The glucagon-like peptide-1 receptor agonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ETB receptor expression.

摘要

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutideis an incretin hormone mimetic used in the treatment of diabetes.However, the effects of liraglutide on pulmonary hypertension(PH) and pulmonary endothelin (ET) system are unknown.Eight-week-old C57BL6/J mice were injected liraglutide or vehiclefor 5 weeks. One week after injection, the mice were exposed toeither room air (normoxia) or chronic hypoxia (10 % O2) for4 weeks. The right ventricular systolic pressure (RVSP) wassignificantly higher in hypoxia + vehicle group than in normoxia+ vehicle group. ET-1 mRNA expression in the lungs wascomparable among all the groups. ETB mRNA and proteinexpression in the lungs was significantly lower in hypoxia +vehicle group than in normoxia + vehicle group. The abovechanges were normalized by liraglutide treatment. Theexpression of phospho-eNOS and phospho-AMPK proteins in thelungs was significantly higher in hypoxia + liraglutide group thanin normoxia + vehicle group. We demonstrated for the first timethat liraglutide effectively improved RVSP and RV hypertrophy inhypoxia-induced PH mice by activating eNOS throughnormalization of impaired ETB pathway and augmentation ofAMPK pathway. Therefore, GLP-1R agonists can be promisingtherapeutic agents for PH.