Cerivastatin reduces cytokine-induced surface expression of ICAM-1 via increased shedding in human endothelial cells

Abstract

Activation of endothelial cells is an incipient process in atherogenesis and leads to induction of the cellular adhesion molecules ICAM-1 and VCAM-1. Their expression can be induced by cytokines as well as other inflammatory mediators. The effects of HMG-CoA reductase inhibitors (statins) include mediation of anti-inflammatory properties. The aim of this study was the comparison of cerivastatin and simvastatin-mediated effects on inflammation-induced ICAM-1 and VCAM-1 expression in human umbilical venous endothelial cells (HUVEC). In HUVEC, TNF-alpha induced ICAM-1 and VCAM-1 mRNA and surface expression. Co-incubation with cerivastatin, but not simvastatin reduced TNF-alpha-induced up-regulation of ICAM-1 surface expression whereas both statins reduced VCAM-1 surface expression; all reductions in surface expression correlated with an increase in the soluble forms of ICAM-1 and VCAM-1 in cell culture supernatants. Mevalonate and nonsteroidal isoprenoids significantly reversed protein expression and shedding. Both statins caused an aggravation of TNF-alpha-induced ICAM-1 and VCAM-1 mRNA expression which was dependent on RNA synthesis. The statin-mediated increase in ICAM-1 and VCAM-1 mRNA expression correlated with the degradation of IkappaBa. Nuclear translocation of p65 was not significantly affected by statin-treatment of cytokine-treated cells. We conclude that cerivastatin and simvastatin reduce TNF-alpha-induced up-regulation of ICAM-1 and VCAM-1 surface expression via increased protein shedding mediated by HMG-CoA reductase inhibition and subsequent isoprenoid depletion.