Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension

• Published in: Journal of biomedical science Vol. 26; no. 1; p. 6
• Main Authors: Wang, Jingjing, Yu, Min, Xu, Jian, Cheng, Yusheng, Li, Xiang, Wei, Guihong, Wang, Hong, Kong, Hui, Xie, Weiping
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.01.2019; BioMed Central; BMC
• Subjects: Analysis; Atherosclerosis; Bleomycin; Blood pressure; Cadherins; Cell adhesion & migration; Cell cycle; Cell growth; Dipeptidyl-peptidase IV; Down-regulation; DPP-4i; Endothelial cells; GLP-1; Glucagon; Glucagon-like peptide 1; Heart; Hypertension; Hypoxia; IL-1β; Inflammation; Influence; Inhibition; Kinases; Laboratory animals; Lungs; Mesenchyme; Monocrotaline; Peptidase; Peptides; Phosphorylation; Proteases; Pulmonary arteries; Pulmonary hypertension; Pulmonary vascular remodeling; Rodents; Smad3 protein; Smooth muscle; Systolic pressure; Transforming growth factor-b1; Umbilical vein; Veins & arteries; Ventricle; United States > US; Pulmonary vascular remodeling; GLP-1; DPP-4i
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-019-0496-y

Pulmonary hypertension (PH) is a progressive disease leading to death ultimately. Our recently published data demonstrated that inhibiting dipeptidyl peptidase IV (DPP-4) alleviated pulmonary vascular remodeling in experimental PH. However, whether glucagon-like peptide-1 (GLP-1) mediated the protective effect of DPP-4 inhibition (DPP-4i) on PH is unclear. In the present study, GLP-1 receptor antagonist (exendin-3) abolished the protective effects of DPP-4 inhibitor (sitagliptin) on right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling (PVR) in monocrotaline (MCT, 60 mg/kg)-induced PH in rat. Notably, activation of GLP-1 receptor by GLP-1 analogue liraglutide directly attenuated RVSP and PVR in MCT-induced PH, as well as bleomycin- and chronic hypoxia-induced PH. Moreover, liraglutide potently inhibited MCT-induced inflammation and suppressed MCT-induced down-regulation of vascular endothelial marker (VE-cadherin and vWF) in lung. In vitro studies showed liraglutide reversed TGF-β1 (5 ng/ml) combining IL-1β (5 ng/ml) induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs), which could be abolished by GLP-1 receptor antagonist (exendin-3). Furtermore, liraglutide suppressed TGF-β1-IL-1β-induced phosphorylation of both Smad3 and ERK1/2. Our data suggest that GLP-1 mediated the protective effects of DPP-4i on pulmonary vascular and RV remodeling in experimental PH, which may be attributed to the inhibitory effect on EndMT.