Cardiovascular Surgery, Vol. 11, No. 1, pp. 52–60, 2003  2003 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. All rights reserved. 0967-2109/03 $30.00 www.elsevier.com/locate/cardiosur doi:10.1016/S0967-2109(02)00117-5 Fluvastatin induces apoptosis of vascular endothelial cells: blockade by glucocorticoids C. J. Newton * , Y. -X. Xie * , C. H. Burgoyne † , I. Adams † , S. L. Atkin † , A. Abidia ‡ and P. T. McCollum ‡ * Jacob’s Well Medical Research Laboratory, Beverley HU17 8BH, UK, † Diabetes and Endocrinology, Hull and York Medical School, University of Hull, Hull HU6 7RX, UK and ‡ Vascular Surgery, Hull and York Medical School, University of Hull, Hull HU6 7RX, UK Statins block de novo synthesis of cholesterol by inhibiting the enzyme, HMG CoA reductase. The product of this reaction, mevalonic acid, is also a precursor of isoprenoids, molecules required for the activation of signaling G-proteins, such as Ras. Signal transduction pathways involving Ras are important for cell survival and this may be why statins induce apoptotic death of several cell types. Given that statins are used to treat vascular disease, surprisingly no studies have been conducted on vascular endothelial cells. Here we show that fluvastatin (FS), at concentrations from 1–2 μM, blocks growth and induces apoptosis of the endothelial cell line, EA.hy 926. Considerable redundancy is known to exist in cell signaling and in vivo toxicity of FS might be prevented by other signaling pathways, like those activated by adrenal or sex steroids. RT-PCR analysis revealed the expression of the androgen and glucocorticoid receptor in EA.hy 926 cells. Although the androgen, dihydrotestesterone (DHT) had no effect, the glucocorticoid, dexamethasone (Dex), blocked FS-induced apoptosis. Cell cycle analysis revealed that 24 h exposure to FS prevented cells from leaving G1 and 24–48 h later a marked sub-G1 peak was observed. Dex was able to reduce the sub-G1 peak, but it failed to block accumulation of cells in G1, indicating that it’s effect was specific for blockade of apoptosis, and not specific to an effect on FS alone. This study strongly suggests that glucocorticoids have a role to play in preventing vascular injury and they may provide the reason why statins are not inherently toxic to vascular endothelial cells, in vivo.  2003 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved. Keywords: statins, glucocorticoids, apoptosis Introduction Statins are a class of compound that inhibit HMGCoA reductase and result in the inhibition of cholesterol biosynthesis [1]. Due to this property, statins are now one of the most widely used agents for the treatment of high cholesterol-related vascular disease [2]. Several reports over the last five years have indicated that statins induce apoptosis of a Correspondence to: C.J. Newton. Tel.: 07947 733609 (mobile); e-mail: CJNewton@Compuserve.com CARDIOVASCULAR SURGERY FEBRUARY 2003 VOL 11 NO 1 52 number of cell types including vascular smooth mus- cle cells [3–5]. To a large extent this may be explained by the fact that mevalonic acid, the pro- duct of the enzyme HMGCoA reducates, is not only a precursor for cholesterol biosynthesis, but is also a building block for isoprenoids [6]. As a component of one of the major cell signaling pathways, the small Ras, G-protein, is activated by isoprelylation [7] and isoprenylation inhibitors have been widely reported to induce apoptosis [8]. Indeed, the covalent modi- fication of Ras is currently a major target in cancer drug development [9–11]. Recently, confirmation that the inhibition of Ras prenylation is the mech-