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All rights reserved. http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_5 http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/version 20131211 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_3 http://purl.org/dc/elements/1.1/identifier AHA Abstracts 428 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_3 http://purl.org/dc/elements/1.1/title AHA Abstracts 428 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_3 http://purl.org/dc/elements/1.1/type Other http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_4 http://www.w3.org/ns/prov#value Background Complement-mediated vascular injury is important in the pathophysiology of atherosclerosis and myocardial infarction. As recent evidence shows that the statins, HMGCoA reductase inhibitors, have beneficial effects on endothelial cell (EC) function independent of lipid-lowering, we explored the hypothesis that statins modulate vascular EC resistance to complement through upregulation of complement-inhibitory proteins. Methods/Results Human umbilical vein EC (HUVEC) were treated with atorvastatin or simvastatin and expression of decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 was measured by flow-cytometry. A dose-dependent increase in DAF expression of upto 4 fold was seen 24-48h post-treatment. CD59 expression was increased by 50% whilst MCP was unchanged. Similar results were obtained with human aortic EC. Statin-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. Inclusion of L-mevalonate, or geranylgeranyl pyrophosphate, reversed the effect on DAF expression, confirming the role of HMGCoA reductase inhibition and suggesting that DAF expression is negatively regulated by geranylgeranylation. Neither farnesyl pyrophosphate nor squalene inhibited statin-induced DAF expression suggesting the effect is independent of cholesterol lowering. We found that statin-induced DAF expression is mediated by activation of PKC? and inhibition of RhoA and is independent of PI-3K and nitric oxide activity. The increase of DAF following statin treatment is functionally relevant, resulting in marked reduction in C3 deposition and complement-mediated EC lysis inhibitable by anti-DAF mAb 1H4 (p < 0.05). Conclusions These observations provide evidence for a novel cytoprotective action of the statins on vascular endothelium, independent of the effect on lipids, and resulting in enhanced protection against complement-mediated injury. Modulation of complement regulatory protein expression by statins may contribute to the early beneficial effects of statins in reducing morbidity and mortality associated with atherosclerosis. http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_4 http://www.w3.org/ns/prov#wasQuotedFrom http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_3 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_5 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_3 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#_4 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ#pubinfo http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ http://purl.org/dc/terms/created 2014-07-03T14:31:29.295+02:00 http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RAbT9ea998DlA8fQI7Z0VjtUlx84Fol0sCk16aZorORrQ http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234