Abstract 18070: Pitavastatin Suppresses Apolipoprotein CIII Induced Endothelial Cell Activation and Monocyte Adhesion
Background: Activation of vascular endothelial cells (EC) contributes importantly to inflammation and atherogenesis. We reported that apolipoprotein CIII (apoCIII), a strong independent risk factor for coronary heart disease, enhances adhesion of human monocytes to EC in vitro. The present study examined whether pitavastatin, a recently-developed statin, suppresses apoCIII-induced EC activation in vitro and in vivo.
Methods and Results: A physiologically relevant concentration of human apoCIII (50μg/mL) enhanced attachment of THP-1 cells, a monocytoid cell line, to human primary vascular EC under laminar sheer stress (0.5 dyne/cm2) (Fig A). This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking antibody abolished apoCIII-induced monocyte adhesion. Indeed, apoCIII increased VCAM-1 expression (p<0.05) (Fig B) in EC. Pretreating EC with low and clinically-achievable concentrations of pitavastatin (10–50 nM) for 24 hr suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion (Fig A, B). Nuclear factor κB (NF-κB) mediates apoCIII-induced VCAM-1 expression, as demonstrated via co-incubation with the NF-κB inhibitor SN50 (Fig C). Pitavastatin suppressed the nuclear translocation of the NF-κB p65 subunit, indicating NF-κB inhibition (Fig D). Blocking antibody for Toll-like receptor 2 (TLR2), but not TLR4, reduced apoCIII-triggered VCAM-1 induction, suggesting that this pattern-recognition receptor mediates EC activation by apoCIII. Furthermore, pitavastatin administration in vivo suppressed VCAM-1 induction by apoCIII bolus injection in the aorta of Ldlr−/− mice at mRNA (Fig E) and protein levels (immunofluorescence, Fig F).
Conclusions: These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of pitavastatin improve vascular disease in the population with elevated plasma apoCIII.
- © 2010 by American Heart Association, Inc.