Jing Wang1, Ang Ma2, Ming Zhao3, Haibo Zhu4. 1. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, China; Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China. 2. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, China. 3. Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, USA. Electronic address: m-zhao@northwestern.edu. 4. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, China. Electronic address: zhuhaibo@imm.ac.cn.
Abstract
BACKGROUND AND AIMS: CC chemokine receptor 2 (Ccr2) governs migration of inflammatory Ly6Chi monocytes from the bone marrow (BM) to the circulating blood, which is a key step for macrophage accumulation during progression of atherosclerosis. Hyperlipidemia is often accompanied by low AMP-activated kinase (AMPK) activity and increased expression of Ccr2. The aim of this study was to examine whether there is a link between AMPK and chemokine networks. METHODS: ApoE-/- mice were fed a western diet and treated daily with AMPK activators (AICAR, A769662, or Metformin) or vehicle for 10 weeks. The effect of AMPK activators on pro-inflammatory myeloid cell numbers within the BM, blood, spleen, and aorta of ApoE-/- mice was then examined. RESULTS: We found that AMPK activation significantly reduced the number of Ly6Chi monocytes in the blood and atherosclerotic plaques. This reduction was caused by down-regulation of Ccr2 protein expression, which inhibited Ccr2-mediated migration of Ly6Chi monocytes from the BM to the circulation. There was no effect on proliferation or apoptosis of BM-derived Ly6Chi monocytes. AMPK activation caused Ly6Chi monocytes to accumulate in the BM, with a concomitant reduction in numbers in the blood and spleen. CONCLUSIONS: AMPK activation reduces the formation of atheromata-inducing macrophages in ApoE-/--deficient mice by inhibiting expression of Ccr2, thereby preventing the Ccr2-mediated migration of Ly6Chi monocytes from the BM. Therefore, AMPK may be a promising target for the treatment of atherosclerosis.
BACKGROUND AND AIMS: CC chemokine receptor 2 (Ccr2) governs migration of inflammatory Ly6Chi monocytes from the bone marrow (BM) to the circulating blood, which is a key step for macrophage accumulation during progression of atherosclerosis. Hyperlipidemia is often accompanied by low AMP-activated kinase (AMPK) activity and increased expression of Ccr2. The aim of this study was to examine whether there is a link between AMPK and chemokine networks. METHODS:ApoE-/- mice were fed a western diet and treated daily with AMPK activators (AICAR, A769662, or Metformin) or vehicle for 10 weeks. The effect of AMPK activators on pro-inflammatory myeloid cell numbers within the BM, blood, spleen, and aorta of ApoE-/- mice was then examined. RESULTS: We found that AMPK activation significantly reduced the number of Ly6Chi monocytes in the blood and atherosclerotic plaques. This reduction was caused by down-regulation of Ccr2 protein expression, which inhibited Ccr2-mediated migration of Ly6Chi monocytes from the BM to the circulation. There was no effect on proliferation or apoptosis of BM-derived Ly6Chi monocytes. AMPK activation caused Ly6Chi monocytes to accumulate in the BM, with a concomitant reduction in numbers in the blood and spleen. CONCLUSIONS: AMPK activation reduces the formation of atheromata-inducing macrophages in ApoE-/--deficient mice by inhibiting expression of Ccr2, thereby preventing the Ccr2-mediated migration of Ly6Chi monocytes from the BM. Therefore, AMPK may be a promising target for the treatment of atherosclerosis.
Authors: Yu Kataoka; Stephen J Nicholls; Jordan Andrews; Kiyoko Uno; Samir R Kapadia; E Murat Tuzcu; Steven E Nissen; Rishi Puri Journal: Cardiovasc Diagn Ther Date: 2022-02
Authors: Juan M Suárez-Rivero; Carmen J Pastor-Maldonado; Mario de la Mata; Marina Villanueva-Paz; Suleva Povea-Cabello; Mónica Álvarez-Córdoba; Irene Villalón-García; Alejandra Suárez-Carrillo; Marta Talaverón-Rey; Manuel Munuera; José A Sánchez-Alcázar Journal: Int J Mol Sci Date: 2019-10-20 Impact factor: 5.923
Authors: Nicholas D LeBlond; Peyman Ghorbani; Conor O'Dwyer; Nia Ambursley; Julia R C Nunes; Tyler K T Smith; Natasha A Trzaskalski; Erin E Mulvihill; Benoit Viollet; Marc Foretz; Morgan D Fullerton Journal: J Lipid Res Date: 2020-09-25 Impact factor: 5.922
Authors: Anusha Seneviratne; Luke Cave; Gareth Hyde; Soren Kragh Moestrup; David Carling; Justin C Mason; Dorian O Haskard; Joseph James Boyle Journal: Cardiovasc Res Date: 2021-04-23 Impact factor: 13.081