title: Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation.
abstract: Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone produced by gastrointestinal tract in response to food ingestion. GLP-1 plays a very important role in the glucose homeostasis by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, reducing appetite and food intake. Because of these actions, the GLP-1 peptide-mimetic exenatide is one of the most promising new medicines for the treatment of type 2 diabetes. In vivo treatments with GLP-1 or exenatide prevent neo-intima layer formation in response to endothelial damage and atherosclerotic lesion formation in aortic tissue. Whether GLP-1 modulates vascular smooth muscle cell (VSMC) migration and proliferation by controlling mitochondrial dynamics is unknown. In this report, we showed that GLP-1 increased mitochondrial fusion and activity in a PKA-dependent manner in the VSMC cell line A7r5. GLP-1 induced a Ser-637 phosphorylation in the mitochondrial fission protein Drp1, and decreased Drp1 mitochondrial localization. GLP-1 inhibited PDGF-BB-induced VSMC migration and proliferation, actions inhibited by overexpressing wild type Drp1 and mimicked by the Drp1 inhibitor Mdivi-1 and by overexpressing dominant negative Drp1. These results show that GLP-1 stimulates mitochondrial fusion, increases mitochondrial activity and decreases PDGF-BB-induced VSMC dedifferentiation by a PKA/Drp1 signaling pathway. Our data suggest that GLP-1 inhibits vascular remodeling through a mitochondrial dynamics-dependent mechanism.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
authors.forename: Gloria
authors.initials: G
authors.lastname: Torres
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Morales
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Marina
authors.initials: M
authors.lastname: García-Miguel
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Norambuena-Soto
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Cartes-Saavedra
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Vidal-Peña
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Moncada-Ruff
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Sanhueza-Olivares
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
authors.forename: Alejandra
authors.initials: A
authors.lastname: San Martín
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Centro Estudios Moleculares de la Célula (CEMC), Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile. Electronic address: mchiong@uchile.cl.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000378:metabolism / Q000494:pharmacology*; D018929:Cell Culture Techniques; D054337:Cell Dedifferentiation / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
chemical_list: D024101:Mitochondrial Proteins; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1
keywords: Drp1; GLP-1; Mitochondrial dynamics; VSMC; VSMC dedifferentiation