title: Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways.
abstract: Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling.
authors: Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Internal Medicine, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan.
authors: Mei-Yueh
authors: MY
authors: Lee
authors: Department of Pathology, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan.
authors: Kun-Bow
authors: KB
authors: Tsai
authors: Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Jong-Hau
authors: JH
authors: Hsu
authors: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors: Shyi-Jang
authors: SJ
authors: Shin
authors: Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Jiunn-Ren
authors: JR
authors: Wu
authors: Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors: Jwu-Lai
authors: JL
authors: Yeh
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002453:Cell Cycle; D002465:Cell Movement; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000378:metabolism; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000069450:Liraglutide / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline / Q000737:chemistry*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D016686:Monocrotaline; D000069450:Liraglutide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP