Tags

Type your tag names separated by a space and hit enter

Simvastatin reduces lipoprotein-associated phospholipase A2 in lipopolysaccharide-stimulated human monocyte-derived macrophages through inhibition of the mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 mitogen-activated protein kinase pathway.
J Cardiovasc Pharmacol. 2011 Feb; 57(2):213-22.JC

Abstract

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.

Authors+Show Affiliations

Department of Cardiology, Peking University People’s Hospital, No. 11 Xizhimen South St, Xicheng District, Beijing 100044, China.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21052011

Citation

Song, Jun-Xian, et al. "Simvastatin Reduces Lipoprotein-associated Phospholipase A2 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, vol. 57, no. 2, 2011, pp. 213-22.
Song JX, Ren JY, Chen H. Simvastatin reduces lipoprotein-associated phospholipase A2 in lipopolysaccharide-stimulated human monocyte-derived macrophages through inhibition of the mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 mitogen-activated protein kinase pathway. J Cardiovasc Pharmacol. 2011;57(2):213-22.
Song, J. X., Ren, J. Y., & Chen, H. (2011). Simvastatin reduces lipoprotein-associated phospholipase A2 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), 213-22. https://doi.org/10.1097/FJC.0b013e31820376ac
Song JX, Ren JY, Chen H. Simvastatin Reduces Lipoprotein-associated Phospholipase A2 in Lipopolysaccharide-stimulated Human Monocyte-derived Macrophages Through Inhibition of the Mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 Mitogen-activated Protein Kinase Pathway. J Cardiovasc Pharmacol. 2011;57(2):213-22. PubMed PMID: 21052011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simvastatin reduces lipoprotein-associated phospholipase A2 in lipopolysaccharide-stimulated human monocyte-derived macrophages through inhibition of the mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 mitogen-activated protein kinase pathway. AU - Song,Jun-Xian, AU - Ren,Jing-Yi, AU - Chen,Hong, PY - 2010/11/6/entrez PY - 2010/11/6/pubmed PY - 2012/3/1/medline SP - 213 EP - 22 JF - Journal of cardiovascular pharmacology JO - J. Cardiovasc. Pharmacol. VL - 57 IS - 2 N2 - 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. SN - 1533-4023 UR - https://www.unboundmedicine.com/medline/citation/21052011/Simvastatin_reduces_lipoprotein_associated_phospholipase_A2_in_lipopolysaccharide_stimulated_human_monocyte_derived_macrophages_through_inhibition_of_the_mevalonate_geranylgeranyl_pyrophosphate_RhoA_p38_mitogen_activated_protein_kinase_pathway_ L2 - http://dx.doi.org/10.1097/FJC.0b013e31820376ac DB - PRIME DP - Unbound Medicine ER -