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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
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
2011-02-01
DOI10.1097/FJC.0b013e31820376ac
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
WOS记录号WOS:000286922700012
引用统计
被引频次:14[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/53633
专题北京大学第二临床医学院_心血管内科
作者单位Peking Univ, Peoples Hosp, Dept Cardiol, Beijing 100044, Peoples R China
推荐引用方式
GB/T 7714
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.
APA Song, Jun-Xian,Ren, Jing-Yi,&Chen, Hong.(2011).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.JOURNAL OF CARDIOVASCULAR PHARMACOLOGY,57(2),213-222.
MLA Song, Jun-Xian,et al."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".JOURNAL OF CARDIOVASCULAR PHARMACOLOGY 57.2(2011):213-222.
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