Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor

• Published in: Molecular and cellular endocrinology 2010-08, Vol.325 (1), p.26-35
• Main Authors: Erdogdu, Ö., Nathanson, D., Sjöholm, Å., Nyström, T., Zhang, Q.
• Format: Article
• Language: English
• Subjects: Activation; Arteries; Cell Proliferation - drug effects; Cells, Cultured; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic AMP-Dependent Protein Kinases - physiology; Dose-Response Relationship, Drug; Endothelial cell; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Exendin-4; GLP-1 receptor; Glucagon-like peptide-1 (GLP-1); Glucagon-Like Peptide-1 Receptor; Human; Humans; Inhibitors; Integrity; MAP Kinase Signaling System - drug effects; Medicin och hälsovetenskap; Nitric Oxide Synthase Type III - metabolism; Nitric Oxide Synthase Type III - physiology; Oncogene Protein v-akt - metabolism; Oncogene Protein v-akt - physiology; Pathways; Peptides - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation - drug effects; Proliferation; Receptors; Receptors, Glucagon - metabolism; Receptors, Glucagon - physiology; Signal Transduction - drug effects; Venoms - pharmacology
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2010.04.022

Endothelial cells have a robust capacity to proliferate and participate in angiogenesis, which underlies the maintenance of intimal layer integrity. We previously showed the presence of the GLP-1 receptor in human coronary artery endothelial cells (HCAECs) and the ameliorative actions of GLP-1 on endothelial dysfunction in type 2 diabetic patients. Here, we have studied the effect of exendin-4 on cell proliferation and its underlying mechanisms in HCAECs. Incubation of HCAECs with exendin-4 resulted in a dose-dependent increase in DNA synthesis and an increased cell number, associated with an enhanced eNOS and Akt activation, which were inhibited by PKA, PI3K, Akt or eNOS inhibitors and abolished by a GLP-1 receptor antagonist. Similar effects were obtained by applying GLP-1 (7–36) or GLP-1 (9–36). Co-incubation of exendin-4 and GLP-1 did not show additive effects. Our results suggest that exendin-4 stimulates proliferation of HCAECs through PKA-PI3K/Akt-eNOS activation pathways via a GLP-1 receptor-dependent mechanism.