Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis

被引:43
|
作者
Shen, Zhu-Xia [1 ,2 ,3 ]
Chen, Xiao-Qing [4 ]
Sun, Xue-Nan [1 ,3 ]
Sun, Jian-Yong [3 ]
Zhang, Wu-Chang [1 ]
Zheng, Xiao-Jun [1 ,3 ]
Zhang, Yu-Yao [1 ,3 ]
Shi, Huan-Jing [3 ]
Zhang, Jia-Wei [3 ]
Li, Chao [1 ,3 ]
Wang, Jun [2 ]
Liu, Xu [4 ]
Duan, Sheng-Zhong [1 ]
机构
[1] Shanghai Jiao Tong Univ, Peoples Hosp 9, Shanghai Res Inst Stomatol,Sch Med, Shanghai Key Lab Stomatol,Sch Stomatol,Lab Oral M, Shanghai 200011, Peoples R China
[2] Fudan Univ, Dept Cardiol, Jingan Dist Ctr Hosp Shanghai, Huashan Hosp,Jingan Branch, Shanghai 200040, Peoples R China
[3] Univ Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci,Chinese Acad Sci, Shanghai 200031, Peoples R China
[4] Shanghai Jiao Tong Univ, Sch Med, Shanghai Chest Hosp, Dept Cardiol, Shanghai 200030, Peoples R China
基金
中国国家自然科学基金;
关键词
SELECTIVE ALDOSTERONE BLOCKER; ANGIOTENSIN-II; PPAR-ALPHA; KEY ROLE; EPLERENONE; DELETION; HEART; ACCUMULATION; INFLAMMATION; PHENOTYPE;
D O I
10.1074/jbc.M116.739243
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, MRKOdecreased 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, MRKOreduces 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.
引用
收藏
页码:925 / 935
页数:11
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