Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
Departments of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
Exp Mol Med. 2023 May;55(5):965-973. doi: 10.1038/s12276-023-00988-0. Epub 2023 May 1.
Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). We generated cardiac conduction cell-specific inducible IGF-1 receptor (IGF-1R) knockout (KO) (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double-KO (CSDIRKO) mice and evaluated their phenotypes. Telemetric electrocardiography revealed regular sinus rhythm in CSIGF1RKO mice, indicating that IGF-1R is dispensable for normal pacemaking. In contrast, CSIRKO and CSDIRKO mice exhibited profound sinus bradycardia. CSDIRKO mice showed typical sinus node dysfunction characterized by junctional rhythm and sinus pauses on electrocardiography. Interestingly, the lack of an insulin receptor in the SAN cells of CSIRKO and CSDIRKO mice caused sinus nodal fibrosis. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) protein expression significantly decreased in the CSIRKO and CSDIRKO mice relative to the controls. A patch-clamp study of the SAN cells of CSIRKO mice revealed a significant decrease in the funny current, which is responsible for spontaneous diastolic depolarization in the SAN. This result suggested that insulin receptor loss reduces the heart rate via downregulation of the HCN4 channel. Additionally, HCN1 expression was decreased in CSDIRKO mice, explaining their sinus node dysfunction. Our results reveal a previously unrecognized role of insulin/IGF-1 signaling in sinus node structural maintenance and pacemaker function.
胰岛素和胰岛素样生长因子 1（IGF-1）信号调节心肌细胞的生长和葡萄糖代谢。然而，它们在心脏传导系统细胞中的生理作用从未被探索过。因此，我们试图确定胰岛素/IGF-1 受体在窦房结（SAN）中的时空功能。我们生成了心脏传导细胞特异性诱导型 IGF-1 受体（IGF-1R）敲除（CSIGF1RKO）、胰岛素受体（IR）敲除（CSIRKO）和 IR/IGF-1R 双敲除（CSDIRKO）小鼠，并评估了它们的表型。遥测心电图显示 CSIGF1RKO 小鼠具有规律的窦性节律，表明 IGF-1R 对于正常起搏是可有可无的。相比之下，CSIRKO 和 CSDIRKO 小鼠表现出明显的窦性心动过缓。CSDIRKO 小鼠表现出典型的窦性结功能障碍，表现为心电图上结性节律和窦性暂停。有趣的是，SAN 细胞中的胰岛素受体缺失导致 CSIRKO 和 CSDIRKO 小鼠的窦房结纤维化。从机制上讲，CSIRKO 和 CSDIRKO 小鼠中的超极化激活环核苷酸门控通道 4（HCN4）蛋白表达明显低于对照组。对 CSIRKO 小鼠 SAN 细胞的膜片钳研究显示，有趣电流明显减少，有趣电流是 SAN 中自发性舒张去极化的原因。这一结果表明，胰岛素受体缺失通过下调 HCN4 通道降低心率。此外，CSDIRKO 小鼠中的 HCN1 表达减少，解释了它们的窦房结功能障碍。我们的研究结果揭示了胰岛素/IGF-1 信号在窦房结结构维持和起搏器功能中的先前未知作用。
