Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation

• Type of Material: Article
• Authors: Gloria Torres, Universidad de Chile; Pablo E. Morales, Universidad de Chile; Marina García-Miguel, Universidad de Chile; Ignacio Norambuena-Soto, Universidad de Chile; Benjamín Cartes-Saavedra, Universidad de Chile; Gonzalo Vidal-Peña, Universidad de Chile; David Moncada-Ruff, Universidad de Chile; Fernanda Sanhueza-Olivares, Universidad de Chile; Alejandra San Martin Almeyda, Emory University; Mario Chiong, Universidad de Chile
• Language: English
• Date: 2016-03-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bcp.2016.01.013
• Title of Journal or Parent Work: Biochemical Pharmacology
• ISSN: 0006-2952
• Volume: 104
• Start Page: 52
• End Page: 61
• Grant/Funding Information: P.M. and DM-R hold CONICYT PhD fellowships.; This research was funded in part by Comision Nacional de Ciencia y Tecnologia (CONICYT), Chile (FONDECYT 1110180 and 1140329 to M.C.; FONDAP 15130011 to M.C.). HL113167 from the National Institute of Health (to ASM).
• Keywords: GLYCEMIC CONTROL; GLP-1; INTIMAL HYPERPLASIA; METABOLISM; Drp1; ATHEROSCLEROTIC LESION; Science & Technology; RECEPTOR AGONIST; VSMC dedifferentiation; DRP1; THERAPEUTIC TARGET; Mitochondrial dynamics; Life Sciences & Biomedicine; PROLIFERATION; VSMC; DEPENDENT PROTEIN-KINASE; FISSION; Pharmacology & Pharmacy
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology

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.