title: MCP-1-induced enhancement of THP-1 adhesion to vascular endothelium was modulated by HMG-CoA reductase inhibitor through RhoA GTPase-, but not ERK1/2-dependent pathway.
abstract: Monocyte-endothelial interaction plays a pivotal role in atherosclerosis. We previously showed that HMG CoA reductase inhibitor reduces adhesion, however, not the rolling of monocytes to vascular endothelium under flow in vitro. In the present study, we investigated the effect of pitavastatin, a novel HMG CoA reductase inhibitor, on the transition from monocyte rolling on vascular endothelium to stable adhesion induced by MCP-1 under flow (shear stress = 1.0 dyne/cm(2)). Control THP-1 cells rolled on activated (IL-1beta, 4 hours) human umbilical vein endothelial cells (HUVEC) and the number of adhered THP-1 cells were significantly enhanced following the addition of 50 nM of MCP-1 (p < 0.002). In contrast, MCP-1 failed to convert pitavastatin-treated (10 microM, 48 hours) THP-1 rolling to stable adhesion, as compared to baseline adhesion, prior to the addition of MCP-1 (p > 0.4). Pitavastatin-induced changes in THP-1 cells were reversed by treatment with 10 microM of mevalonate, the intermediate of cholesterol biosynthesis. To elucidate the mechanism by which pitavastatin modulates MCP-1-induced THP-1 adhesive interactions, the possible involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) was examined. Western blotting analysis using an anti-ERK1/2 Ab and an antibody against phosphorylated-ERK1/2 (p-ERK) revealed that pitavastatin treatment significantly inhibited the MCP-1-induced phosphorylation of ERK1/2. Further, a RhoA pull-down assay revealed that activation of RhoA GTPase was reduced after pitavastatin treatment. Interestingly, an inhibitor of RhoA GTPase, but not that of the ERK1/2 pathway, attenuated MCP-1-dependent adhesion of THP-1 cells to HUVEC. These findings indicate a role for pitavastatin in modulating the MCP-1-induced phenotypic changes of monocyte-endothelial interactions, which may account for the anti-inflammatory effects of statins.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima Building D-256, Bunkyo, Tokyo 113-8519, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Noriko
authors.initials: N
authors.lastname: Nitta
authors.forename: Miyudzu
authors.initials: M
authors.lastname: Nagai
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shimokado
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C515334:CCR2 protein, human; D018932:Chemokine CCL2; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; C108475:pitavastatin