Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation.
To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.
Hillyard
Dianne Z
DZ
Renal Research Group, BHF Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. d.hillyard@clinmed.gla.ac.uk
Nutt
Cian D
CD
Thomson
Jacqueline
J
McDonald
Kenneth J
KJ
Wan
Ray K
RK
Cameron
Angus J M
AJ
Mark
Patrick B
PB
Jardine
Alan G
AG
D000328:Adult; D000368:Aged; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D020014:K562 Cells; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D016030:Kidney Transplantation; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D010865:Pilot Projects; D017368:Protein Prenylation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D002784:Cholesterol; D019821:Simvastatin