title: Atorvastatin attenuates remnant lipoprotein-induced monocyte adhesion to vascular endothelium under flow conditions.
abstract: Remnant lipoproteins have been reported to play a causative role in atherogenesis. We investigated the effect of remnant-like lipoprotein particles (RLPs) on monocyte-endothelial interaction and their potential regulation by atorvastatin. Monocytic U937 cells were incubated with RLPs isolated from hypertriglyceridemia subjects and their adhesion to human umbilical vein endothelial cells (HUVECs) was examined under flow conditions. Incubation of U937 cells with 15 micro g protein/mL RLPs increased their adhesion to HUVECs activated with IL-1beta (untreated: 6.8+/-1.6 cells/HPF versus RLPs: 16.2+/-3.3 cells/HPF, P<0.05). Flow cytometric analysis revealed that incubation with RLPs increased expression levels of CD11a, CD18, and CD49d in U937 cells. Moreover, RLP-induced RhoA activation as well as FAK activation was seen in U937 cells, and RLP-induced RhoA activation seemed to be involved with PKC-dependent signaling. To explore the effect of atorvastatin on RLP-induced U937 cell adhesion to HUVECs, U937 cells were incubated with RLPs in the presence of atorvastatin. Pretreatment of U937 cells with 10 micro mol/L atorvastatin significantly decreased RLP-induced U937 cell adhesion to activated HUVECs (RLP 15.2+/-1.5 cells/HPF versus atorvastatin+RLP 10.2+/-1.0 cells/HPF; P<0.05) and decreased the enhanced integrin expression in RLP-treated U937 cells. Atorvastatin also inhibited RLP-induced RhoA activation and FAK activation in U937 cells. In summary, RLPs induced monocyte adhesion to vascular endothelium by sequential activation of PKC, RhoA, FAK, and integrins, indicating a role of remnant lipoproteins in vascular inflammation during atherogenesis. Atorvastatin attenuated this enhanced monocyte adhesion to HUVECs, suggesting an antiinflammatory role for this compound.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kawakami
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Nakajima
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shimokado
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000069059:Atorvastatin; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016023:Integrins / Q000096:biosynthesis; D008055:Lipids / Q000032:analysis; D008074:Lipoproteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020298:U937 Cells; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016023:Integrins; D008055:Lipids; D008074:Lipoproteins; D011758:Pyrroles; D014280:Triglycerides; C112017:remnant-like particle cholesterol; D002784:Cholesterol; D000069059:Atorvastatin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D011493:Protein Kinase C; D020742:rhoA GTP-Binding Protein