Apolipoprotein A-I inhibits LPS-induced atherosclerosis in ApoE-/- mice possibly via activated STAT3-mediated upregulation of tristetraprolin

Aim： To investigate the effects of the major component of high-density lipoprotein apolipoprotein A-I （apoA-I） on the development of atherosclerosis in LPS-challenged ApoE / mice and the underlying mechanisms. Methods Male ApoE-KO mice were daily injected with LPS （25 μg, sc） or PBS for 4 weeks. The...

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Published in:Acta pharmacologica Sinica 2013-06, Vol.34 (6), p.837-846
Main Authors: Yin, Kai, Tang, Shi-lin, Yu, Xiao-hua, Tu, Guang-hui, He, Rong-fang, Li, Jin-feng, Xie, Di, Gui, Qing-jun, Fu, Yu-chang, Jiang, Zhi-sheng, Tu, Jian, Tang, Chao-ke
Format: Article
Language:English
Subjects:
Animals
Apolipoprotein A-I - administration & dosage
Apolipoprotein A-I - metabolism
Apolipoproteins E - genetics
Atherosclerosis - pathology
Cytokines - metabolism
Humans
Inflammation - pathology
Inflammation Mediators - metabolism
Lipopolysaccharides - toxicity
LPS
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Original
STAT3
STAT3 Transcription Factor - metabolism
Tristetraprolin - genetics
Up-Regulation
动脉粥样硬化
小鼠巨噬细胞
激活
诱导
载脂蛋白A-I
载脂蛋白AI
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Summary:Aim： To investigate the effects of the major component of high-density lipoprotein apolipoprotein A-I （apoA-I） on the development of atherosclerosis in LPS-challenged ApoE / mice and the underlying mechanisms. Methods Male ApoE-KO mice were daily injected with LPS （25 μg, sc） or PBS for 4 weeks. The LPS-challenged mice were intravenously injected with rAAV-apoA-I-GFP or rAAV-GFP. After the animals were killed, blood, livers and aortas were collected for biochemical and histological analyses. For ex vivo experiments, the abdominal cavity macrophages were harvested from each treatment group of mice, and cultured with autologous serum, then treated with LPS. Results： Chronic administration of LPS in ApoE-/- mice significantly increased the expression of inflammatory cytokines （TNF-a, IL-1β, IL-6, and MCP-1）, increased infiltration of inflammatory cells, and enhanced the development of atherosclerosis. In LPS-challenged mice injected with rAAV-apoA-I-GFP, viral particles and human apoA-I were detected in the livers, total plasma human apoA-I levels were grammatically increased; HDL-cholesterol level was significantly increased, TG and TC were slightly increased. Furthermore, overexpression of apoA-I significantly suppressed the expression of proinflammatory cytokines, reduced the infiltration of inflammatory cells, and decreased the extent of atherosclerotic lesions. Moreover, overexpression of apoA-I significantly increased the expression of the cytokine mRNA-destabilizing protein tristetraprolin （TFP）, and phosphorylation of JAK2 and STAT3 in aortas. In ex vivo mouse macrophages, the serum from mice overexpressing apoA-I significantly increased the expression of TTP, accompanied by accelerated decay of mRNAs of the inflammatory cytokines. Conclusion： ApoA-I potently suppresses LPS-induced atherosclerosis by inhibiting the inflammatory response possibly via activation of STAT3 and upre~ulation of TTP.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2013.10