Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany; Institute of Immunology, Charité Campus Berlin Buch, Lindenberger Weg 80, 13125 Berlin, Germany.
Cell Rep. 2020 Nov 17;33(7):108404. doi: 10.1016/j.celrep.2020.108404.
Stressful experiences early in life can increase the risk of cardiovascular diseases. However, it remains largely unknown how stress influences susceptibility to the disease onset. Here, we show that exposure to brain-processed stress disrupts myocardial growth by reducing cardiomyocyte mitotic activity. Activation of the glucocorticoid receptor (GR), the primary stress response pathway, reduces cardiomyocyte numbers, disrupts trabecular formation, and leads to contractile dysfunction of the developing myocardium. However, a physiological level of GR signaling is required to prevent cardiomyocyte hyperproliferation. Mechanistically, we identify an antagonistic interaction between the GR and the cytokine interleukin-4 (IL-4) as a key player in cardiac development. IL-4 signals transcription of key regulators of cell-cycle progression in cardiomyocytes via signal transducer and activator of transcription 3 (Stat3). GR, on the contrary, inhibits this signaling system. Thus, our findings uncover an interplay between stress and immune signaling pathways critical to orchestrating physiological growth of the heart.
早期生活中的压力经历会增加患心血管疾病的风险。然而，压力如何影响疾病发作的易感性在很大程度上仍不清楚。在这里，我们表明，大脑处理的压力会通过降低心肌细胞有丝分裂活性来破坏心肌生长。糖皮质激素受体 (GR) 的激活，即主要的应激反应途径，会减少心肌细胞数量，破坏小梁形成，并导致发育中的心肌收缩功能障碍。然而，生理水平的 GR 信号对于防止心肌细胞过度增殖是必需的。从机制上讲，我们发现 GR 和细胞因子白细胞介素 4 (IL-4) 之间的拮抗相互作用是心脏发育的关键因素。IL-4 通过信号转导和转录激活因子 3 (Stat3) 信号转导在心肌细胞中转录细胞周期进程的关键调节剂。相反，GR 会抑制这种信号系统。因此，我们的研究结果揭示了压力和免疫信号通路之间的相互作用，这对协调心脏的生理生长至关重要。
