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Oxidized low density lipoprotein induces apoptosis in cultured human umbilical vein endothelial cells by common and unique mechanisms
Oxidized low density lipoprotein (oxLDL) induces apoptosis in vascular cells. To elucidate the mechanisms involved in this apoptosis, we studied the apoptosis-inducing activity in lipid fractions of oxLDL and the roles of two common mechanisms, ceramide generation and the activation of caspases, in...
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Published in: | The Journal of biological chemistry 1998-04, Vol.273 (16), p.9681-9687 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Oxidized low density lipoprotein (oxLDL) induces apoptosis in vascular cells. To elucidate the mechanisms involved in this
apoptosis, we studied the apoptosis-inducing activity in lipid fractions of oxLDL and the roles of two common mechanisms,
ceramide generation and the activation of caspases, in apoptosis in human umbilical vein endothelial cells treated with oxLDL.
We also studied the effects of antioxidants and cholesterol. oxLDL induced endothelial apoptosis in a time- and dose-dependent
fashion. Apoptosis-inducing activity was recovered in the neutral lipid fraction of oxLDL. Various oxysterols in this fraction
induced endothelial apoptosis. Neither the phospholipid fraction nor its component lysophosphatidylcholine induced apoptosis.
oxLDL induced ceramide accumulation temporarily at 15 min in a dose-dependent fashion. Two inhibitors of acid sphinogomyelinase
inhibited both the increase in ceramide and the apoptosis induced by oxLDL. Furthermore, a membrane-permeable ceramide (C 2 -ceramide) induced endothelial apoptosis. These findings demonstrated that ceramide generation by acid sphingomyelinase is
indispensable for the endothelial apoptosis induced by oxLDL. Inhibitors of both caspase-1 and caspase-3 inhibited the apoptosis,
suggesting that oxLDL induced apoptosis by activating these cysteine proteases. The antioxidants butylated hydroxytoluene
and superoxide dismutase but not catalase inhibited the apoptosis induced by oxLDL or 25-hydroxycholesterol. This suggests
not only that superoxide plays an important role but also that a critical interaction between oxLDL and the cell takes place
on the outer surface of the membrane, because superoxide dismutase is not membrane-permeable. Exogenous cholesterol also inhibited
the apoptosis. Our study demonstrated that neutral lipids in oxLDL induce endothelial apoptosis by activating membrane sphingomyelinase
in a superoxide-dependent manner, as well as by activating caspases. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.273.16.9681 |