Fluvastatin reduces oxidative damage in human vascular endothelial cells by upregulating Bcl-2.
BACKGROUND
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been widely used in clinical practise and their efficacy in reducing cardiovascular risk has been well described.


OBJECTIVE
To investigate the effect of low doses of fluvastatin (nanomolar) on H(2)O(2)-induced cell damage and the underlying mechanism.


RESULTS
Primary cultures of human umbilical vein endothelial cells were used, and the effects of fluvastatin on H(2)O(2)-induced apoptosis, necrosis, and proliferation were observed. H(2)O(2) at a concentration of 100 mum significantly induced apoptotic cell death after 24-h cell culture. Fluvastatin at low concentrations (10-100 nm) prevented H(2)O(2)-induced apoptosis, as determined by a DNA fragmentation assay and by cell counting with trypan blue and Hoechst 33342 nuclei staining. The protective effect of fluvastatin was mediated by the upregulation of Bcl-2 expression as probed by real-time polymerase chain reaction and Western blotting. Using siRNA to knock down the expression of Bcl-2, the protective effect of fluvastatin was abolished. Fluvastatin had no direct effect on the H(2)O(2)-sensitive TRPM2 calcium channel.


CONCLUSIONS
These results suggest that fluvastatin has a potent protective effect against H(2)O(2)-induced apoptosis via upregulation of Bcl-2 expression. The findings provide a new insight into the mechanism by which fluvastatin is able to modulate the influence of oxidative stress on vascular endothelial cells.
Xu
S Z
SZ
Postgraduate Medical Institute and Hull York Medical School, University of Hull, Hull, UK. s.xu@hull.ac.uk
Zhong
W
W
Watson
N M
NM
Dickerson
E
E
Wake
J D
JD
Lindow
S W
SW
Newton
C J
CJ
Atkin
S L
SL
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D019254:Genes, bcl-2 / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000187:drug effects; D014471:Umbilical Veins; D015854:Up-Regulation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D000077340:Fluvastatin; D006861:Hydrogen Peroxide