Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor.
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.
Erdogdu
O
O
Karolinska Institutet, Department of Clinical Science and Education, Unit for Diabetes Research, Södersjukhuset, Stockholm, Sweden.
Nathanson
D
D
Sjöholm
A
A
Nyström
T
T
Zhang
Q
Q
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D018027:Receptors, Glucagon / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology*
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D017868:Cyclic AMP-Dependent Protein Kinases