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IR@PKUHSC  > 北京大学第二临床医学院  > 心血管内科  > 期刊论文
学科主题: 临床医学
题名:
Simvastatin Reduces Lipoprotein-associated Phospholipase A(2) in Lipopolysaccharide-stimulated Human Monocyte-derived Macrophages Through Inhibition of the Mevalonate-Geranylgeranyl Pyrophosphate-RhoA-p38 Mitogen-activated Protein Kinase Pathway
作者: Song, Jun-Xian; Ren, Jing-Yi; Chen, Hong
关键词: atherosclerosis ; 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor ; inflammation ; lipoprotein-associated phospholipase A(2) ; macrophages
刊名: JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
发表日期: 2011-02-01
DOI: 10.1097/FJC.0b013e31820376ac
卷: 57, 期:2, 页:213-222
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Cardiac & Cardiovascular Systems ; Pharmacology & Pharmacy
研究领域[WOS]: Cardiovascular System & Cardiology ; Pharmacology & Pharmacy
关键词[WOS]: FACTOR ACETYLHYDROLASE ACTIVITY ; A REDUCTASE INHIBITORS ; CORONARY-HEART-DISEASE ; NITRIC-OXIDE SYNTHASE ; SMOOTH-MUSCLE CELLS ; SIGNAL-TRANSDUCTION ; THERAPEUTIC TARGET ; GENE-EXPRESSION ; ATHEROSCLEROSIS ; INFLAMMATION
英文摘要:

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), which is produced primarily by macrophages and is predominately found in the blood and in atherosclerotic plaques, represents a potentially promising target for combating atherosclerosis. Although statins are known to decrease the levels and activity of circulating and plaque Lp-PLA(2) during atherosclerosis, little is known regarding the mechanisms underlying inhibition of Lp-PLA(2) by statins. Therefore, the aim of this study was to explore the molecular mechanisms responsible for inhibition of Lp-PLA(2) by statins. Our results showed that treatment with simvastatin inhibited lipopolysaccharide (LPS)-induced increases in Lp-PLA(2) expression and secreted activity in human monocyte-derived macrophages in a dose-and time-dependent manner. These effects could be reversed by treatment with mevalonate or geranylgeranyl pyrophosphate (GGPP), but not by treatment with squalene or farnesyl pyrophosphate. Treatment with the Rho inhibitor C3 exoenzyme also inhibited LPS-induced increases in Lp-PLA(2) expression and secreted activity, mimicking the effects of simvastatin. In addition, treatment with simvastatin blocked LPS-induced activation of RhoA, which could be abolished by treatment with GGPP. Inhibition of p38 mitogen-activated protein kinase (MAPK), but not extracellular signal regulated kinase 1/2 or Jun N-terminal kinase, suppressed LPS-induced increases in Lp-PLA(2) expression and secreted activity, similar to the effects of simvastatin. Treatment of human monocyte-derived macrophages with either simvastatin or C3 exoenzyme prevented LPS-induced activation of p38 MAPK, which could be abolished by treatment with GGPP. Together, these results suggest that simvastatin reduces Lp-PLA(2) expression and secreted activity in LPS-stimulated human monocyte-derived macrophages through the inhibition of the mevalonate-GGPP-RhoA-p38 MAPK pathway. These observations provide novel evidence that statins have pleiotropic effects and suggest that inhibition of Lp-PLA(2) via this mechanism may account, at least in part, for the clinical benefit of statins in combating atherosclerosis.

语种: 英语
所属项目编号: 30570712 ; 30840040 ; 7092109
项目资助者: National Natural Science Foundation of China ; Beijing Natural Science Foundation
WOS记录号: WOS:000286922700012
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/53633
Appears in Collections:北京大学第二临床医学院_心血管内科_期刊论文

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作者单位: Peking Univ, Peoples Hosp, Dept Cardiol, Beijing 100044, Peoples R China

Recommended Citation:
Song, Jun-Xian,Ren, Jing-Yi,Chen, Hong. Simvastatin Reduces Lipoprotein-associated Phospholipase A(2) in Lipopolysaccharide-stimulated Human Monocyte-derived Macrophages Through Inhibition of the Mevalonate-Geranylgeranyl Pyrophosphate-RhoA-p38 Mitogen-activated Protein Kinase Pathway[J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY,2011,57(2):213-222.
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