Increasing evidence suggests human cytomegalovirus (HCMV) infection, and particularly the cellular effects of its immediate early (IE) gene products, contributes to the development of atherosclerosis and of restenosis. We therefore assessed the effects of CMV infection on 2 mechanisms playing a role in atherogenesis--SMC migration (SMC migration from the media to the neointima is a crucial event of atherogenesis and restenosis) and the accumulation of lipid-laden foam cells (derived from macrophages and SMCs, and one of the earliest events in plaque formation). In a model in which only these gene products are expressed (human CMV infection of rat SMCs) we found that CMV infection, and specifically CMV's IE gene products: 1) increase SMC migration, and 2) increase oxidized LDL uptake by SMCs, an effect caused, at least in part, by increased SR gene expression mediated by an IE72-induced transactivation of the SR promotor. Because it not known how CMV is delivered to vessel walls and how it is activated once there, we examined the following hypothesis: CMV is transported by monocytes, which are recruited to sites of vascular injury, and the virus is activated by endothelial cell (EC) contact and by oxidized low-density lipoproteins (LDL). Our studies showed that ECs can become infected with monocyte-derived CMV, and that when monocyte precursors (transfected with a reporter gene driven by the CMV major IE promoter) are in contact with ECs or with oxidized LDL, such contact enhances CMV gene expression. These results provide a link between CMV infection and the development of atherosclerosis, and also suggest another mechanism whereby oxidized LDL predisposes to atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL004975-01
Application #
5203594
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code