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

作　　者：Kai YIN Shi-lin TANG Xiao-hua YU Guang-hui TU Rong-fang HE Jin-feng LI Di XIE Qing-jun GUI Yu-chang FU Zhi-sheng JIANG Jian TU Chao-ke TANG 

机构地区：[1]Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang 421001, China [2]Department of Diagnostics, the Medical College, University of South China, Hengyang 421001, China [3]Department of Intensive Care Unit, the First Affiliated Hospital of University of South China, Hengyang 421001, China [4]Department of Pathology, Nan Xian Peoples Hospital, Yiyang 413200, China [5]Department of Pathology, the First Affiliated Hospital, University of South China, Hengyang 421001, China [6]Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA [7]Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China

出　　处：《Acta Pharmacologica Sinica》2013年第6期837-846,共10页中国药理学报（英文版）

基　　金：The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China （81070220, 81170278, and 81100213）; the Heng Yang Joint Funds of Hunan Provincial Natural Sciences Foundation of China （10JJ9019）; the Hunan Provincial Natural Sciences Foundation of China （06jj5058）; the Science ＆ Technology Department Funds of Heng Yang of Hunan Province （2010kj17 and 2010kj41）; and the Hunan Provincial Postgraduate Innovation Fund （CX2010B379）.

摘　　要：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.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.

关 键 词：apolipoprotein A-I heart ATHEROSCLEROSIS inflammation cytokines JAK2/STAT3 signaling pathway TRISTETRAPROLIN lipopolysaccharide ApoE-/- mice macrophage 

分 类 号：Q345.21[生物学—遗传学] Q513.5