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Human cardiac microvascular and macrovascular endothelial cells respond differently to oxidatively modified LDL
M Gräfe1, W Auch-Schwelk, H Hertel
1Department of Medicine/Cardiology, German Heart Institute and Virchow Klinikum, Humboldt University, Berlin. graefe@dhzb.de
Insights
Oxidized LDL (ox-LDL) significantly impacts coronary endothelial cells, increasing thrombosis risk. Macrovascular cells are more susceptible to ox-LDL than microvascular cells, influencing atherosclerotic plaque development.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Function
- Atherosclerosis Pathogenesis
Background:
- Oxidation of low-density lipoproteins (LDL) is a critical factor in atherosclerosis.
- Endothelial cell dysfunction in generating coagulatory and anticoagulatory factors contributes to coronary artery thrombosis.
Purpose of the Study:
- To investigate the differential effects of native LDL (n-LDL) and oxidized LDL (ox-LDL) on human coronary endothelial cells.
- To compare the responses of macrovascular and microvascular endothelial cells to LDL oxidation.
Main Methods:
- Isolation of LDL via ultracentrifugation and copper-induced oxidation.
- Measurement of malondialdehyde (MDA) equivalents to quantify LDL oxidation.
- Incubation of human coronary artery macrovascular and cardiac microvascular endothelial cells with n-LDL and ox-LDL.
- Assays for tissue plasminogen activator (t-PA) secretion, plasminogen activator inhibitor-1 (PAI-1) antigen and activity, procoagulant activity, and angiotensin-converting enzyme (ACE) activity.
Main Results:
- Ox-LDL significantly decreased t-PA secretion and increased PAI-1 antigen and activity in macrovascular endothelial cells, but had minimal effects on microvascular cells.
- Procoagulant activity was elevated in macrovascular endothelial cells upon ox-LDL exposure.
- The effects of ox-LDL on PAI-1 were dependent on the degree of oxidation and were inhibited by the antioxidant probucol.
- ACE activity remained unchanged, indicating specific effects on coagulation factors.
Conclusions:
- Macrovascular endothelial cells exhibit higher susceptibility to ox-LDL compared to microvascular cells.
- Ox-LDL-induced changes in endothelial cell coagulatory and anticoagulatory factor production may contribute to thrombus formation and atherosclerotic plaque localization in hyperlipidemic patients.
Abstract:
Oxidation of low density lipoproteins (LDL) is considered a key event in the pathogenesis of atherosclerotic lesions. Disturbed generation of coagulatory and anticoagulatory factors by endothelial cells contributes to thrombosis and the progression of atherosclerosis in coronary arteries. In this study, the effects of native LDL (n-LDL) and oxidized LDL (ox-LDL) on human coronary endothelial cells were measured. The reaction of coronary endothelial cells to LDL were compared with those of cardiac microvascular endothelial cells grown under comparable conditions. LDL was isolated by ultracentrifugation and copper oxidized. The degree of oxidation was expressed as malondialdehyd (MDA) equivalents and was 0.78+/-0.14 nM MDA/mg LDL for native LDL and 13.63+/-1.18 nmol MDA/mg LDL for ox-LDL. Basal secretion of t-PA and PAI-1 activity were higher in macrovascular endothelial cells. Incubation of n-LDL in concentrations ranging from 3 to 100 microM/ml LDL-protein did not change t-PA-secretion, PAI-1 activity or procoagulant activity in both cell types. Ox-LDL (3 to 100 microM/ml LDL protein) decreased t-PA secretion in a concentration dependent manner from 30.9+/-1.7 to 13.7+/-30 ng/ml per 24 h per 10(6) cells (P < 0.01), increased PAI-1 antigen from 2772+/-587 to 4441+/-766 ng/ml per 24 h per 10(6) cells (P < 0.05) as well as PAI-1 activity from 34+/-6 to 55+/-9 AU/ml per 24 h per 10(6) cells (P < 0.05) in macrovascular endothelial cells but had only minor effects on microvascular endothelial cells. Procoagulant activity measured as coagulation time, similarly increased only in macrovascular endothelial cells from 197+/-6 to 76+/-6 s/24 h per 10(6) cells (P < 0.05). The effect on PAI-1 secretion showed a dependency to the degree of oxidation and could be completely blocked by the antioxidant probucol. The angiotensin converting enzyme (ACE), which represents an endothelial enzyme not related to coagulation, remained unchanged during incubation with ox-LDL. Basal ACE activity was higher in microvascular endothelial cells. The higher susceptibility of macrovascular endothelial cells to ox-LDL may partially determine the localization of thrombus formation and the development of atherosclerotic plaques in hyperlipidemic patients.
