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

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Jingjing Wang, Min Yu, Jian Xu, Yusheng Cheng, Xiang Li, Guihong Wei, Hong Wang, Hui Kong, Weiping Xie
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 26 Issue 1 Pg. 6 (Jan 12 2019) ISSN: 1423-0127 [Electronic] England
• PMID: 30634956 (Publication Type: Journal Article)

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Incretins
• Peptides
• Protective Agents
• exendin 3
• Liraglutide
• Sitagliptin Phosphate

Topics

• Animals
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Hypertension, Pulmonary (drug therapy)
• Incretins (pharmacology)
• Liraglutide (pharmacology)
• Male
• Peptides (pharmacology)
• Protective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sitagliptin Phosphate (pharmacology)