Endothelial injury is believed to be a requirement for the initiation of atherosclerotic lesions; subsequently, lipid accumulation, macrophage recruitment, intimal proliferation of smooth muscle cells, and fibrosis may occur; ultimately thrombosis may result in vessel occlusion. The terminal complement proteins C5b-9 have been demonstrated in atherosclerotic plaques in man, and in endothelium prior to lesion development in a hypercholesterolemic animal model of atherosclerosis. Evidence also suggests that complement plays a role in the accelerated atherosclerosis observed in human cardiac allografts. our previous work has demonstrated that complement induces procoagulant responses from endothelial cells, and preliminary data suggests that deposition of the C5b-9 proteins alters both the endothelial-lipoprotein interface and endothelial surface regulation of fibrinolysis. This research proposal explores these two mechanisms by which complement activation may contribute to progression of atherosclerosis.
Specific aims are: 1) to determine whether complement effects the endothelial binding or metabolism of LDL or acetylated LDL, or alters endothelial permeability to these lipoproteins; 2) to determine the mechanism of the increased binding of HDL (and its apoproteins) observed in response to C5b-9, and to evaluate functional effects of altered HDL/apoprotein binding on endothelial cell cholesterol homeostasis; 3) to determine whether complement alters binding or metabolism of lipoprotein(a) ; and 4) to characterize the complement-induced plasminogen binding sites on endothelial cells, and determine whether plasminogen activation is facilitated or impaired on these cells. Defining complement-induced alterations in endothelial lipid metabolism and fibrinolysis is fundamental to understanding how complement may modulate progression of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048688-04
Application #
2224760
Study Section
Pathology A Study Section (PTHA)
Project Start
1992-08-01
Project End
1995-12-01
Budget Start
1995-08-01
Budget End
1995-12-01
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Christiansen, V J; Sims, P J; Hamilton, K K (1997) Complement C5b-9 increases plasminogen binding and activation on human endothelial cells. Arterioscler Thromb Vasc Biol 17:164-71