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.
| 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 |
