Fluvastatin induces apoptosis of vascular endothelial cells: blockade by glucocorticoids.
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 microM, 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 G(1) and 24-48 h later a marked sub-G(1) peak was observed. Dex was able to reduce the sub-G(1) peak, but it failed to block accumulation of cells in G(1), 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.
Newton
C J
CJ
Jacob's Well Medical Research Laboratory, Beverley HU17 8BH, UK. CJNewton@Compuserve.com
Xie
Y-X
YX
Burgoyne
C H
CH
Adams
I
I
Atkin
S L
SL
Abidia
A
A
McCollum
P T
PT
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005434:Flow Cytometry; D000077340:Fluvastatin; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D005938:Glucocorticoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D003907:Dexamethasone