Exendin-4, a glucagon-like peptide-1 receptor agonist, regulates ductus arteriosus by vasodilation and anti-remodeling through the PKA pathway

  • Eur J Pharmacol. 2024 Dec 15:985:177106. doi: 10.1016/j.ejphar.2024.177106.
Yi-Ching Liu  1 ,  Yu-Hsin Tseng  2 ,  Yen-Hsien Wu  1 ,  Lorraine Tong  3 ,  Siao-Ping Tsai  4 ,  Shang-En Huang  5 ,  Bin-Nan Wu  6 ,  Shih-Hsing Lo  2 ,  I-Chen Chen  7 ,  Zen-Kong Dai  7 ,  Jwu-Lai Yeh  8 ,  Jong-Hau Hsu  9
Affiliations
  • 1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 2. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 3. School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 4. Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 5. Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 6. Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • 7. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 8. Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address: [email protected].
  • 9. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: [email protected].
PMID: 39515563 DOI: 10.1016/j.ejphar.2024.177106
Abstract

The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. Previous findings indicate that the glucagon-like peptide-1 receptor agonist (GLP-1RA) exhibits antihypertensive and anti-remodeling effects in the pulmonary circulation. However, its role in the DA remains unknown. This study aimed to investigate whether exendin-4 (Ex-4), a GLP-1RA, can regulate DA patency and elucidate its mechanisms. After confirming the presence of GLP-1R in neonatal rat DA tissue in vivo, the effects of Ex-4 on DA patency in neonatal rats were sequentially examined. Two hours after birth, we observed spontaneous closure of the DA in control rats. In contrast, Ex-4 prevented the closure of DA, accompanied by reduced intimal thickening. Ex-4 attenuated oxygen-induced vasoconstriction in isolated DA rings ex vivo. This effect was diminished in the presence of H89, a PKA Inhibitor. In vitro, Ex-4 inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of DA smooth muscle cells. Additionally, Ex-4 inhibited PDGF-BB-induced Reactive Oxygen Species (ROS) production, calcium mobilization, and signal transduction of MAPK and Akt pathways. Furthermore, Ex-4 preserved the nuclear expression of Nrf2 attenuated by PDGF-BB. Similarly, all these in vitro effects of Ex-4 were blunted by H89. In conclusion, Ex-4 maintains postnatal DA patency through vasodilatation and anti-remodeling via the PKA pathway. The GLP-1R/PKA pathway emerges as a promising target of DA patency in clinical management.

Keywords
Anti-remodeling; Ductus arteriosus; Exendin-4; Glucagon-like peptide-1 receptor; PKA pathway; Vasodilation.
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