因B（Nur77）的水平降低；然而，其在衰老过程中心脏纤维化中的作用尚不清楚.这里,我们发现Nur77基因敲除增加心脏结构异常,收缩和舒张功能障碍，心脏肥大,和纤维化标志物在15月龄小鼠中的表达。此外，Nur77缺乏诱导转化生长因子β（TGF-β）处理的H9c2细胞中I型胶原（Col-1）和α-平滑肌肌动蛋白过度产生，而Nur77过表达减弱了这种作用。体内和体外Nur77缺乏症下调糖原合成酶激酶（GSK）-3β表达和β-catenin活性增加，而其过表达增加了GSK-3β的表达。GSK-3β敲低抵消了Nur77对TGF-β处理的H9c2细胞的抗纤维化作用。染色质免疫沉淀和荧光素酶报告基因测定结果表明GSK-3β是Nur77的直接靶标。我们的发现表明，Nur77部分通过GSK-3β/β-catenin途径直接启动GSK-3β转录和年龄相关的心脏纤维化。这项研究提出了Nur77调节心脏纤维化的新机制，并建议Nur77作为预防和治疗衰老相关心脏纤维化和心力衰竭的靶标。
