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

• Published in: The Journal of biological chemistry Vol. 292; no. 3; pp. 925 - 935
• Main Authors: Shen, Zhu-Xia, Chen, Xiao-Qing, Sun, Xue-Nan, Sun, Jian-Yong, Zhang, Wu-Chang, Zheng, Xiao-Jun, Zhang, Yu-Yao, Shi, Huan-Jing, Zhang, Jia-Wei, Li, Chao, Wang, Jun, Liu, Xu, Duan, Sheng-Zhong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2017; American Society for Biochemistry and Molecular Biology
• Subjects: aldosterone; Angiotensin II - adverse effects; Angiotensin II - pharmacology; Animals; Apoptosis; atherosclerosis; Atherosclerosis - chemically induced; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cholesterol - adverse effects; Cholesterol - metabolism; Cholesterol - pharmacology; Disease Models, Animal; efferocytosis; Female; foam cell; Foam Cells - metabolism; Foam Cells - pathology; macrophage; Male; Mice; Mice, Knockout; mineralocorticoid receptor; Molecular Bases of Disease; phagocytosis; Receptors, Mineralocorticoid - deficiency; Receptors, Mineralocorticoid - metabolism; Up-Regulation; atherosclerosis; phagocytosis; aldosterone; efferocytosis; macrophage; foam cell; mineralocorticoid receptor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.739243

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.