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.
Highlights
Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes
The aims of this study were to investigate the effects of liraglutide on monocrotaline (MCT) induced pulmonary arterial hypertension (PAH) in rats and its influence on the protein expressions of endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), protein kinase G (PKG) and Rho kinase of lung tissue and pulmonary artery smooth muscle cells (PASMCs)
There were no significant differences in mean heart rate or glucose level in the prevention or treatment groups
Summary
Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. We investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Cell migration and cell cycle were determined Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. 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 MCTinduced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. CGMP-dependent protein kinase or protein kinase G (PKG) is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell division, and nucleic acid synthesis[9]. GLP-1 increases myocardial glucose uptake during aerobic perfusion, independent of insulin-stimulated Akt phosphorylation and glucose transporter 4 (GLUT4) translocation, in association with increased p38 mitogen-activated protein kinase (MAPK) activity, enhanced NO production, and increased GLUT1 protein levels at the sarcolemmal membrane[12]
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