Ángela Vinué1, Jorge Navarro1,2,3, Andrea Herrero-Cervera1, Marta García-Cubas1, Irene Andrés-Blasco1, Sergio Martínez-Hervás1,4,5, José T Real1,4,5, Juan F Ascaso1,4,5, Herminia González-Navarro6,7. 1. Institute of Health Research-INCLIVA, Avda Menéndez Pelayo 4, 46010, Valencia, Spain. 2. Clinic Hospital and Department of Medicine, University of Valencia, Institute of Health Research-INCLIVA, Valencia, Spain. 3. CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain. 4. Endocrinology and Nutrition Department, Clinic Hospital and Department of Medicine, University of Valencia, Valencia, Spain. 5. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain. 6. Institute of Health Research-INCLIVA, Avda Menéndez Pelayo 4, 46010, Valencia, Spain. herminia.gonzalez@uv.es. 7. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain. herminia.gonzalez@uv.es.
Abstract
AIMS/HYPOTHESIS: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated. METHODS: Atherosclerosis development was evaluated in Apoe -/- Irs2 +/- mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in Apoe -/- Irs2 +/- mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways. RESULTS: Treatment of Apoe -/- Irs2 +/- mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6Chigh monocytes and activated T cells. In vitro analysis showed that, in macrophages from Apoe -/- Irs2 +/- mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques. CONCLUSIONS/ INTERPRETATION: Lixisenatide decreases atheroma plaque size and instability in Apoe -/- Irs2 +/- mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.
AIMS/HYPOTHESIS: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated. METHODS:Atherosclerosis development was evaluated in Apoe -/- Irs2 +/- mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in Apoe -/- Irs2 +/- mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways. RESULTS: Treatment of Apoe -/- Irs2 +/- mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6Chigh monocytes and activated T cells. In vitro analysis showed that, in macrophages from Apoe -/- Irs2 +/- mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques. CONCLUSIONS/ INTERPRETATION:Lixisenatidedecreases atheroma plaque size and instability in Apoe -/- Irs2 +/- mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.
Entities:
Keywords:
Atherosclerosis; GLP-1; Inflammation; Macrophage; STAT
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