title: Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis.
abstract: Mineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control mice or from myeloid MR knock-out (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO decreased atherosclerotic lesion area in LDLRKO mice. In another mouse model of atherosclerosis, MRKO/APOEKO mice and floxed control/APOEKO mice were generated and treated with angiotensin II. Similarly, MRKO inhibited the atherosclerotic lesion area in APOEKO mice. Histological analysis showed that MRKO increased collagen coverage and decreased necrosis and macrophage accumulation in the lesions. In vitro results demonstrated that MRKO suppressed macrophage foam cell formation and up-regulated the expression of genes involved in cholesterol efflux. Furthermore, MRKO decreased accumulation of apoptotic cells and increased effective efferocytosis in atherosclerotic lesions. In vitro study further revealed that MRKO increased the phagocytic index of macrophages without affecting their apoptosis. In conclusion, MRKO reduces high cholesterol- or angiotensin II-induced atherosclerosis and favorably changes plaque composition, likely improving plaque stability. Mechanistically, MR deficiency suppresses macrophage foam cell formation and up-regulates expression of genes related to cholesterol efflux, as well as increases effective efferocytosis and phagocytic capacity of macrophages.
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.|the Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Huashan Hospital Jing'an Branch, Fudan University, Shanghai 200040, China.|the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Zhu-Xia
authors.initials: ZX
authors.lastname: Shen
authors.affiliation: the Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.|the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Xue-Nan
authors.initials: XN
authors.lastname: Sun
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Sun
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Wu-Chang
authors.initials: WC
authors.lastname: Zhang
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.|the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Zheng
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.|the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Yu-Yao
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Huan-Jing
authors.initials: HJ
authors.lastname: Shi
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.|the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: the Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Huashan Hospital Jing'an Branch, Fudan University, Shanghai 200040, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China, duansz@shsmu.edu.cn.
authors.forename: Sheng-Zhong
authors.initials: SZ
authors.lastname: Duan
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018161:Receptors, Mineralocorticoid / Q000172:deficiency* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D002784:Cholesterol
keywords: aldosterone; atherosclerosis; efferocytosis; foam cell; macrophage; mineralocorticoid receptor; phagocytosis