Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.

Abstract

AIMS:

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.

METHODS AND 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: Chunyu Zheng, Veronica Azcutia, Elena Aikawa, Jose-Luiz Figueiredo, Kevin Croce, Hiroyuki Sonoki, Frank M Sacks, Francis W Luscinskas, Masanori Aikawa
• Journal: European heart journal (Eur Heart J) Vol. 34 Issue 8 Pg. 615-24 (Feb 2013) ISSN: 1522-9645 [Electronic] England
• PMID: 22927557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein C-III
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• NF-kappa B
• Quinolines
• Vascular Cell Adhesion Molecule-1
• pitavastatin

Topics

• Animals
• Aorta
• Apolipoprotein C-III (antagonists & inhibitors)
• Cell Adhesion (physiology)
• Cells, Cultured
• Endothelial Cells (physiology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Leukocytes, Mononuclear (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Quinolines (pharmacology)
• Saphenous Vein
• Vascular Cell Adhesion Molecule-1 (metabolism)