Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritisReportar como inadecuado

Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Arthritis Research and Therapy

, 8:R130

First Online: 21 July 2006Received: 30 January 2006Revised: 03 July 2006Accepted: 21 July 2006


Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis RA. Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation.

Flow-cytometric analysis showed that CD59 expression on endothelial cells EC was unaffected by atorvastatin in normoxia 21% O2, whereas in hypoxic conditions 1% O2 an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by N-monomethyl-L-arginine and N-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor DAF, is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.

AbbreviationsCIP= complement-inhibitory protein

CoCl2= cobalt chloride

DAF= decay-accelerating factor

DFO= desferrioxamine

EC= endothelial cells

HIF= hypoxia-inducible factor

HMG-CoA= 3-hydroxy-3-methylglutaryl coenzyme A

HUVEC= human umbilical vein endothelial cells

IL= interleukin

L-NAME= N-nitro-L-arginine methyl ester

L-NMMA= N-monomethyl-L-arginine

mAb= monoclonal antibody

MAC= membrane attack complex

MCP= membrane cofactor protein

NF= nuclear factor

NO= nitric oxide

RA= rheumatoid arthritis

PCR= polymerase chain reaction

RFI= relative fluorescence intensity

VBSG= veronal buffered saline-1% gelatin.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2019 contains supplementary material, which is available to authorized users.

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