The 60th Annual Meeting of Japanese Society of Pediatric Cardiology and Cardiac Surgery

Presentation information

JCK-AP session

Miscellaneous

JCK-AP session 5-1 (II-JCKAP5-1)
Miscellaneous 1

Fri. Jul 12, 2024 3:30 PM - 4:20 PM ROOM 8・JCK-AP Forum (5F 502+503)

Chair:Ken Takahashi(Department of Pediatrics, Juntendo University Urayasu Hospital)
Chair:Jae Young Lee(The Catholic University of Korea School of Medicine)

[II-JCKAP5-1-1] Exendin-4, A Glucagon-Like Peptide-1 Receptor Agonist, Regulates Ductus Arteriosus by Vasodilation and Anti-Remodeling Through the PKA Pathway

Yi-Ching Liu1, Yu-Hsin Tseng1, Ju-Lai Yeh2, Yen-Hsien Wu1, Zen-Kong Dai1,3, Shih-Hsing Lo1, I-Chen Chen1,3 (1.Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 2.Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 3.Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung)

Keywords:GLP-1, ductus ateriosus , anti-remodeling

Objective:
The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. We have previously found that glucagon-like peptide-1 receptor agonist (GLP-1RA) conveys antihypertensive and anti-remodeling effects in pulmonary circulation. This study was to investigate if exendin-4 (Ex-4), a GLP-1RA, can prevent DA closure in neonatal rats.
Methods:
In vivo, we first examined the GLP-1R expression on DA. In addition, neonatal rats were intraperitoneally injected Ex-4 or normal saline immediately after birth. We observed luminal patency and intimal thickening of DA 2h later. Ex vivo, in isolated DA rings, we determined effects of Ex-4 on vasodilation after oxygen-induced constriction. In vitro, in cultured DA smooth muscle cells (DASMCs), we investigated mechanisms underlying DA regulation including proliferation, migration, reactive oxygen species (ROS), MAPK, and Akt signal transduction.
Results:
In vivo, we demonstrated GLP-1 receptor expression in DA declined after birth. In addition, Ex-4 prevented DA closure and intimal thickening at 2h. Ex vivo, Ex-4 attenuated oxygen-induced DA constriction which was blunted by the PKA-inhibitor. In vitro, our results showed that Ex-4 inhibited PDGF-induced proliferation and migration of DASMCs with downregulation of mitochondrial ROS production, MAPK, and Akt signaling.
Conclusion:
Ex-4 maintains postnatal DA patency by vasodilatation and anti-remodeling through the PKA pathway. The GLP-1R/PKA pathway can be a promising target of DA patency in clinical management.