title: Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.
abstract: OBJECTIVE
  Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo.
  
  
  RESULTS
  Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr(-/-) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect.
  
  
  CONCLUSIONS
  These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, 3 Blackfan Circle, CLSB, Floor 17, Boston, MA 02115, USA. czheng1@rics.bwh.harvard.edu
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zheng
authors.forename: Veronica
authors.initials: V
authors.lastname: Azcutia
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sonoki
authors.forename: Frank M
authors.initials: FM
authors.lastname: Sacks
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
mesh_terms: D000818:Animals; D001011:Aorta; D053305:Apolipoprotein C-III / Q000037:antagonists & inhibitors*; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D012501:Saphenous Vein; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D053305:Apolipoprotein C-III; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011804:Quinolines; D019010:Vascular Cell Adhesion Molecule-1; C108475:pitavastatin