Monocytes harboring cytomegalovirus: interactions with endothelial cells, smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms for activating virus delivered by monocytes to sites of vascular injury.
Cytomegalovirus (CMV) infection and its periodic reactivation from latency may contribute to atherogenesis and restenosis. It is unknown how CMV is delivered to the vessel wall and is reactivated. We examined the following hypothesis: CMV, present in monocytes recruited to sites of vascular injury, is activated by endothelial cell (EC) or smooth muscle cell (SMC) contact and by oxidized low-density lipoproteins (oxLDLs). The CMV major immediate-early promoter (MIEP) controls immediate-early (IE) gene expression, and thereby viral replication. To determine whether elements of the vessel wall can activate CMV present in monocytes, we transiently transfected the promonocytic cell line HL-60 with a chloramphenicol acetyltransferase reporter gene construct driven by MIEP. MIEP activity increased 1.7 +/- 0.5-fold (P = .02) when the transfected HL-60 cells were cocultured with ECs, 4.5 +/- 1.5-fold when cocultured with SMCs (P = .03), and 2.0 +/- 0.5-fold (P = .01) when exposed to oxLDL. The combination of oxLDL and EC coculture increased MIEP activity over 7-fold. We also found that freshly isolated human monocytes, infected with endothelium-passaged CMV, were capable of transmitting infectious virus to cocultured ECs or SMCs. CMV-related progression of atherosclerosis or restenosis may, at least in part, involve monocyte delivery of the virus to the site of vascular injury, where the vascular milieu, ie, contact with ECs, SMCs, and oxLDL, can contribute to viral reactivation and/or replication by enhancing CMV IE gene expression. The virus may then infect neighboring ECs or SMCs, initiating a cascade of events predisposing to the development of atherogenesis-related processes.
Guetta
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Department of Cell Biology, Cleveland Clinic Foundation, OH 44195, USA. GUETTAE@ceamtp.ccf.org
Guetta
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Shibutani
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Epstein
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D001161:Arteriosclerosis / Q000209:etiology; D001808:Blood Vessels / Q000382:microbiology*; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000235:genetics / Q000254:growth & development*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D008077:Lipoproteins, LDL / Q000502:physiology*; D009000:Monocytes / Q000382:microbiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011506:Proteins; D014162:Transfection
D008077:Lipoproteins, LDL; D011506:Proteins; D015500:Chloramphenicol O-Acetyltransferase