Glucagon-Like Peptide-1 Receptor Agonist Attenuates Autophagy to Ameliorate Pulmonary Arterial Hypertension through Drp1/NOX- and Atg-5/Atg-7/Beclin-1/LC3β Pathways.

Mitochondrial dysfunction is associated with cardiovascular diseases and diabetes. Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, and the abnormal proliferation, apoptosis and migration of pulmonary arterial smooth muscle cells (PASMCs). The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, has been shown to prevent pulmonary hypertension in monocrotaline-exposed rats. The aim of this study was to investigate the effect of liraglutide on autophagy, mitochondrial stress and apoptosis induced by platelet-derived growth factor BB (PDGF-BB). PASMCs were exposed to PDGF-BB, and changes in mitochondrial morphology, fusion-associated protein markers, and reactive oxygen species (ROS) production were examined. Autophagy was assessed according to the expressions of microtubule-associated protein light chain 3 (LC3)-II, LC3 puncta and Beclin-1. Western blot analysis was used to assess apoptosis, mitochondrial stress and autophagy markers. Liraglutide significantly inhibited PDGF-BB proliferation, migration and motility in PASMCs. PDGF-BB-induced ROS production was mitigated by liraglutide. Liraglutide increased the expression of α-smooth muscle actin (α-SMA) and decreased the expression of p-Yes-associated protein (p-YAP), inhibited autophagy-related protein (Atg)-5, Atg-7, Beclin-1 and the formation of LC3-β and mitochondrial fusion protein dynamin-related (Drp)1. Therefore, liraglutide can mitigate the proliferation of PASMCs via inhibiting cellular Drp1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) pathways and Atg-5/Atg-7/Beclin-1/LC3β-dependent pathways of autophagy in PAH.