Rheb (Ras Homolog Enriched in Brain 1) Deficiency in Mature Macrophages Prevents Atherosclerosis by Repressing Macrophage Proliferation, Inflammation, and Lipid Uptake

Zhang, Qinghai1,2; Hu, Jie1; Wu, Yan1; Luo, Hairong1; Meng, Wen1; Xiao, Bo1,3; Xiao, Xianzhong4; Zhou, Zhiguang1; Liu, Feng1,5

2019-09

10.1161/ATVBAHA.119.312870

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   影响因子和分区

1079-5642

1524-4636

Objective: Macrophage foam cell formation is an important process in atherosclerotic plaque development. The small GTPase Rheb (Ras homolog enriched in brain 1) regulates endocytic trafficking that is critical for foam cell formation. However, it is unclear whether and how macrophage Rheb regulates atherogenesis, which are the focuses of the current study. Approach and Results: Immunofluorescence study confirmed the colocalization of Rheb in F4/80 and Mac-2 (galectin-3)-labeled lesional macrophages. Western blot and fluorescence-activated cell sorting analysis showed that Rheb expression was significantly increased in atherosclerotic lesions of atherosclerosis-prone (apoE(-/-) [apolipoprotein E deficient]) mice fed with Western diet. Increased Rheb expression was also observed in oxidized LDL (low-density lipoprotein)-treated macrophages. To investigate the in vivo role of macrophage Rheb, we established mature Rheb(mKO) (macrophage-specific Rheb knockout) mice by crossing the Rheb floxed mice with F4/80-cre mice. Macrophage-specific knockout of Rheb in mice reduced Western diet-induced atherosclerotic lesion by 32%, accompanied with a decrease in macrophage content in plaque. Mechanistically, loss of Rheb in macrophages repressed oxidized LDL-induced lipid uptake, inflammation, and macrophage proliferation. On the contrary, lentivirus-mediated overexpression of Rheb in macrophages increased oxidized LDL-induced lipid uptake and inflammation, and the stimulatory effect of Rheb was suppressed by the mTOR (mammalian target of rapamycin) inhibitor rapamycin or the PKA (protein kinase A) activator forskolin. Conclusions: Macrophage Rheb plays important role in Western diet-induced atherosclerosis by promoting macrophage proliferation, inflammation, and lipid uptake. Inhibition of expression and function of Rheb in macrophages is beneficial to prevent diet-induced atherosclerosis.

atherosclerosis foam cells inflammation macrophages mice

SCI

英语

其他

National Natural Science Foundation of China[81730022] ; National Natural Science Foundation of China[31400652]

Hematology ; Cardiovascular System & Cardiology

Hematology ; Peripheral Vascular Disease

WOS:000484343600014

LIPPINCOTT WILLIAMS & WILKINS

CLINICAL MEDICINE

Web of Science

1.Cent S Univ, Dept Metab & Endocrinol, Metab Syndrome Res Ctr,Xiangya Hosp 2, Key Lab Diabet Immunol,Natl Clin Res Ctr Metab Di, Changsha, Hunan, Peoples R China
2.Univ South China, Affiliated Hosp 1, Dept Metab & Endocrinol, Hengyang, Hunan, Peoples R China
3.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China
4.Cent S Univ, Xiangya Sch Med, Dept Palhophysiol, Changsha, Hunan, Peoples R China
5.UT Hlth San Antonio, Dept Pharmacol, San Antonio, TX USA

Zhang, Qinghai,Hu, Jie,Wu, Yan,et al. Rheb (Ras Homolog Enriched in Brain 1) Deficiency in Mature Macrophages Prevents Atherosclerosis by Repressing Macrophage Proliferation, Inflammation, and Lipid Uptake[J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,2019,39(9):1787-1801.

Zhang, Qinghai.,Hu, Jie.,Wu, Yan.,Luo, Hairong.,Meng, Wen.,...&Liu, Feng.(2019).Rheb (Ras Homolog Enriched in Brain 1) Deficiency in Mature Macrophages Prevents Atherosclerosis by Repressing Macrophage Proliferation, Inflammation, and Lipid Uptake.ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,39(9),1787-1801.

Zhang, Qinghai,et al."Rheb (Ras Homolog Enriched in Brain 1) Deficiency in Mature Macrophages Prevents Atherosclerosis by Repressing Macrophage Proliferation, Inflammation, and Lipid Uptake".ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 39.9(2019):1787-1801.