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Regulation of endothelial cell protein C activation by native and oxidized low density lipoprotein
B D Wilson1, R E Pitas, G M Rodgers
1Department of Medicine, University of Utah Medical Center, Salt Lake City 84132.
Insights
Oxidized LDL (Ox-LDL) suppresses protein C activation, a key anticoagulant function, impacting vascular health. Native LDL and HDL, however, enhance this activation, revealing complex lipoprotein roles in coagulation.
Area of Science:
- Cardiovascular Biology
- Lipoprotein Metabolism
- Hemostasis and Thrombosis
Background:
- Low-density lipoprotein (LDL) modification, particularly oxidation, is implicated in cardiovascular disease pathogenesis.
- Protein C activation by endothelial cells is a critical anticoagulant pathway.
- The precise impact of various lipoprotein species on endothelial protein C activation remains incompletely understood.
Purpose of the Study:
- To investigate the differential effects of native LDL, oxidized LDL (Ox-LDL), and HDL on endothelial protein C activation.
- To elucidate the mechanisms underlying Ox-LDL's influence on this crucial anticoagulant pathway.
- To explore the potential link between lipoprotein modification and vascular disease/thrombosis.
Main Methods:
- Assessed protein C activation in human venous and arterial endothelial cells exposed to native LDL, Ox-LDL, and HDL.
- Utilized the antioxidant probucol to investigate the role of oxidation in Ox-LDL's effects.
- Employed a scavenger receptor antagonist (fucoidin) to examine the involvement of the acetyl LDL receptor pathway.
Main Results:
- Ox-LDL significantly suppressed endothelial protein C activation in both venous and arterial cells.
- This inhibitory effect of Ox-LDL was prevented by the antioxidant probucol.
- Native LDL and both native and oxidized HDL enhanced protein C activation, contrasting with Ox-LDL's suppressive action.
Conclusions:
- Modified lipoproteins, specifically Ox-LDL, can impair vascular anticoagulant activity by suppressing protein C activation.
- The mechanism of Ox-LDL's effect does not appear to involve uptake via the acetyl LDL receptor.
- These findings suggest that alterations in lipoprotein composition influence hemostasis and may contribute to vascular disease and thrombosis.
Abstract:
The effects of native LDL and Ox-LDL and HDL on endothelial cell protein C activation were examined. Ox-LDL, which is postulated to contribute to cardiovascular disease, markedly suppressed activation of protein C, an important vascular anticoagulant activity. This effect was seen with both human venous and arterial endothelial cells. Endothelial cells modified LDL to a form that reduced protein C activation, an effect prevented by the anti-oxidant, probucol. Endothelial cells are known to express the acetyl LDL (scavenger) receptor, which binds chemically modified and Ox-LDL. The effect of Ox-LDL on protein C activation does not appear to result from uptake via the acetyl LDL receptor, since a known scavenger receptor antagonist (fucoidin) did not inhibit the oxidized LDL effect. In contrast to the results with Ox-LDL, native LDL and both native and oxidized HDL increased protein C activation. These data indicate that native and modified lipoproteins regulate blood coagulation by affecting vascular anticoagulant activity and suggest mechanisms that may link modified lipoproteins with both vascular disease and thrombosis.