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

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• 作者：Gloria Torres^a ; ^b ; ¹ ; Pablo E. Morales^a ; ¹ ; Marina Garcí ; a-Miguel^a ; ¹ ; Ignacio Norambuena-Soto^a ; Benjamí ; n Cartes-Saavedra^a ; Gonzalo Vidal-Peñ ; a^a ; David Moncada-Ruff^a ; Fernanda Sanhueza-Olivares^a ; Alejandra San Martí ; n^b ; Mario Chiong^a ; ^{mchiong@uchile.cl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ΔΨm ; mitochondrial membrane potential ; Drp1 ; dynamin related protein 1 ; Fis1 ; fission protein 1 ; GAPDH ; glyceraldehyde 3-phosphate dehydrogenase ; GLP-1 ; glucagon-like peptide-1 ; Mfn1/2 ; mitofusin-1/2 ; MTO ; MitoTracker Orange ; OCR ; oxygen consumption rate ; Opa1 ; optic atrophy 1 protein ; PDGF-BB ; platelet-derived growth factor-BB ; PKA ; protein kinase A ; ROS ; reactive oxygen species ; VSMC ; vascular smooth muscle cell
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：104
• 期：Complete
• 页码：52-61
• 全文大小：1637 K

文摘

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.