Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.

转录因子在心血管适应压力方面发挥着重要作用。核受体亚家族 4 A 组成员 2 (NR4A2；NURR1) 是一种立即早期基因和转录因子，在许多器官中具有多种作用。在成年哺乳动物心脏中，特别是在心肌细胞中，NR4A2 响应 β-肾上腺素能刺激而强烈上调。这种增加的生理影响仍不清楚。在这项研究中，我们的目的是探讨正常条件下心脏 NR4A2 上调以及压力超负荷时心脏 NR4A2 上调的后果。在小鼠中，他莫昔芬依赖性、心肌细胞限制性 NR4A2 过度表达导致心肌细胞肥大、左心室扩张、心力衰竭，并在 40 天内死亡。慢性 NR4A2 诱导还会在横主动脉缩窄 (TAC) 引起的压力超负荷期间导致心脏代偿失调。从机制上讲，NR4A2 导致成年心肌细胞恢复到胎儿样表型，并转变为糖酵解代谢和肌节结构分解。NR4A2 还重新激活细胞周期进程并刺激 DNA 复制和核分裂，但未能诱导胞质分裂，从而促进心肌细胞的多核化。细胞周期检查点的激活导致细胞凋亡反应的诱导，最终导致心肌细胞过度损失和左心室收缩功能受损。总之，出生后哺乳动物心脏中 NR4A2 的肌细胞特异性过度表达导致细胞周期重入和 DNA 复制增加，但不会导致心肌细胞分裂。我们的研究结果揭示了核受体作为心肌细胞自我更新和心脏再生的关键调节因子的新功能。