title: Endothelial cells' activation and apoptosis induced by a subset of antibodies against human cytomegalovirus: relevance to the pathogenesis of atherosclerosis.
abstract: BACKGROUND
  Human cytomegalovirus (hCMV) is involved in the pathogenesis of atherosclerosis. We have previously shown in patients with atherosclerosis that antibodies directed against the hCMV-derived proteins US28 and UL122 are able to induce endothelial cell damage and apoptosis of non-stressed endothelial cells through cross-rection with normally expressed surface molecules. Our aim was to dissect the molecular basis of such interaction and to investigate mechanisms linking innate immunity to atherosclerosis.
  
  
  RESULTS
  We analysed the gene expression profiles in endothelial cells stimulated with antibodies affinity-purified against either the UL122 or the US28 peptides using the microarray technology. Microarray results were validated by quantitative PCR and by detection of proteins in the medium. Supernatant of endothelial cells incubated with antibodies was analysed also for the presence of Heat Shock Protein (HSP)60 and was used to assess stimulation of Toll-Like Receptor-4 (TLR4). Antibodies against UL122 and US28 induced the expression of genes encoding for adhesion molecules, chemokines, growth factors and molecules involved in the apoptotis process together with other genes known to be involved in the initiation and progression of the atherosclerotic process. HSP60 was released in the medium of cells incubated with anti-US28 antibodies and was able to engage TLR4.
  
  
  CONCLUSIONS
  Antibodies directed against hCMV modulate the expression of genes coding for molecules involved in activation and apoptosis of endothelial cells, processes known to play a pivotal role in the pathogenesis of atherosclerosis. Moreover, endothelial cells exposed to such antibodies express HSP60 on the cell surface and release HSP60 in the medium able to activate TLR4. These data confirm that antibodies directed against hCMV-derived proteins US28 and UL122 purified from patients with coronary artery disease induce endothelial cell damage and support the hypothesis that hCMV infection may play a crucial role in mediating the atherosclerotic process.
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Verona, Italy. claudio.lunardi@univr.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.forename: Marzia
authors.initials: M
authors.lastname: Dolcino
authors.forename: Dimitri
authors.initials: D
authors.lastname: Peterlana
authors.forename: Caterina
authors.initials: C
authors.lastname: Bason
authors.forename: Riccardo
authors.initials: R
authors.lastname: Navone
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.forename: Elisa
authors.initials: E
authors.lastname: Tinazzi
authors.forename: Ruggero
authors.initials: R
authors.lastname: Beri
authors.forename: Roberto
authors.initials: R
authors.lastname: Corrocher
authors.forename: Antonio
authors.initials: A
authors.lastname: Puccetti
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics
chemical_list: D000914:Antibodies, Viral; D018834:Chaperonin 60; D051197:Toll-Like Receptor 4; D014764:Viral Proteins