LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells

• Published in: Biochemical and biophysical research communications Vol. 437; no. 1; pp. 62 - 66
• Main Authors: Dai, Yao, Mercanti, Federico, Dai, Dongsheng, Wang, Xianwei, Ding, Zufeng, Pothineni, Naga Venkata, Mehta, Jawahar L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2013
• Subjects: Animals; Aorta - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Fluorescence; Gene Deletion; GLP-1; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; Humans; Lipoproteins, LDL - pharmacology; Liraglutide; LOX-1; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Ox-LDL; Reactive Oxygen Species - metabolism; Receptors, Glucagon - metabolism; ROS; Scavenger Receptors, Class E - metabolism; GLP-1; LOX-1; ROS; Ox-LDL
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.06.035

•GLP-1 activation and mitochondrial ROS generation in blood vessels are interconnected.•LOX-1 acts as a bridge between GLP-1 activation and ROS generation.•Evidence based on use of LOX-1 antibody and LOX-1 over-expression in vascular smooth muscle cells. A growing body of evidence indicates that glucagon-like peptide-1 (GLP-1) agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors play an important role in modulating oxidant stress in vascular beds. However, the underlying mechanism of this process remains unclear. In recent studies, we observed an increase in GLP-1 receptor (GLP-1R) expression in the aorta of LOX-1 knock-out mice. Since LOX-1 is a pivotal regulator of reactive oxygen species (ROS), we conducted studies to identify relationship between LOX-1, ROS and GLP-1 agonism or DPP-4 antagonism. We observed a sustained decrease in GLP-1R expression in human vascular smooth muscle cells (VSMCs) treated with ox-LDL. When VSMCs were treated with different concentration of liraglutide (a GLP-1 agonist) or NVPDPP728 (a DPP-4 inhibitor), expression of ROS decreased compared with ox-LDL alone treatment. To further prove that LOX-1 plays a pivotal role in ROS and GLP-1R expression, we treated VSMCs with LOX-1 antibody or transfected cells with human LOX-1 cDNA. The inhibitory effect of ox-LDL on GLP-1R expression was reversed with anti-LOX-1 antibody treatment, while the inhibitory effect of liraglutide and NVPDPP728 on ROS generation was attenuated when cells were transfected with LOX-1 cDNA. Our results suggest that LOX-1 may play a bridging role in GLP-1 activation and ROS interaction.