The effect of the GLP-1 agonist, liraglutide, on the right ventricle in pulmonary hypertension

Abstract

Right ventricular (RV) function is the major determinant of prognosis in pulmonary hypertension (PH) and dysregulated myocardial metabolism is a prominent feature of RV dysfunction. Glucagon-like peptide-1 (GLP-1) is one of the incretin hormones that potentiates insulin secretion and reduces glucagon release. Recent studies have shown that GLP-1 agonist liraglutide, an approved diabetes treatment, reduces the risk of heart failure in diabetes patients and improves pulmonary endothelial function in PH rats. My PhD project hypothesized that liraglutide is an emerging PH treatment, aiming to define its effects on RV function. I established cardiac magnetic resonance imaging (MRI) as a key translational tool to characterize the RV functional and structural remodelling, especially the RV uncoupling features, employing monocrotaline (MCT) and Sugen hypoxia (SuHx) PH models, along the course of PH development, together with pathological and molecular assessment. In both MCT and SuHx rats, treatment with liraglutide attenuated pulmonary artery pressure and pulmonary remodelling. Importantly, I demonstrated that liraglutide reversed the MCT or SuHx induced RV structural and functional remodelling by MRI cine, T1 mapping and gadolinium-enhanced scans. Moreover, pathological examination indicated that liraglutide reduced cardiac fibrosis and cardiomyocyte hypertrophy, as well as capillary rarefaction. Further study using the pulmonary artery banding mice validated and confirmed the direct effect of liraglutide on the RV. I examined the molecular pathways involved in RV remodelling that are impacted by liraglutide using RNA sequencing. Data from the PAB and SuHx models indicated the important involvement of liraglutide in the regulation of PI3K-Akt and AMPK pathways. My PhD project presented important preclinical evidence that liraglutide saves RV structural and functional remodelling in PH by modulating the cardiac metabolic homeostasis in addition to its pulmonary effects, supporting liraglutide as a potential future therapeutic option for PH patients.