한빛사논문
- 조회486
Sangmi Ock1, Seong Woo Choi2,3, Seung Hee Choi4, Hyun Kang5, Sung Joon Kim2, Wang-Soo Lee6 and Jaetaek Kim1
1Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
2Departments of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
3Department of Physiology, Dongguk University College of Medicine, Gyeongju, Korea.
4Division of Endocrinology and Metabolism, Departments of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Korea.
5Department of Anesthesiology, College of Medicine, Chung-Ang University, Seoul, Korea.
6Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
Corresponding authors : Correspondence to Wang-Soo Lee or Jaetaek Kim.
Abstract
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.
논문정보
- Research article
- 2023년 05월 (BRIC 등록일 2023-05-19)
- 국내 연구진
- 의약학 > 응용의학
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