Liraglutide, a GLP-1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atherosclerosis in ApoE deficient mice

Autor: Kohsuke Uchida, Kikuo Kasai, Toshie Iijima, Kazunori Yanagi, Takanori Tomotsune, Kunihiro Suzuki, Kazumi Akimoto, Yoshimasa Aso, Teruo Jojima
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Apolipoprotein E
medicine.medical_specialty
Vascular smooth muscle
Mice
Knockout
ApoE
Myocytes
Smooth Muscle
AMP-Activated Protein Kinases
Diet
High-Fat
Incretins
Glucagon-Like Peptide-1 Receptor
Muscle
Smooth
Vascular
03 medical and health sciences
AMP-activated protein kinase
Internal medicine
medicine
Animals
Phosphorylation
Rats
Wistar
Protein kinase A
Receptor
Cells
Cultured
Cell Proliferation
Dose-Response Relationship
Drug
biology
Cell growth
Liraglutide
Angiotensin II
AMPK
Atherosclerosis
Plaque
Atherosclerotic
Enzyme Activation
G2 Phase Cell Cycle Checkpoints
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
Disease Progression
cardiovascular system
biology.protein
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.drug
Zdroj: Atherosclerosis. 261:44-51
ISSN: 0021-9150
DOI: 10.1016/j.atherosclerosis.2017.04.001
Popis: Background and aims Several studies have demonstrated that both native glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists suppress the progression of atherosclerosis in animal models. Methods We investigated whether liraglutide, a GLP-1 analogue, could prevent the development of atherosclerosis in apolipoprotein E knockout mice ( ApoE −/− ) on a high-fat diet. We also examined the influence of liraglutide on angiotensin II-induced proliferation of rat vascular smooth muscle cells (VSMCs) via enhancement of AMP-activated protein kinase (AMPK) signaling and regulation of cell cycle progression. Results Treatment of ApoE −/− mice with liraglutide (400 μg/day for 4 weeks) suppressed atherosclerotic lesions and increased AMPK phosphorylation in the aortic wall. Liraglutide also improved the endothelial function of thoracic aortas harvested from ApoE −/− mice in an ex vivo study. Furthermore, liraglutide increased AMPK phosphorylation in rat VSMCs, while liraglutide-induced activation of AMPK was abolished by exendin 9-39, a GLP-1 antagonist. Moreover, angiotensin (Ang) II-induced proliferation of VSMCs was suppressed by liraglutide in a dose-dependent manner, and flow cytometry of Ang II-stimulated VSMCs showed that liraglutide reduced the percentage of cells in G2/M phase (by arrest in G0/G1 phase). Conclusions These findings suggest that liraglutide may inhibit Ang II-induced VSMC proliferation by activating AMPK signaling and inducing cell cycle arrest, thus delaying the progression of atherosclerosis independently of its glucose-lowering effect.
Databáze: OpenAIRE
Externí odkaz: