Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
Int J Mol Sci. 2023 Aug 19;24(16):12985. doi: 10.3390/ijms241612985.
The dorsomedial hypothalamus nucleus (DMH) is an important component of the autonomic nervous system and plays a critical role in regulating the sympathetic outputs of the heart. Stress alters the neuronal activity of the DMH, affecting sympathetic outputs and triggering heart rate variability. However, the specific molecular mechanisms behind stress leading to abnormal DMH neuronal activity have still not been fully elucidated. Therefore, in the present study, we successfully constructed a stressed rat model and used it to investigate the potential molecular mechanisms by which IL-6 regulates GABAA receptors in the DMH through activation of the JAK/STAT pathway and thus affects heart rate variability in rats. By detecting the c-Fos expression of neurons in the DMH and electrocardiogram (ECG) changes in rats, we clarified the relationship between abnormal DMH neuronal activity and heart rate variability in stressed rats. Then, using ELISA, immunohistochemical staining, Western blotting, RT-qPCR, and RNAscope, we further explored the correlation between the IL-6/JAK/STAT signaling pathway and GABAA receptors. The data showed that an increase in IL-6 induced by stress inhibited GABAA receptors in DMH neurons by activating the JAK/STAT signaling pathway, while specific inhibition of the JAK/STAT signaling pathway using AG490 obviously reduced DMH neuronal activity and improved heart rate variability in rats. These findings suggest that IL-6 regulates the expression of GABAA receptors via the activation of the JAK/STAT pathway in the DMH, which may be an important cause of heart rate variability in stressed rats.
背内侧下丘脑核（DMH）是自主神经系统的重要组成部分，在调节心脏的交感输出方面起着关键作用。应激会改变 DMH 的神经元活动，影响交感输出并引发心率变异性。然而，导致 DMH 神经元活动异常的应激的具体分子机制仍未完全阐明。因此，在本研究中，我们成功构建了应激大鼠模型，并利用该模型研究了 IL-6 通过激活 JAK/STAT 通路调节 DMH 中 GABA A 受体，从而影响大鼠心率变异性的潜在分子机制。通过检测 DMH 神经元的 c-Fos 表达和大鼠心电图（ECG）变化，我们阐明了应激大鼠中 DMH 神经元活动异常与心率变异性之间的关系。然后，我们通过 ELISA、免疫组织化学染色、Western blot、RT-qPCR 和 RNAscope 进一步探讨了 IL-6/JAK/STAT 信号通路与 GABA A 受体之间的相关性。研究数据表明，应激引起的 IL-6 增加通过激活 JAK/STAT 信号通路抑制 DMH 神经元中的 GABA A 受体，而使用 AG490 特异性抑制 JAK/STAT 信号通路明显降低了 DMH 神经元的活性并改善了大鼠的心率变异性。这些发现表明，IL-6 通过激活 DMH 中的 JAK/STAT 通路调节 GABA A 受体的表达，这可能是应激大鼠心率变异性的重要原因。
