Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

Dianne Z Hillyard; Cian D Nutt; Jacqueline Thomson; Kenneth J McDonald; Ray K Wan; Angus J M Cameron; Patrick B Mark; Alan G Jardine

doi:10.1016/j.atherosclerosis.2006.05.037

Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

Atherosclerosis. 2007 Apr;191(2):319-25. doi: 10.1016/j.atherosclerosis.2006.05.037. Epub 2006 Jun 30.

Authors

Dianne Z Hillyard¹, Cian D Nutt, Jacqueline Thomson, Kenneth J McDonald, Ray K Wan, Angus J M Cameron, Patrick B Mark, Alan G Jardine

Affiliation

¹ 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

PMID: 16814295
DOI: 10.1016/j.atherosclerosis.2006.05.037

Abstract

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Cholesterol / blood
Cholesterol / metabolism*
Cytotoxicity, Immunologic / drug effects*
Dose-Response Relationship, Drug
Fatty Acids, Monounsaturated / pharmacology
Female
Fluvastatin
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Indoles / pharmacology
K562 Cells
Kidney Failure, Chronic / blood
Kidney Failure, Chronic / drug therapy
Kidney Failure, Chronic / immunology
Kidney Transplantation
Killer Cells, Natural / drug effects*
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Male
Membrane Microdomains / drug effects*
Membrane Microdomains / metabolism
Middle Aged
Myocardial Ischemia / blood
Myocardial Ischemia / drug therapy
Myocardial Ischemia / immunology
Pilot Projects
Protein Prenylation / drug effects*
Signal Transduction / drug effects
Simvastatin / pharmacology

Substances

Fatty Acids, Monounsaturated
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Indoles
Fluvastatin
Cholesterol
Simvastatin